An Overview of Synthetic and Semisynthetic Flavonoid Derivatives and Analogues: Perspectives in Drug Discovery

Chapter 2

An Overview of Synthetic and Semisynthetic Flavonoid Derivatives and Analogues: Perspectives in Drug Discovery Valentina Uivarosi*,1, Alexandra-Cristina Munteanu* and George Mihai Nițulescu† *

Department of General and Inorganic Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania † Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 1 Corresponding author: e-mail: [email protected]

Chapter Outline Introduction Synthetic/Semisynthetic Flavonoid Derivatives With Antiviral Activity Anti-HIV Agents Anti-Coxsackievirus B3 Synthetic/Semisynthetic Flavonoid Derivatives With Antibacterial and Antifungal Activity Synthetic/Semisynthetic Flavonoid Derivatives With Antiparasitic Activity Synthetic/Semisynthetic Flavonoid Derivatives With Anti-Alzheimer Activity Multitarget-Directed Agents Selective Acetylcholinesterase Inhibitors

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Beta Secretase 1 Inhibitors Synthetic/Semisynthetic Flavonoid Derivatives With Antidepressant Activity Synthetic/Semisynthetic Flavonoid Derivatives With Antiinflammatory Activity Synthetic/Semisynthetic Flavonoid Derivatives With Antidiabetic Activity Synthetic/Semisynthetic Flavonoid Derivatives With Antiobesity Activity Synthetic/Semisynthetic Flavonoid Derivatives With Cardioprotective Activity Catecholamine Release Inhibitors and b-Adrenergic Receptor Blockers

Studies in Natural Products Chemistry, Vol. 60. https://doi.org/10.1016/B978-0-444-64181-6.00002-4 Copyright © 2018 Elsevier B.V. All rights reserved.

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Angiotensin-Converting Enzyme (ACE) Inhibitors 61 XO Inhibitors 62 Other Mechanisms 63 Synthetic/Semisynthetic Flavonoid Derivatives With Hepatoprotective Activity 63

Synthetic/Semisynthetic Flavonoid Derivatives With Anticancer Activity Protein Kinase Inhibitors Tubulin Inhibitors Other Enzyme Inhibitors Conclusion References

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INTRODUCTION Flavonoids are a subclass of polyphenols based on the 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) structure. Depending on the position of the C atom of the aromatic ring linking the benzopyran (chromane) moiety, this group of natural products may be divided into three classes: the flavonoids (2-phenylbenzopyrans), isoflavonoids (3-benzopyrans), and the neoflavonoids (4-benzopyrans) [1]. Depending on the degree of oxidation of the g-pyranone ring, they can be categorized into different subclasses, such as flavones, flavonols, and flavanones [2]. Within each subclass, individual flavonoids and isoflavones can be distinguished by the hydroxylation and conjugation patterns of the B ring (Fig. 2.1), as well as the conjugation patterns of hydroxyls on the A and C rings [3,4]. Other flavonoid derivatives are represented by anthocyanins and some flavonoids with modified C rings (namely, chalcones, aurones, and auronols) (Fig. 2.1). Flavonoids occur as aglycones, glycosides, and methylated derivatives. Most flavonoids are present in nature as glycosides that are associated with sugar in conjugated form as monoglycosidic, diglycosidic, etc., derivatives. The glycosidic linkage is normally located at position 3 or 7, and the carbohydrate unit is usually L-rhamnose, D-glucose, glucorhamnose, galactose, or arabinose [5]. The best described property of flavonoids is their capacity to act as antioxidants; flavones and catechins seem to be the most powerful flavonoids [6]. As a consequence of the protective effect they exhibit against reactive oxygen species (ROS), flavonoids exert antiinflammatory, antiallergic, antiviral, and anticancer activities, as well as a beneficial effect on cardiovascular diseases [7–10]. Despite the biological value of natural flavonoid derivatives, there are some major drawbacks that include poor and variable (depending on the dietary source) oral bioavailability and lack of selectivity. In general terms the bioavailability of aglycones is higher than that of glycoside forms. Extensive and rapid conjugation of free hydroxyl groups represents one of the most important causes for the poor oral bioavailability of flavonoids. The increased hydrophobicity of flavonoids achieved, for example, by replacing hydroxyl groups with methyl groups or acyl groups results in improved intestinal absorption and hepatic metabolism [11]. The versatility of flavonoids in terms of biological

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Flavonoids

Isoflavonoids

Neoflavonoids

Chalcones

Aurones

Auronols

Flavones

Flavon-3-ols

Flavanones

Flavanon-3-ols

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Flavan-3-ols

Anthocyanins

FIG. 2.1 Different structures of the major flavonoid categories.

activity and their ability to interact with multiple cellular and molecular targets may also cause lack of selectivity and possible toxic effects. These aspects are necessary for the structural optimization of natural compounds. The structural pattern of flavonoids is susceptible to fine chemical tuning to improve their physicochemical and biological properties. Many flavonoid derivatives, some of which are discussed below, have been obtained using a number of general procedures: alkylation, esterification, acylation, halogenation, alkoxylation, aromatic hydroxylation, and conjugation with different organic compounds resulting in flavonoid hybrid structures.

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIVIRAL ACTIVITY An overwhelming number of studies in the literature have reported the excellent antiviral activity of various naturally occurring flavonoids [12]. Baicalein

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and quercetin are potently active against human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV). The chalcone butein is moderately active against HIV-1 protease, and xanthohumol is effective against several herpes viruses, including HCMV. Chrysin is effective against enterovirus 71 (EV71) [13]. Semisynthetic/synthetic flavonoids have been proven to be particularly effective against certain types of RNA viruses: HIV-1, a (+)ssRNA retrovirus [14]; influenza virus, a (
)ssRNA virus [15]; hepatitis C virus, a (
)ssRNA virus [16].

Anti-HIV Agents HIV integrase (IN) belongs to the superfamily of DDE (D64, D116, E152) motif transposases. IN plays an essential role in viral replication and, very importantly, has no mammalian counterparts; therefore it is an appealing target for anti-AIDS (acquired immunodeficiency syndrome) drugs. IN mediates the integration of viral DNA into the host cell genome in a two-step process: 30 -processing (30 -P) and end joining or strand transfer (ST). In the 30 -P step a small nucleotide sequence is hydrolytically removed from the 30 ends of two linear viral DNA strands. Hence a functional nucleoprotein complex is formed, containing two viral DNA ends and at least four IN monomers. In the ST step the viral DNA fragments are inserted into the host DNA in a concerted cleavage–ligation reaction. The catalytic core domain of IN, critical to its enzymatic function, comprises the acidic triad DDE motif, which coordinates two Mg2+ ions [17]. The design of efficient IN inhibitors targets the chelation of critical metal cofactors or a nonactive (although still essential for its enzymatic function) site, such as a cofactor-binding site or an oligomerization hotspot. HIV-1 IN ST inhibitors, such as Raltegravir, Elvitegravir, and Dolutegravir (FDA approved), bind the Mg2+ ions through a ketoenol carboxyl moiety and establish hydrophobic interactions with the DDE motif via a coplanar aromatic group (Fig. 2.2). Lens epithelium-derived growth factor/p75 (LEDGF/p75), a human protein, has been found to stimulate IN activity by tethering IN to host cell chromatins. Hence, promising new anti-AIDS drugs act as inhibitors of the IN–LEDGF/p75 interaction [12]. Flavonoids are recognized as excellent metal chelators. Therefore natural flavonoids containing a b-ketoenol moiety have been selected and subjected to pharmacophore-based design and structure–activity relationship (SAR) studies to render new IN inhibitors. A series of mono 3/5/7/30 /40 -substituted flavonoid derivatives potently inhibited HIV-1 IN activity in enzyme-based assays and displayed effective antiviral activity in cell-based assays. For comparison, a hydrophobic (aromatic or alkyl) or hydrophilic (morpholine) group was introduced into the b-ketoenol skeleton of these selected flavonoids. The experimental results and SAR studies regarding the inhibition of catalytic

FIG. 2.2 (A) Structures of the three FDA-approved HIV-1 integrase inhibitors belonging to the b-diketo acid (DKA) class and a pharmacophore model for metal binding at the active site [14] and (B) opening the C ring of a prodrug followed by conformational rearrangement. The formation of tautomeric forms is crucial to the orientation/preparation of a hypothetical anti-HIV-IN O,O,O-pharmacophore site [18].

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activities revealed that the most favorable position of the hydrophobic moiety on the quercetin core was C-7, while substitutions with a hydrophilic group, such as morpholine at C-7 or with 4-F-benzyl of the phenolic hydroxyls at the 3, 6, 30 , 40 sites, were unfavorable for activity. Moreover, destruction of the catechol or the ketoenol structure by the substitution on the hydroxyls led to decreased IN inhibitory activity, which suggests that the chelation motif of flavonoids played an important role in enzyme inhibition. b-Ketoenol containing derivatives block the interaction between IN and LEDGF/p75 with low- to sub-micromolar IC50 values. IN–LEDGF/p75 inhibitory activity was reduced when the catechol structure was replaced by hydrophobic groups; in contrast, the introduction of a hydroxy or polar group at C-7 increased IN–LEDGF/p75 inhibition. Ketoenol compounds with a catechol group efficiently inhibited the IN–LEDGF/p75 interaction [14]. Two more studies offer support for IN inhibitory activity based on the chemical modification of the diketo acid pharmacophoric group. The a- or b-hydroxy– carbonyl motif of flavonoids mimics the ketoenol tautomer of the b-diketo group (Fig. 2.3) and results in IN inhibitory activity enzyme-based assays [19] and antiviral activity in cell-based assays [20]. The results of the SAR and 3D quantitative structure–activity relationship (3D-QSAR) study suggest that: bulky groups (such as the benzyl, chloro phenoxy, and thiophene groups) on the B ring favor IN inhibitory activity for both the 30 -P and ST steps (the increase in activity was most pronounced for the o-benzyloxy substituent for both the 30 -P and ST steps); substitution with Cl and Br increased IN inhibitory activity (hinting at the existence of a binding pocket with high affinity for halogenated phenyl rings); electronegative groups in the 30 , 50 , 60 -positions were favorable; electron-donating groups (methoxy, methyl, and cyclopentoxy) decreased inhibitory activity; and the introduction of strong electron-withdrawing groups (trifluoromethyl and nitro) also resulted in a decrease in activity [19]. The conclusions of the SAR studies are summarized in Fig. 2.3.

F Cl Hydrophobic (aromatic or alkyl) groups Hydrophilic (morpholine) groups Hydrophilic (4-F-benzyl)

4-F-benzyl 3′ 4′

2′ 8

1 O

A

C

7

1′ 2

4-F-benzyl

B

Cl

5′ 6′

F Cl

F

Br Br I

Cl

3

6 4

5 OH

O

Electron donating groups (methoxy, methyl, cyclopentoxy) Strong electron withdrawing groups (–CF3, –NO2)

FIG. 2.3 Structure–activity relationship for HIV integrase-inhibitory activity of flavonoid derivatives. Downward red arrows indicate a decrease in activity; upward green arrows indicate an increase in activity.

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Anti-HIV-1 IIIB and anti-HIV-2 ROD activities have been reported for a series of chalcones and flavonoid derivatives (Fig. 2.4). Chalcone derivatives displayed relatively homogeneous antiviral activity (IC50 40 mM), generally higher than other flavonoid derivatives, but were also more toxic in the cytotoxicity assay (against MT-4 uninfected cells). However, no specificity between HIV-1 and HIV-2 was observed for chalcone derivatives, which with a few exceptions was also the case for other flavonoid derivatives. The aminomethoxyflavone 7e was selectively active against HIV-1 and 7d, 7f, and 7i were selectively active against HIV-2 (ROD) [21].

Anti-Coxsackievirus B3 Recently, the antiviral activity of chrysin derivatives against Coxsackievirus B3 (CVB3) has been reported based on in vitro and in vivo experiments. Infections with CVB3 can result in pericarditis and myocarditis, which may lead to permanent heart damage or death. Moreover, infection with CVB3 may be linked to pancreatic dysfunction, which in turn may lead to type 1 diabetes. Unfortunately, to date there is no approved treatment for CVB3 infection [20]. Song et al. demonstrated the antiviral activity of chrysin in infected Vero (African green monkey kidney) cells. Since the natural flavonoid induced mild cellular toxic effects, 11 new chrysin derivatives were synthesized to increase antiviral activity and reduce cytotoxicity. The most potent derivative (Fig. 2.5) was

FIG. 2.4 Chalcone and flavonoid derivatives with anti-HIV-1 IIIB and anti-HIV-2 ROD activities. 1–7a: R ¼ H; 1–7b: R ¼ 20 -OCH3; 1–7c: R ¼ 30 -OCH3; 1–7d: R ¼ 40 -OCH3; 1–7e: R ¼ 20 -F; 1–7f: R ¼ 30 -F; 1–7g: R ¼ 40 -F; 1–7h: R ¼ 30 -CF3; 1–7i: R ¼ 40 -CF3 [21].

FIG. 2.5 Chrysin derivative with antiviral activity against Coxsackievirus B3 [22].

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administered in CVB3-infected mice and showed no toxic effects. Although body weight loss after CVB3 infection could not be prevented by the treatment, no signs of CVB3-induced pancreatic damage have been observed and the levels of CXCL1 (a serum chemokine) have been significantly reduced. It has been observed that flavonoid derivatives inhibit CVB3 3Cpro, a viral protease. It causes apoptosis in infected cells by cleaving the inhibitor of the nuclear factor kappa B (IkBa). This may result in the inhibition of IkBa cleavage, NF-kBmediated CXCL1 transcription and, consequently, viral replication. Following infection the levels of CXCL1 increased dramatically, which could be due to increased levels of NF-kB signaling related to increased endoplasmic reticulum (ER) stress caused by CVB3 infection. Therefore, flavonoid derivatives are thought to intervene in the regulation of the ER stress response; however, this theory needs to be further confirmed by experimental studies [22].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY Natural compounds (especially those produced by microorganisms) have been proven to be highly effective against pathogens and represent the chemical scaffold of most of the antibiotics currently used in therapy [23]. These include the penicillins, the tetracyclines, and the glycopeptides [24]. However, the phenomenon of bacterial resistance is expanding at an increasing and alarming pace; hence the urgent need to develop new therapeutic strategies active against different targets than those currently in use. In recent decades modern antibacterial drug discovery has been strongly influenced by genomic data, technological innovations, and bioinformatics. Much progress has been registered in identifying novel, specific targets in bacterial cells, which have facilitated the selection of active antimicrobial compounds. However, to date no new drugs have resulted from this modern approach. Infections caused by gram-negative bacteria are especially difficult to treat, due to insufficient understanding of their efflux systems and mechanisms of envelope permeability. For instance, Gram-positive bacteria have a significantly simple cell wall structure that is reasonably porous and thus foreign molecules can easily traverse this outer layer. In contrast, Gram-negative bacteria have much more complex cell wall structures with a less porous outer layer. Moreover, it is well known that the cell walls of Gram-positive bacteria contain much more peptidoglycan than Gram-negative bacteria [25]. Furthermore, based on the fact that at a physiological pH the outer cell walls of all microbes become negatively charged (the major component of the bacterial cell wall is negatively charged phosphatidylethanolamine at a level of 70%), it is only logical that flavonoid derivatives are synthesized so as to be positively charged. Thus, flavonoid cations target oppositely charged biological structures, such as the cell walls of microorganisms, which leads to the bacteriostatic effect.

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FIG. 2.6 5,7-Dihydroxyflavanone derivatives. 2: R1 ¼ H, R2 ¼ F, R3 ¼ H; 3: R1 ¼ F, R2 ¼ F, R3 ¼ H; 4: R1 ¼ F, R2 ¼ F, R3 ¼ F; 5: R1 ¼ F, R2 ¼ Cl, R3 ¼ H; 6: R1 ¼ Cl, R2 ¼ Cl, R3 ¼ H; 7: R1 ¼ OH, R2 ¼ OH, R3 ¼ OH; 8: R1 ¼ H, R2 ¼ MeO, R3 ¼ H [26].

Zhang et al. tested seven 5,7-dihydroxyflavanone derivatives (Fig. 2.6) as antibacterial agents on a series of Gram-positive (Bacillus subtilis, Bacillus anthracis, Bacillus cereus, Staphylococcus aureus), Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae), and yeast (Saccharomyces cerevisiae) species. Halogenated derivatives exhibited antimicrobial activity against Gram-positive bacteria, the Gram-negative bacterium V. cholerae, and against S. cerevisiae, but were ineffective against E. coli and P. aeruginosa. The lowest minimum inhibitory concentration (MIC) values (10–20 mg mL
1) were obtained for the dichlorinated flavanone 6. Nonhalogenated derivatives exhibited no growth-inhibitory effect on Grampositive strains, nor did trifluorinated derivatives. However, compound 4 did exhibit a growth-inhibitory effect against S. cerevisiae [26]. Sheikh et al. reported synthesizing biologically active compounds, comprising one chromone, one pyrazole, and one glucose moiety, in a single molecular framework. Antibacterial activity was tested in vitro against Gram-negative bacteria (E. coli and Klebsiella aerogenes) and Gram-positive bacteria (S. aureus and B. subtilis), and in vitro antifungal activity was tested against Aspergillus niger and Candida albicans. Preliminary SAR analysis indicated that inserting an appropriate disubstituted pyrazole ring into position 3 of the chromen-4-one ring increased antibacterial activity. Petra/Osiris/Molinspiration (POM) computational analysis revealed that compounds 3a–3i and 5a–5i act as prodrugs that open the B ring to form active metabolites, carrying one keto and two hydroxyl groups, which act as a potential antibacterial/antiviral/antifungal O,O,Opharmacophore site (Fig. 2.7). The study authors also theorized that a dipolar (Xd
–Yd+) pharmacophore site is required for a compound to possess antibacterial activity. An antiviral drug, on the other hand, should possess a Xd
–Yd
pharmacophore site, a dihedral angle of 0–10 degrees, and a distance dx–dy of ˚ [18] (Fig. 2.8). 3–3.5 A Bahrin et al. synthesized a series of flavanone dithiocarbamic esters and their corresponding 1,3-dithiolium derivatives (Fig. 2.9) and tested their antibacterial activity against S. aureus and E. coli. All derivatives were highly active against S. aureus, and 1,3-dithiolium derivatives were also potently

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FIG. 2.7 General structure of POM-analyzed 3a–3i and 5a–5i compounds. a: R ¼ H; b: R ¼ 4Cl; c: R ¼ 4-Br; d: R ¼ 4-CH3; e: R ¼ 4-OCH3; f: R ¼ 2,4-Cl2; g: R ¼ 3,4-Cl2; h: R ¼ 3-NO2; i: R ¼ 4-NO2; R0 ¼ OH for the 3a–3i series; R0 ¼ glucose for the 5a–5i series [18].

active against E. coli. Substituting chlorine with a methoxy group in the benzene ring at the para position decreased activity, which may be due to the fact that the oxygen atom in the methoxy group is able to participate in hydrogen bonding; thus the transport of this derivative inside bacterial cells might be considerably hindered. Moreover, substituting the hydrogen atom in C(8) with I or Br diminished activity against both bacteria strains, which suggests that some steric hindrance may influence transport through the cell membrane. Equilibrium ion dissociation versus formation of a tight ion pair influences the interaction of cationic tricyclic flavonoids with bacteria. Therefore a series of 1,3-dithiolium tetrafluoroborates were synthesized and slightly enhanced antibacterial properties were observed for tetrafluoroborate derivatives. Furthermore, tricyclic flavonoids probably exhibit higher antibacterial activity than dithiocarbamic derivatives as a result of interactions between the electrophilic C(2) atom of the 1,3-dithiolium ring with the nucleophilic moieties present in the outer cell wall and/or membrane (e.g., peptides, substituted polysaccharides) or the purinic bases from bacterial DNA [27]. The results for similar 1,3-dithiolium tetrafluoroborate tricyclic halogenated flavonoid derivatives indicate that the bulkier the atom in the 40 -position, the greater the antibacterial activity against both bacterial strains [28]. The in vitro antibacterial activity of some tetracyclic compounds (Fig. 2.10) was evaluated by Dongamanti and colleagues against B. subtilis, S. aureus, E. coli, P. aeruginosa, and K. pneumoniae, and the antifungal activity of these tetracyclic compounds was tested on two fungal strains (namely, C. albicans and Candida tropicalis). Fig. 2.10 shows that the most active compounds of the series (with low MIC values of under 0.050 mM) proved to be promising antibacterial agents. However, tetracyclic compounds did not show any antifungal activity up to a concentration of 200 mg mL
1. In silico studies were used to assess the interaction of these compounds with b-ketoacyl carrier protein synthase (KAS) III. KAS III is an enzyme that catalyzes the first step in the biosynthesis of fatty acids in most bacteria and is key to overcoming the phenomenon of bacterial resistance [29].

FIG. 2.8 (A) Plausible mechanism for opening the C ring of prodrugs 3–5 followed by the regeneration of bioactive metabolites 30 –50 bearing an O,O,Opharmacophore and (B) structure of the dual antibacterial/antifungal pharmacophore site of prodrugs 3–5 [18].

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FIG. 2.9 Flavanone dithiocarbamic esters and their corresponding 1,3-dithiolium derivatives. a: R1 ¼ H; R2 ¼ Br; R3 ¼ Cl; b: R1 ¼ H; R2 ¼ Br; R3 ¼ OCH3; c: R1 ¼ I; R2 ¼ I; R3 ¼ Cl; d: R1 ¼ Br; R2 ¼ Br; R3 ¼ Cl; e: R1 ¼ H; R2 ¼ H; R3 ¼ Cl; 4a–c: X
¼ ClO4
; 5a–e: X
¼ BF4
[27].

FIG. 2.10 Structures of tetracyclic compounds incorporating a flavonoid framework [29].

FIG. 2.11 (E)-1-(4-bromophenyl)-3-(4-iodophenyl)prop-2-en-1-one [30].

Zainuri et al. synthesized a novel chalcone derivative (Fig. 2.11) and tested its antimicrobial activity against various microorganisms that reside on the skin, including the Gram-positive bacteria S. aureus, Staphylococcus epidermidis, Micrococcus luteus, and Corynebacterium minutissimum, the Gram-negative bacterium P. aeruginosa, the yeast C. albicans, and the fungi Malassezia furfur, Microsporum canis, and Trichophyton rubrum. Even though the derivative was found to be ineffective against the Gram-negative bacteria strains and the fungi, it was proven to be active on S. aureus, S. epidermidis, M. luteus, C. albicans, and C. minutissimum [30]. Three series of chalcone derivatives containing aminoguanidine or acylhydrazone moieties were synthesized by Wei et al. The compounds were screened against Gram-positive strains of S. aureus, Streptococcus mutans, clinical

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isolates of multidrug-resistant Gram-positive bacterial strains (MRSA-, QRSA– methicillin-, and quinolone-resistant S. aureus, respectively), Gram-negative strains of E. coli, Salmonella typhimurium, P. aeruginosa, and one fungus (C. albicans). Compounds 4f and 4h (Fig. 2.12) were found to be the most potent antibacterial agents of the series, with MIC values similar to those of the standard drugs gatifloxacin and moxifloxacin, against E. coli, S. typhimurium, and C. albicans, respectively. The bromo-substituted compound 4h was the most potent agent of the series against MRSA and QRSA, displaying MIC values similar to those registered for gatifloxacin and norfloxacin. The results also indicated that the aminoguanidine moiety is crucial to the antimicrobial activity of these chalcone derivatives, since the corresponding acylhydrazone derivatives displayed weaker activities [31]. Banday et al. synthesized a series of chalconyl derivatives of pregnenolone. The bacterial strains used for antibacterial screening were B. subtilis, S. epidermidis, Proteus vulgaris, and P. aeruginosa and the fungal strains used were A. niger and Penicillium chrysogenum. All compounds showed significant antimicrobial activity against all microbial strains used for testing and the derivatives bearing a –F substituent were more active against P. chrysogenum than fluconazole [32]. Some novel chrysin-based derivatives, such as 6-methoxy-2-(piperazin-1-yl)4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen4-one (Fig. 2.13), have been tested as antibacterial and antifungal agents against S. aureus, B. subtilis, E. coli, S. typhimurium bacterial strains and the

FIG. 2.12 Chemical structures of chalcone derivatives 4f and 4h containing an aminoguanidine moiety [31].

FIG. 2.13 Structures of (A) 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and (B) 5,7dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one derivatives [33].

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fungi C. albicans, A. niger, Aspergillus flavus, Fusarium solani. SAR analysis suggests that the presence of a CdC or CdN multiple bond or that of an dNH2 hydrogen bond donor group increases antimicrobial activity. Substituents, such as the cyano, alkenylalkyl, or amino alkyl groups on the piperazine ring, were found to have potent antibacterial and antifungal activities. Derivatives bearing N-methyl-2-(pyrrolidin-1-yl)-ethenamine, N-benzyl-N-ethylpiperidin-4amine, and benzyl-N-methylpiperidin-4-amine displayed higher activity. The introduction of an electron donor atom (O) or group (such as dCOOH) on the piperazine ring significantly decreased antimicrobial activity. The aforementioned active compounds were found to be 2–2.5-fold more potent than the standard drugs ciprofloxacin and miconazole, respectively [33].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIPARASITIC ACTIVITY The antiparasitic activity of the compounds described in Fig. 2.14 has been tested on the nematode Caenorhabditis elegans. Exposure to compounds 2e, 3b, and 3c caused the worms to show delayed larval development. Adults were scarce in plates containing 3b-treated nematodes; mostly larvae in the first stages of development were found. Slow and uncoordinated movement was observed for worms exposed to 2e, possibly caused by flavonoid derivatives interacting with ionotropic GABA receptors, which are implicated in neural transmission [34]. Apart from their antiviral activity the compounds in Fig. 2.5 also exhibited antiproliferative activity against Plasmodium falciparum parasites. Chalcones were more selective against P. falciparum than THP1 (human monocytic) cells. The highest specific activity against P. falciparum was observed for the methoxyflavone and aminomethoxyflavone derivatives, while the lowest IC50 value and the highest selectivity were obtained for compound 7b [21]. Flavonoid derivatives have also been reported to exhibit antileishmanial activity. Boeck et al., for example, synthesized new chalcone derivatives of natural chalcone DMC (20 ,60 -dihydroxy-40 -methoxychalcone), which were tested in vitro for their inhibitory activity against promastigotes and intracellular amastigotes of Leishmania amazonensis. The derivatives bearing nitro,

FIG. 2.14 Structures of new derivatives of chrysin containing (A) 2-mercaptopyridine (2a–2e) and (B) 5-(trifluoromethyl)-2-mercaptopyridine (3a–3e). a: n ¼ 2; b: n ¼ 3; c: n ¼ 4; d: n ¼ 5; e: n ¼ 6 [34].

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fluorine, or bromine groups at the para and meta positions on the B ring displayed higher and more selective antiparasitic activity than natural chalcone. Very importantly, these compounds are nontoxic to host macrophages, indicating that they act upon specific parasite targets. Moreover, chalcone derivatives with a dNO2 substituent at the meta position on the B ring were found to be more effective at controlling lesion growth and parasite burden than the reference drug Pentostan at treating murine cutaneous leishmaniasis, at a dose 100 times higher than that of the parent chalcone [35]. Other flavonoid derivatives with different substituents on the A ring (mainly at C-7) and B ring were reported by Lewin and colleagues to display antileishmanial activity. Their antiparasitic potency was evaluated in vitro on promastigote and intramacrophage amastigote forms of Leishmania donovani. The results highlighted the importance of the C-7 substituent, since the most active flavonoid derivatives (IC50 < 10 mM) bear a substituent with an amine function at C-7 [36].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTI-ALZHEIMER ACTIVITY Alzheimer’s disease (AD) is a chronic, progressive, and irreversible neurodegenerative brain disorder characterized by dementia, cognitive decline, memory loss, and behavioral impairments [37]. Neuropathologically, AD is triggered by the accumulation of amyloid-b peptide (Ab) in brain cells. Ab self-aggregates through a cascade and stochastic process into oligomers, fibrils, and neuritic (senile) plaques located in the parenchyma and blood vessels. Ab aggregates formed in this way are potent synaptotoxins, elevating intracellular Ca2+ levels, acting as inhibitors of mitochondrial activity and proteasome function and activators of inflammatory processes. Furthermore, Ab is indirectly involved in hyperphosphorylation of the microtubule-associated protein tau, physiologically involved in regulating axonal transport. Hyperphosphorylated tau accumulation leads to the formation of neurofibrillary tangles and toxic species of soluble tau. AD is also associated with decreased levels of acetylcholine (ACh) in brain areas dealing with memory, learning, behavior, and emotional responses. Current therapeutic strategies for AD treatment involve inhibitors of Ab aggregation, tau hyperphosphorylation, and targeting several enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), beta secretase 1 (BACE1), glycogen synthase kinase-3b (GSK-3b), and monoamineoxidase (MAO) A and B [38]. A very appealing modern strategy toward the development of novel anti-AD agents is the multitarget-directed ligand (MTDL) approach, which involves designing novel anti-AD agents with multiple activities [39]. Flavonoids, which are known to possess a number of properties, such as neuroprotective, Ab fibril formation inhibitory, GSK and tau aggregation inhibitory, AChE and/or BuChE inhibitory, are considered potent candidates in the MTDL approach [38].

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FIG. 2.15 General structures of 4-dimethylamino-substituted and one 7-aminoalkyl-substituted flavonoid derivatives (A) [40], (B) 6d [41], and (C) [42].

series

of

Multitarget-Directed Agents With multitarget-directed agents in mind, two series of 4-dimethylamino- and one series of 7-aminoalkyl-substituted flavonoid derivatives (Fig. 2.15) were synthesized by Luo et al. and tested for their cholinesterase-inhibitory activity. 4-Dimethylamino derivatives were also evaluated for Ab aggregation-inhibitory activity and antioxidant activity [40,41]. The first series of compounds (Fig. 2.15A) showed they were capable of powerfully inhibiting both AChE and BuChE, at concentrations similar to or smaller than those of rivastigmine. The AChE-inhibitory activity of compounds with a diethylamine or pyrrolidine group was higher than that of compounds with a piperidine or benzylmethylamine group. The inhibitory activity of benzyl-methylamino derivatives was the weakest for both AChE and BuChE [40]. The second series of compounds (Fig. 2.15B) displayed inhibitory effects that were more potent than the first series on both AChE and BuChE. Chain length is particularly significant for BuChE-inhibitory activity: a longer chain length leads to higher activity. A molecular modeling study has indicated that these compounds bind both the catalytic active site (CAS) and the peripheral anionic site (PAS) in the AChE structure. Note that these derivatives have been proven to be powerful peroxyl radical scavengers (presumably due to the addition of the 4-dimethylamino group to the flavonoid framework) and to be active against anti-Ab aggregation, the most active compound 6d being approximately twice as potent as curcumin. Additionally, 6d showed neuroprotective activity in vitro against H2O2-induced cell death in PC12 neurons; however, 6d was slightly less potent than quercetin [41]. The inhibitory activity of 7-aminoalkyl-substituted flavonoid derivatives (Fig. 2.15C) was stronger for both AChE and BuChE than the first series

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FIG. 2.16 General structures of multifunctional tacrine-flavonoid hybrid derivatives [43].

FIG. 2.17 General structures of multifunctional aurone derivatives 14–16 [44].

of compounds, but weaker than the second. Additionally, most of these compounds demonstrated low to no toxic effects on PC12 and HepG2 cell lines [42]. A series of tacrine-flavonoid hybrids (Fig. 2.16) exhibited significant ChEinhibitory activity and self-induced Ab aggregation in in vitro studies. Kinetic and molecular modeling studies have revealed a mixed-type mechanism of inhibition, in which these compounds were found to be able to bind simultaneously to CAS, PAS, and mid-gorge sites of AChE. SAR studies suggested that the optimal tether for the linker between the two active moieties (m + n) seemed to be 6, particularly m ¼ n ¼ 3. The introduction of hydroxy and methoxy groups at the C-5 position of the flavonoid moiety slightly increased AChE inhibition, but not BuChE inhibition. Moreover, an electron-withdrawing group at the 40 -position of the B ring in the flavonoid moiety increased both inhibitory activity and selectivity toward AChE. Interestingly, compounds lacking the B ring in the flavonoid moiety proved to be more potent inhibitors of both AChE and BuChE, probably due to the high hydrophobicity and/or steric hindrance of the phenyl ring [43]. Furthermore, Li et al. synthesized a series of 4-hydroxyl aurone derivatives (Fig. 2.17) and tested the resulting compounds as potential multitarget-directed drugs for the treatment of AD in terms of self- and Cu2+-induced Ab aggregation, MAO-A and -B inhibition, and antioxidant activity. SAR studies have revealed that dihydroxy aurones display much higher activities than corresponding monohydroxy aurones. Moreover, the 6-OH group in aurone strengthened the interaction with Ab protein, the substitution of 6-OH by 6-N(CH3)2 decreased inhibitory activity, and the a,b-unsaturated ketone skeleton of aurone was found to be critical to activity. Cyclic amine-substituted aurones presented MAO-B-selective inhibition, while noncyclic aminesubstituted aurones were more selective toward MAO-A. The 6-OH group

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FIG. 2.18 Chemical structure of the homoisoflavonoid Mannich base derivative 10d [45].

was critical to MAO-A-inhibitory activity, while 6-methoxy favored MAO-Bselective inhibition. Additionally, some compounds of this series displayed high antioxidant activities, good metal-chelating abilities, and blood–brain barrier (BBB) permeabilities in vitro [44]. In addition, Li et al. in a further paper designed and synthesized a series of homoisoflavonoid Mannich base derivatives (Fig. 2.18) as selective AChE and MAO-B dual inhibitors, which generally displayed a more favorable therapeutic profile for AD treatment than the previous series. SAR analysis has revealed that the addition of the Mannich base moiety to the homoisoflavonoid scaffold greatly improved AChE-inhibitory activity, and aliphatic amine-substituted compounds showed better AChE-inhibitory activities than benzylamine-substituted analogues. Such compounds are AChE-selective inhibitors (they do not inhibit BuChE). The most potent compound is depicted in Fig. 2.18, which displayed noteworthy AChE- (slightly superior to that of donepezil) and MAO-B-inhibitory activities, good self- and Cu2+-induced Ab aggregation-inhibitory efficacy, antioxidant activity, metal-chelating ability, and high BBB permeability [45].

Selective Acetylcholinesterase Inhibitors Flavanone derivatives with a phenylcarbamate moiety have also been considered for AD treatment as potent AChE inhibitors and antiamnestic agents. Introduction of the phenyl carbamate moiety to replace the dOH group of ring B in the flavanone scaffold led to significantly increased AChEinhibitory activity. Moreover, the presence of two electron-donating methoxy groups in positions 5 and 7 of ring A further enhanced AChE-inhibitory activity, as did meta to para repositioning of the carbamate moiety. Electrondonating substituents (e.g., two dOCH3 groups) at ring B appear to increase AChE inhibition more than electron-withdrawing groups (e.g., dNO2). The most potent compound (Fig. 2.19) was effective in a mouse model of scopolamine-induced amnesia in terms of time spent in target quadrant and escape latency time, suggesting that flavanone derivatives with a phenylcarbamate moiety can ameliorate memory impairment [46]. Shen et al. developed a series of flavonoid (isoflavone, flavone, flavanone, and chalcone) derivatives (Fig. 2.20B) as dual binding AChE inhibitors. SAR analysis has revealed that the isoflavone series generally displayed the most potent AChE-inhibitory activity, while almost all the compounds belonging

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FIG. 2.19 Chemical structures of 3,5-di-OMe and 30 ,50 -di-OMe flavanone derivatives with phenylcarbamate moieties [46].

FIG. 2.20 (A) Donepezil; (B) general structure of flavonoid derivatives [47]; and (C) isoflavone derivatives [48] as dual binding AChE inhibitors.

to the flavanone and chalcone series displayed weak activity. Generally, compounds with an oxygen linker were more potent than compounds with an dOCH2 linker, possibly due to the fact that the first category of compounds have an optimal length to bind to both the PAS and CAS of AChE. Moreover, most of the compounds showed highly selective inhibition of AChE over BuChE [47]. Shen et al. also designed a new series of flavonoid derivatives (Fig. 2.20C) with improved AChE-inhibitory activities and selectivity, the most potent inhibitors being the isoflavone derivatives. Introduction of the aminomethyl group at the para position of ring B was more favorable to inhibitory activity than meta substitution. Moreover, compounds with pyrrolidine or piperidine (conformationally constrained hydrophobic groups) substituents were more potent than the corresponding methylethylamino- or diethylaminosubstituted derivatives [48]. The lead compound of the first series was roughly four times less active [47] than donepezil, the reference drug, regarding in vitro AChE-inhibitory activity while the lead compound of the second series was three times more potent [48]. Another series of nitrogen-containing flavonoid derivatives demonstrating AChE-inhibitory activity has been reported by Li and colleagues. The design

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of these compounds was based on the concept that terminal amine groups protonated at a physiological pH could establish cation–p interactions with the CAS of AChE, while the flavonoid moiety could bind to the PAS via aromatic stacking interactions. A flexible carbon spacer was introduced as a linker between the two active moieties, and the length of this carbon chain was changed so as to obtain a conformation that would allow optimal interaction of these compounds with both the CAS and PAS of AChE. It has been determined that 4- and 5-carbon spacers would be optimal for this interaction. Most compounds proved to be potent AChE inhibitors and displayed high selectivity for AChE over BuChE, and moderate to good Ab aggregation inhibition. Flavonoid derivatives bearing cyclic monoamine (pyrrolidine, 2-methylpiperidine, piperidine) and chain monoamine (diethylamine and dimethylamine) moieties showed strong AChE-inhibitory activities, indicating that both moieties had the ability to enter the CAS of AChE. In contrast, the addition of an oxygen or a second nitrogen atom to the terminal group (which increases the electron-withdrawing effect) decreased the ability to inhibit AChE, probably by reducing the electronic density of the terminal nitrogen and therefore weakening its cation–p interaction with CAS. The most potent AChE inhibitor of the series (Fig. 2.21) displayed an IC50 value 20 times lower than galanthamine and twice as small as tacrine, inhibited Ab aggregation (close to the reference compound), and displayed good metal-chelating ability [49]. Various hesperetin derivatives have also been synthesized as potential AChE dual-site inhibitors (Fig. 2.22). In vitro tests revealed that the resulting

FIG. 2.21 Nitrogen-containing flavonoid derivative with a diethylamine group linked to the flavonoid scaffold by a 4-carbon spacer [49] as an AChE inhibitor.

FIG. 2.22 Hesperetin derivatives [50] as potential AChE dual-site inhibitors.

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FIG. 2.23 (A) General structures of flavokawain B Mannich base derivatives [51] and (B) general structures of chalcone derivatives [52] as AChE inhibitors.

compounds displayed stronger inhibitory activity against and higher selectivity for AChE than BuChE when targeting both the PAS and CAS of AChE. Furthermore, the derivatives strongly inhibited self-induced Ab aggregation and possessed peroxyl radical-scavenging ability. Moreover, these compounds did not affect the viability of SH-SY5Y neurons, and the most active compound of the series displayed a significant neuroprotective effect against H2O2-induced cell death in PC12 neurons, slightly better than that of quercetin at 5 mM [50]. A series of flavokawain B derivatives (Fig. 2.23A) [51] and a series of other chalcone derivatives (Fig. 2.23B) [52] have been designed, synthesized, and evaluated for their inhibitory activity against AChE. The most promising compounds of the series, substituted with a piperidine group at the C-30 position or with a dimethylamino group, respectively, were twice as active as rivastigmine and, according to docking studies, were able to interact with both the CAS and PAS of AChE. Additionally, based on the logP values determined, these compounds were stated to be sufficiently lipophilic to pass the blood–brain barrier in vivo [51,52].

Beta Secretase 1 Inhibitors A series of hydroxychalcones has been designed based on the structure of isoliquiritigenin, a natural flavonoid with neuroprotective effects [53]. The series compounds demonstrate the good in vitro inhibitory activities of BACE1, although not as good as those of hydroxyethylamine, the positive control. Regarding the dOH substituent on the B ring, position 2 was the most favorable for BACE1-inhibitory activity; however, replacement of the dOH group with either electron-donating (dOCH3) or electron-withdrawing (dCl, dOCH2CH]CH2, dNO2) groups diminished the activity. Compounds with two hydroxyl groups on the A and B ring, respectively, showed higher inhibition efficacy than compounds with one or no hydroxyl group, with the dOH groups at positions 2, 20 , and 40 of the chalcone scaffold playing a critical role in BACE1-inhibitory activity [54].

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SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIDEPRESSANT ACTIVITY Depression and anxiety disorders are chronic and disabling mental illnesses characterized by decreased ability to experience interest or pleasure. Most antidepressant drugs (ADs) regulate the levels of monoamine neurotransmitters in the brain, such as serotonin [5-hydroxytryptamine (5-HT)], noradrenaline (NA), and dopamine (DA) [55]. Several natural flavonoids are credited with potential antidepressant activity, such as apigenin, taxifolin, diosmetin, naringin, eriocitrin, isorhamnetin, hesperidin [56], and kaempferol [57]. Two series of chalcone derivatives, 20 ,40 ,60 -trihydroxychalcones [58] and 0 2 -hydroxy-40 ,60 -diisoprenyloxychalcones [59], have been evaluated for their antidepressant activity. The results showed that several of these compounds significantly reduced times during the forced swimming test (FST). The most active compound of the first series and two of the most potent compounds of the second series (Fig. 2.24) significantly reduced the duration of immobility times in the FST and tail suspension test in mice [58,59]. In addition, two of these derivatives were tested in two behavioral mouse models and the results indicated that both the serotonergic and the noradrenergic systems were likely involved in the antidepressant-like effect of these compounds [59]. Moreover, chalcone-1203 (Fig. 2.24) significantly increased the concentrations of 5-HT and NA in the hypothalamus, hippocampus, and cortex and reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT in the hippocampus and cortex in various murine models of depression [60]. Similar behavior was registered for a series of 7-prenyloxy-2,3-dihydroflavanone derivatives (Fig. 2.24) [61]. Endogenous brain-derived neurotrophic factor and its receptor TrkB play a key role in the mechanism of action of antidepressant drugs. Antidepressant treatment activates the TrkB neutrophin receptor in the cerebral cortex. Normal TrkB signaling is required for the behavioral effects typically produced by antidepressants, while ablation of TrkB in transgenic mice results in resistance to the effects of antidepressant treatment. Activation of TrkB triggers mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase– protein kinase B (PI3K/Akt) and other intracellular cascades [62]. This led Liu et al. to synthesize a series of 7,8-dihydroxyflavone derivatives and test their agonistic effect on TrkB. The most active compound (Fig. 2.25) strongly activated Akt in primary cortical cell cultures, potently activated the TrkB receptor, and promoted neurogenesis in the hippocampus upon oral administration to mice [63].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIINFLAMMATORY ACTIVITY Acute and/or chronic inflammation can be controlled by chemical mediators, such as cytokines, chemokines, histamine, serotonin, and eicosanoids. Tumor

FIG. 2.24 (A) 2-Bromo-20 ,40 ,60 -trihydroxychalcone [58]; (B) 2,4-dichloro-20 -hydroxy-40 ,60 -diisoprenyloxychalcone [59]; (C) 4-methoxyl-20 -hydroxy-40 ,60 diisoprenyloxychalcone [59]; (D) chalcone 1203 [60]; (E) 40 -bromo-7-prenyloxy-2,3-dihydroflavanone; and (F) 20 ,60 -dichloro-7-prenyloxy-2,3-dihydroflavanone [61].

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necrosis factor-a (TNF-a) is a cytokine that activates nuclear factor-kB (NFkB), one of the central transcription factors in inflammatory processes. NF-kB activation promotes the transcription of certain genes encoding for the synthesis of new cytokines, chemokines, and proinflammatory enzymes, including cyclooxygenase (COX)-1 and COX-2, 5-lipoxygenase (5-LOX), and inducible nitric oxide synthase (iNOS). COX-2, 5-LOX, and iNOS control the biosynthesis of crucial proinflammatory mediators (prostaglandins, prostacyclin and thromboxane, leukotrienes, and nitric oxide (NO), respectively), which may lead to such symptoms of inflammation as vasoconstriction or dilation, vasopermeability, coagulation, pain, and fever. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit COX-1 and COX-2, the latter especially. TNF-a also interacts with other crucial cellular processes mediated or promoted by cyclin-dependent kinases (CDKs), MAPKs, activator protein-1 (AP-1), the apoptotic pathways, etc. [64]. Long-term therapy with NSAIDs increases the risk of gastrointestinal and cardiovascular complications [65], which has increased interest in developing new antiinflammatory drugs that are safer for long-term use. Flavonoid derivatives have been synthesized with the intention of improving several effects of their natural analogues: direct interaction with proinflammatory proteins, inhibition of the expression of inflammation-related genes, and antioxidant and prooxidant effects [66]. Some derivatives have been demonstrated to interact with proinflammatory mediators either directly or via inhibition of their expression within cells. For example, chalcone derivatives containing aryl-piperazine or aryl-sulfonylpiperazine moieties (Fig. 2.26) inhibited the expression of cytokines IL-6 and TNF-a by RAW264.7 macrophages, with better outcomes obtained for the

FIG. 2.25 40 -Dimethylamino-7,8-dihydroxyflavone [63].

FIG. 2.26 General structure of chalcone derivatives containing aryl-piperazine or aryl-sulfonylpiperazine moieties [67].

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latter series of compounds. Preliminary SAR analysis indicated that the presence of a sulfonyl group and the introduction of an electron-withdrawing group at the 4-position of aryl-piperazine or aryl-sulfonyl-piperazine moieties improved antiinflammatory activity. On the other hand, the addition of various substituents at the 40 -position of the benzene ring was found to be unfavorable for antiinflammatory activity [67]. Furthermore, flavone derivatives with the general structures of 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one demonstrated good in vitro inhibitory activity against TNF-a and IL-6. Most of the active compounds were found to be equally or more potent than the standard dexamethasone at 1 mM, with compounds of the second series being more active than those of the first. SAR analysis revealed that the introduction of electron-donating substituents on the piperazine moiety increased activity, while an electronwithdrawing substituent (e.g., dCN) on the piperazine group had the opposite effect. As a result, the derivative-bearing pyrimidyl group bound to the piperazine ring was found to be the most active member of this series [33]. Dihydroquercetin Mannich condensation products (Fig. 2.27) have been shown to inhibit the expression of collagenase 1 (MMP-1) in human dermal fibroblasts more potently than retinoic acid, used as the reference drug, but showed no notable activity in IL-8 experiments [68]. In addition, a series of minor prenylated flavonoid derivatives has been found to inhibit prostaglandin E2 (PGE2) secretion by LPS-induced murine RAW 264.7 macrophages in a moderate to strong manner (41%–90%). Docking studies predicted that the most active compound of the series (Fig. 2.28), a prenylated chalcone, would have a high binding affinity toward COX-2. The prenyl substituent appears to be crucial, establishing key interactions with the hydrophobic pocket in the active site of COX-2. However, in silico studies revealed the potential hepatotoxicity of this compound [70]. A new macakurzin C derivative, CPD 14 (Fig. 2.29), inhibited the release of inflammatory mediators in LPS-induced murine macrophages and IFN-g/TNF-a-induced human keratinocytes. NF-kB and the nuclear erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1)-signaling pathways were found to be responsible for the antiinflammatory effects of CPD 14. Topical administration of CPD

FIG. 2.27 Dihydroquercetin and its derivatives for MMP-1 and IL-8 tests [68].

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FIG. 2.28 (3,4-Dimethoxyphenyl)-1-(2-hydroxy-4-methoxy-5-(3-methylbut-2-enyl)phenyl)prop2-en-1-one [69].

FIG. 2.29 Macakurzin C derivative CPD14 [71].

FIG. 2.30 (A) General structures of 2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)acetamides with heterocyclic substituents and (B) structure of the most active compound of the series [73].

14 in chronic skin inflammation and acute ear edema mouse models significantly reduced the inflammatory response, inhibiting the expression of proinflammatory mediators (NO, PGE2, IL-1b, IL-6, TNF-a) [72]. Chrysin and 7-hydroxyflavone derivatives bearing an acetamide linker attached to the dOH of C-7, bound to various heterocyclic groups (Fig. 2.30), exhibited potent COX-2 inhibition and increased selectivity over COX-1 in vitro and antiinflammatory activity in vivo. In contrast, corresponding natural flavonoids were found to be inactive; compounds bearing benzimidazole terminal moieties were found to be more active than those with six- or five-membered heterocyclic groups. In silico studies revealed that heterocyclic moieties played a major role in binding to the active pocket of COX-2. Moreover, the representative compound of this series reduced paw edema and prostaglandin (PG) formation after carrageenan injection in albino rats [73].

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Several other flavonoid derivatives have been tested in different animal inflammation models. A series of chalcone derivatives containing aminoguanidine or acylhydrazone moieties have been reported to manifest antiinflammatory properties in a xylene-induced ear edema model in mice. They demonstrated a high level of inhibition against edema formation (92.45%), higher than that obtained under similar conditions for the reference drugs indomethacin and ibuprofen [31]. A flavone derivative, DA-6034 (7-carboxymethoxy-30 ,40 ,5trimethoxy flavone), was tested on inflammatory bowel disease (IBD) models in rats. Oral therapy with DA-6034 attenuated macroscopic and histologic damage of the colon, demonstrating more potent activity than prednisolone and sulfasalazine, the reference drugs, in terms of macroscopic lesion score [69]. The O-alkyl and O-acyl groups of 5-hydroxyflavonoid derivatives exhibited in vivo inhibitory activity against carrageenan-induced paw edema in mice; the most active compounds demonstrated greater antiinflammatory activity than the standards (diclofenac and ketoprofen) [71]. Indomethacin–naringenin and indomethacin–hesperetin hybrid structures were also considered potentially safer alternatives to NSAID treatment. These derivatives displayed potential antiinflammatory and analgesic activity with significantly reduced gastric side effects than equivalent mixtures of the free compounds [74]. Polymorphonuclear neutrophils generate ROS (mainly superoxide anion, O2 
) during macrophage phagocytosis and in reply to various stimuli. Such a functional response, termed an oxidative burst, contributes to host defense mechanisms, but it can also result in injuries to cell tissues, causing an inflammatory response [75]. Inflammation resolution therefore depends on the extent of abnormal neutrophil superoxide production, which as a consequence represents an attractive target for the development of novel antiinflammatory agents. As a result, another approach to developing new flavonoid derivatives with antiinflammatory activity aims at improving the antioxidant properties of natural flavonoids. Hence, several chlorinated flavone derivatives, intended to mimic the chlorinated metabolites of flavonoids, have been found to be more efficient than their parent compounds (flavone, luteolin, quercetin) at modulating neutrophil oxidative bursts by inducing neutrophil apoptosis in a caspase 3-dependent manner. 8-Chloro-30 ,40 ,5,7-tetrahydroxyflavone demonstrated the highest inhibitory activity against neutrophil oxidative bursts [76].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIDIABETIC ACTIVITY Diabetes mellitus is a complex disease with a multifaceted etiology. Any promising new antidiabetic drug must therefore interact with multiple diseaserelated targets. Diabetes mellitus type 2 is characterized by impaired insulin secretion and insulin resistance, leading to uncontrolled glucose production and decreased insulin-dependent peripheral glucose transport and utilization. Insulin resistance is associated with impaired insulin action in adipose tissues, especially in those found in intraabdominal depots. Flavonoid

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derivatives are inhibitors of several enzymes or processes related to type 2 diabetes, mainly a-glucosidase and glucose cotransporters (involved in glucose absorption), aldose reductase (AR), and advanced glycation end product formation (involved in glucose metabolism). Moreover, flavonoids interact with several insulin-signaling pathways associated with type 2 diabetes, including the 50 -monophosphate-activated protein kinase/reduced acetyl–CoA carboxylase (AMPK/ACC) and peroxisome proliferator-activated (PPAR) pathways [77]. The inhibitory effect of a-glucosidase has been tested for several series of semisynthetic or synthetic flavonoids. As a general structural feature, it appears that the hydroxyl group at position 5 of the flavonoid scaffold has an important role in the inhibitory activity of a-glucosidase. Derivatives of chrysin, diosmetin, apigenin, and luteolin alkylated at C-7 have been tested to assess their a-glucosidase inhibitory activity. With the exception of luteolin derivatives, all the semisynthetic flavonoids exceeded the activities of their natural corresponding compounds. SAR studies have revealed that replacement of the OH group at positions 30 , 40 , and 7 of benzopyran by electronwithdrawing groups (dNO2, dOCH3, dOR, etc.) increased inhibitory activity, as does the elongation of alkyl chains [78]. Chalcone triazole derivatives were also reported to display a-glucosidase-inhibitory activity [79]. Moreover, a set of hesperidin derivatives displayed a-glucosidase-inhibitory effects, stimulated glucose uptake of HepG2 cells, and lowered blood glucose level in streptozotocin-induced diabetic mice. Introduction of a benzyl group at the oxygen at C-7 in the A ring led to a significant increase in activity; compounds bearing a benzyl group substituent (Fig. 2.31A) displayed a-glucosidaseinhibitory activity similar to the positive control, acarbose [82]. In addition, various apigenin and chrysin derivatives have been synthesized by linking a terminal nitrate group to the hydroxyl groups in flavonoid

FIG. 2.31 Structure of the most active compound of the series of (A) hesperidin derivatives with a-glucosidase-inhibitory activity; (B) apigenin and chrysin as a-glucosidase inhibitors [80] and (C) luteolin derivatives as NO donors and aldose reductase inhibitors [81].

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structures using a series of ether or ester chains of varying lengths. These compounds have proven to be effective in vitro in inhibiting a-glucosidase activity and releasing NO, the second property being useful in preventing the development of vascular complications associated with diabetes. The most active compound is depicted in Fig. 2.31B. The inhibitory activities of derivatives with an ester chain were found to be superior to those of derivatives with an ether chain between the NO donor and precursor, possibly because of the increased tendency of the first series to form H bonds [80]. Similar organic nitrates of luteolin (Fig. 2.31C) displayed AR-inhibitory and NO-releasing activities in vitro. SAR studies have suggested that introduction of a NO donor group, protection of the catechol structure, and using the ether chain (as opposed to the previously reported series) of a 2-carbon spacer as a coupling chain on the luteolin scaffold increase AR-inhibitory activity. The pronounced lipophilic character of ring B may favor ARinhibitory activity by establishing stronger interactions with the lipophilic pocket of the AR active site [81]. Furthermore, trans-tiliroside derivatives with diversely substituted benzene moieties have been evaluated for their antidiabetic activity on the insulinresistant (IR) HepG2 cell model; compounds 7a, 7c, 7h (Fig. 2.32A) exhibited superior glucose consumption-stimulatory effects than the parent flavonoid and the positive control (metformin). According to preliminary SAR analysis, meta and para substitution (Fig. 2.32B) in the benzene ring by electron-withdrawing groups (e.g., dCN or dCl) enhanced antidiabetic activity [83]. Similar results have been obtained for another series of tiliroside derivatives lacking a glucose moiety. The most active compound of this series, Fla-OEt (Fig. 2.32C), significantly increased AMPK and ACC activities. AMPK plays a major role in glucose and lipid metabolism regulation in the liver (e.g., sustained AMPK activity impairment is known to lead to increased insulin resistance). ACC regulates fatty acid synthesis and degradation [84]. In vivo studies using a diet-induced obesity mouse model have confirmed that Fla-OEt exerts an antidiabetic effect via activation of the AMPK/ACC pathway [85]. Diversely substituted chalcone derivatives have been reported to promote glucose uptake in 3T3-L1 adipocytes; SAR studies concluded that the introduction of chloro, bromo, iodo, and hydroxyl substituents on the A ring is crucial to this activity [86,87]. Isoliquiritigenin- and liquiritigenin-alkylated and isoliquiritigenin- and liquiritigenin-benzoylated derivatives demonstrated a significant blood glucoselowering effect after administration in a hyperglycemic mouse model [88].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTIOBESITY ACTIVITY Obesity is one of the most common metabolic diseases and is frequently associated with multiple pathologies, including hyperlipidemia, insulin resistance, type 2 diabetes, hypertension, and cardiovascular diseases. Obesity is characterized by an elevated fat-cell (adipocyte) count or increased adipocyte size.

FIG. 2.32 (A) General structures of tiliroside derivatives with antidiabetic activity and substituents of the most active compounds of the series 7a, 7c, 7h [83]; (B) general structures of tiliroside derivatives lacking the glucose moiety with antidiabetic activity [84]; and (C) chemical structure of 3-O-[(E)-4-(4-ethoxyphenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-OEt) [85].

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An accelerated adipocyte differentiation process leads to increased body fat mass. Flavonoids and their derivatives interact with several regulatory pathways that promote adipogenesis, the most important of which seems to be the AMPK/ACC pathway [89]. A semisynthesized flavonoid derivative of tiliroside, 3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-CN) (Fig. 2.33), has been found to reduce whole-body adiposity and ameliorate metabolic lipid disorder and insulin resistance in in vivo experiments. The main mechanism was proven to be increased serum leptin and adiponectin levels [90]. Adiponectin and leptin are major adipocytokines secreted by adipocytes; adiponectin mediates the insulin-sensitizing effect by activating AMPK, PPAR-a, and presumably other signaling pathways; leptin effects include fatty acid oxidation, loss of body weight and fat, and glucose decrease [91]. In vitro, Fla-CN significantly inhibited the early stage of adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 adipocytes by microRNA (miR)-27a/b induction and AMPK activation. The miRs are an important class of posttranscriptional regulators of metabolism-related genes, functioning as negative regulators of adipocyte differentiation via PPARg inhibition [89]. The neuromedin U2 receptor (NMU2R) is a receptor for the NMU neuropeptide involved in the central control of food intake. It is therefore an attractive target for drug development against obesity. The discovery of the NMU2R agonist activity of rutin has thus led to a series of flavonoid analogues being synthesized. Based on cell-based reporter gene assay a number of compounds have proven to be selective and highly potent toward NMU2R, the EC50 value of the most active compound (Fig. 2.34) being very close to

FIG. 2.33 Chemical structure of 3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-CN) [90].

FIG. 2.34 Chemical structure of 2-(5-bromo-2-fluorophenyl)-3-hydroxy-4H-chromen-4-one [92].

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that of NMU. According to SAR analysis a 3-OH group in ring C and a 20 -F group in ring B were essential for agonistic activity on NMU2R [92].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH CARDIOPROTECTIVE ACTIVITY Flavonoids have been demonstrated to exert positive effects on various cardiovascular diseases, mainly attributed to their antioxidant properties, which have already been discussed in this chapter. However, apart from their antioxidant activity, flavonoids display several other effects, which might play a role in cardioprotection. These include direct antihypertensive activity, inhibition of enzymes that produce free radical intermediates (lipoxygenases, xanthine oxidase—XO, NADPH oxidase), inhibition of platelet aggregation and leukocyte adhesion, and vasorelaxant properties [93].

Catecholamine Release Inhibitors and b-Adrenergic Receptor Blockers (3-Phenyl-7-flavonoxy) propanolamines (propranolol-like chromones) have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats, the most effective compound being flavodilol (Fig. 2.35), which entered phase II clinical studies as an antihypertensive agent [94]. Interestingly, although they are structurally similar to classical b-blockers, their activity is not due to inhibition of b-adrenergic receptors, but to their catecholaminedepleting properties [95]. A hybrid structure comprising quercetin tetramethyl ether and nicotinic acid (VB3) reduces elevated blood pressure and prolongs activity in hypertensive (but not normotensive) rats [96]. Despite the plethora of research literature on the antihypertensive activity of quercetin the clinical use of this flavonol is limited because of its poor bioavailability, rapid metabolism, and low stability in an aqueous medium. Hence variously substituted quercetin derivatives have been synthesized to overcome these drawbacks. The ethylation of each dOH group of quercetin resulted in increased activity and a ca. 10-fold increase in bioavailability. The most active compound of the series has been found to bind both b1- and b2-adrenergic A

B

FIG. 2.35 Chemical structures of (A) propranolol (1-naphthalen-1-yloxy-3-(propan-2ylamino)propan-2-ol) and (B) flavodilol (7-[2-hydroxy-3-(propylamino)propoxy]-2-phenylchromen-4-one) [94].

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receptors (according to docking analysis), increased relaxation and coronary dilation, and significantly reduced systolic and diastolic pressure in spontaneous hypertensive rats [97].

Angiotensin-Converting Enzyme (ACE) Inhibitors The renin angiotensin aldosterone system is a hormonal cascade that regulates arterial pressure, tissue perfusion, and extracellular volume. Renin is a ratelimiting enzyme that catalyzes the hydrolysis of angiotensinogen into angiotensin I (Ang I). Ang I is then hydrolyzed by ACE into Ang II, which in turn activates aldosterone secretion. Ang II raises blood pressure in a number of ways, the most important being vasoconstriction, increased aldosterone biosynthesis, sympathetic nervous stimulation, and renal activity [98]. Since ACE is a zinc-dependent enzyme a planar structure and the presence of free electron-donating groups able to bind the metal ions are indispensable to inhibition of this enzyme. The flavonoid scaffold has been considered for the development of new agents as ACE inhibitors to treat hypertension. A series of chalcones has been synthesized and compared with similarly structured compounds bearing a pyrazole bridge between the two aromatic rings to determine their ACEinhibitory activity. Chalcones were found to be more active than their pyrazolic analogues, probably because of the more flexible linkage between the two phenyl rings. The most active compound of the series is depicted in Fig. 2.36 [99]. Furthermore, the antihypertensive activity of isoquercitrin (quercetin-3-O-glucoside, Q3G) and phloridzin (PZ) was investigated and compared to their 12 long-chain fatty acid derivatives. According to in vitro enzyme inhibition assays the oleic acid ester of Q3G was the strongest inhibitor of renin, the eicosapentaenoic acid ester of PZ and Q3G were the most potent inhibitors of ACE, while PZ was the weakest inhibitor among all tested compounds. However, all investigated compounds had low or no effect on aldosterone synthase inhibition [100]. In addition, Kumar et al. evaluated the ACE-inhibitory property of a quinolone-appended chalcone derivative ADMQ (Fig. 2.37). In physiological conditions, ADMQ undergoes a structural change from its native form to a b-hydroxyketo form, which strongly

FIG. 2.36 3-(3-Amino-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one [99].

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FIG. 2.37 (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ) [101].

FIG. 2.38 Protoapigenone 10 -O-propargyl ether, the nonaromatic B ring of which favors nonplanar conformation [103].

inhibits ACE both in the absence and presence of bovine serum albumin, a model serum transport protein. The mechanistic profile of this interaction is comparable with that of the standard drug captopril [101].

XO Inhibitors XO, a molybdenum-containing metalloenzyme, plays a key role in the catabolism of purines by catalyzing xanthine oxidation to uric acid, the end product of purine metabolism. Although uric acid is a major antioxidant in human plasma, elevated XO activity also contributes to oxidative stress by producing free radicals (namely, O2 
). XO inhibition therefore has benefits in many pathological conditions, including cardiovascular-related diseases. Several natural flavonoids (e.g., apigenin, luteolin) that possess the ability to adopt a planar 3D structure have been found to inhibit this enzyme. As a consequence, planar conformation has been accepted as being critical to this activity [102]. However, a series of nonplanar protoflavone derivatives have been synthesized starting with apigenin and 40 -OH-b-naphthoflavone and have been reported to possess in vitro XO inhibitory activity; protoapigenone 10 O-propargyl ether (Fig. 2.37) was found to be the most efficient agent of this series [103] (Fig. 2.38).

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Other Mechanisms Flavone and isoflavone derivatives bearing oxime and methyloxime moieties have been evaluated in washed rabbit platelets against arachidonic acidinduced platelet aggregation. Of these compounds, isoflavone-7-yl derivatives were found to be the most active antiplatelet agents [104]. Furthermore, a series of natural and synthetic derivatives from quercetin have been proven to be active vasorelaxant compounds in rat thoracic aorta rings in a phenylephrine-induced contraction model [105]. Based on these results, the same group of authors (Chen et al.) synthesized a series of prenylated flavonoids that had a vasorelaxation effect based on the predictions of a support vector machine classification model. The 11 prenylated flavonoids selected were synthesized by considering the effect of different frameworks (chalcone, flavanone, and flavone) and different substituents, such as hydroxyl, halogen (Br and Cl), or alkoxyl (methoxyl and methylenedioxy), on prenylated flavonoids. Their vasodilatory activities were determined experimentally, and theoretical study was in good agreement with the experimental results. SAR analysis revealed flavanone derivatives to be the most active compounds [106]. Similar results have been obtained for another series of flavonoid analogues, in which chalcone and flavanone derivatives showed higher activities than corresponding flavone and aurone analogues. 6-Hydroxy-8-allyl-40 -chloroflavanone displayed the highest vasodilatory activity [107].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH HEPATOPROTECTIVE ACTIVITY Liver injury is caused by a number of factors, such as chronic alcohol abuse, chronic viral infection, parasitic infestation, immunological attack, and toxic damage. There is a tremendous body of evidence in the literature regarding the hepatoprotective effects of naturally occurring flavonoids and flavonoidcontaining plant extracts. The synthesis of flavonoid derivatives has therefore been considered to improve the activities of natural analogues. HDND-7 and HDND-11, two hesperidin derivatives (Fig. 2.39), have been found to interact with key signaling pathways involved in the pathogenesis of liver fibrosis in cell culture experiments and attenuate liver damage in a CCl4-treated mouse model of liver fibrosis. In addition, the two derivatives have been found to have improved water solubility and oral bioavailability over the parent flavonoid [108,109]. Furthermore, a series of chalcones, flavones, and chromenes have been synthesized as farnesoid X receptor (FXR) antagonists [110]. FXR is a nuclear receptor predominantly expressed in tissues involved in bilirubin metabolism, including the liver, intestines, and kidneys (bile acids are natural ligands of FXRs) [111]. It has been regarded as a potential target for the treatment of various metabolic diseases, cancer, and infectious diseases related to the liver.

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B

FIG. 2.39 Chemical structures of (A) HDND-7 and (B) HDND-11.

Chalcone and chromene derivatives displayed moderate to high activity in in vitro FXR-antagonizing assays, while most flavone derivatives showed no activity. One chalcone analogue showed selective activity against FXR and minimal toxic effects in cell culture tests. One chromene analogue was shown to significantly antagonize FXR activity in isolated mouse primary hepatocytes and to decrease plasma and hepatic triglyceride levels in a diabetic mouse model [110].

SYNTHETIC/SEMISYNTHETIC FLAVONOID DERIVATIVES WITH ANTICANCER ACTIVITY The high versatility of the flavonoid scaffold and the promiscuous affinity of flavonoids toward a plethora of biological targets are extensively used in the design of potential anticancer drugs. Cancer is caused by genetic mutations that produce a malignant phenotype by converting proto-oncogenes to oncogenes, or inactivating some tumor suppressor genes [112]. The identification of specific molecular pathways allowed a whole range of biological targets to be validated and the rational design of selective drugs [113]. Because of their intimate involvement in the oncogenetic process, a number of protein kinases hold out much promise for cancer therapy [114]. Various studies have shown that flavonoids can bind directly to major oncogenes from the protein kinase family, such as Akt/protein kinase B, Janus kinases, MAPKs, CDKs, or phosphoinositide 3-kinase (PI3K) [115]. Flavone 8-acetic acid (FAA) [2-phenyl-8-(carboxy methyl)-benzopyran4-one] (Fig. 2.40) has been identified as an anticancer agent. It acts as an agonist of cytokine, chemokine, and interferon gene expression. Although highly effective in murine models, this compound displayed no antitumor activity in human clinical trials. FAA derivatives, such as FAA dimethylaminoethylester (Fig. 2.40), also proved to be ineffective in humans. The tumor vascular-disrupting agent ASA404 (Vadimezan) (Fig. 2.40), a chemically related compound and a xanthone derivative, has now entered phase III clinical studies for the treatment of advanced nonsmall cell lung cancer [116].

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FIG. 2.40 Chemical structures of three known flavonoid derivatives with anticancer activity that have entered clinical trials.

FIG. 2.41 Flavopiridol.

Protein Kinase Inhibitors Rohitukine is a chromone alkaloid with antiinflammatory, antifertility, anticancer, and immunomodulatory properties. I was discovered in Amoora rohituka and later reported in Dysoxylum binectariferum, both belonging to the Meliaceae family [117]. Based on this scaffold two synthetic flavoalkaloids have been developed, flavopiridol (Fig. 2.41) and P276-00 (Fig. 2.42), which strongly inhibit CDK 1, 2, 4, and 7 resulting in cell cycle progression block and the induction of apoptosis [118]. Chemically, both are 8-nitrogen-saturated heterocycle-substituted derivatives of chrysin. Flavopiridol (Alvocidib) has been designated an orphan drug for treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) and is currently undergoing phase II studies for patients with non-Hodgkin’s lymphoma and renal, prostate, colon, and gastric carcinomas [118,119]. P276-00 is being analyzed in phase II clinical studies for advanced refractory neoplasms and multiple myeloma [119]. In spite of flavopiridol’s success the development of analogues with improved kinaseinhibitory selectivity and higher binding affinity is still a major challenge. SAR

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studies of the flavone class of CDK inhibitors have demonstrated that the formation of at least two key hydrogen bonds between the substrate and the ATPbinding pocket are required [120]. Based on SAR studies, several classes of 8-amino modified flavones related to flavopiridol have been synthesized and tested for their CDKinhibitory profile. Various 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7hydroxyflavone, and heterocyclic analogues of flavopiridol were evaluated in the MCF-7 and ID-8 cancer cell lines, but the antiproliferative and CDK2/ cyclin A-inhibitory activity of these analogues was significantly lower than that of flavopiridol [121]. Other modifications based on the flavopiridol structure indicated that 8-substituted piperidinylmethyl analogues were about 12- or 21-fold more potent than morpholinomethyl analogues on CDK1/cyclin B, but no significant difference between 5-methoxyflavone and hydroxyflavone was found [122]. Using the Mannich reaction similar nitrogen-containing flavonoids were synthesized using the baicalein (5,6,7-trihydroxyflavone) framework. 8-Substitution with morpholinomethyl, thiomorpholinomethyl, or 4-methylpiperazinylmethyl afforded potent CDK1/cyclin B-inhibitory activities at the same level as flavopiridol (IC50 0.33 mM) and about 20-fold more potent than baicalein [123]. Using inhibitory activity screening and SAR studies, 8-hydroxypiperidine-methyl-baicalein (Fig. 2.43) was identified as the most

FIG. 2.42 General structure for the P276-00 series.

FIG. 2.43 8-Hydroxypiperidinylmethyl baicalein.

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effective flavonoid Mannich base derivative on CDK1/cyclin B, with broadspectrum anticancer activity [124]. The PI3K/Akt pathway is involved in cell growth, proliferation, apoptosis, and neoangiogenesis. It has been validated as a therapeutic strategy in many types of cancer [125]. Wogonin (5,7-dihydroxy-8-methoxy-flavone) is an active flavonoid component extracted from Radix Scutellariae and has demonstrated antitumor effects against leukemia, gastrointestinal cancer, and breast cancer. Wogonin has a complex antiproliferative mechanism, an important part of which is inhibition of the Akt pathway by downregulating protein expression of PI3K [126]. Several other natural flavones, like apigenin and luteolin [127], or semisynthesis derivatives, like morin-7-sulfate sodium [128], have been proven to inhibit PI3K and Akt, inducing cell cycle arrest and apoptosis in several cancer cells. Based on this a series of compounds were synthesized to obtain improved activity on the PI3K/Akt pathway. LY294002 (Fig. 2.44) is a simple flavone derivative in which 2-phenyl was substituted by a morpholine and a phenyl group was added in the 8-position. Both LY294002 and its amino derivative, PI828 (Fig. 2.45) demonstrated promising anticancer effects [129]. To improve the lipophilic profile of quercetin, all its isomeric

FIG. 2.44 LY294002.

FIG. 2.45 PI828.

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FIG. 2.46 LYG-202.

O-n-pentyl derivatives were synthesized and tested on Jurkat and CT26 cells. The 7-O-n-pentyl derivate had significant cytotoxic effects since it promoted apoptosis. The compound decreased the levels of phosphorylated forms of various members of the PI3K/Akt pathway and was more effective than LY294002 [130]. LYG-202 (Fig. 2.46) is a 4-(4-methylpiperazin-1-yl)butoxy derivative of wogonin and has been shown to induce apoptosis and cell cycle arrest at the G1/S transition via targeting PI3K/Akt pathway human breast cancer cells. The compound exhibited antitumor effects in nude mice inoculated with MCF-7 tumor [129]. Introduction of a methoxy group at the 60 -position provided LZ-207, a compound with improved water solubility [131]. DHF-18 is a position isomer of LYG-202 and induces apoptosis through a mitochondrial-dependent or -independent pathway in hepatocarcinoma cells [132]. Another wogonin derivative, LW-214, has demonstrated potent antitumor activity in human breast cancer MCF-7 cells by downregulating Trx-1 and activating the JNK pathway, ultimately inducing mitochondria-mediated apoptosis [133]. An investigation focused on substitutions at the 7-position, 8-position, and B ring of wogonin derivatives resulted in new compounds with better cytotoxic activity against HepG2, A549, and BCG-823 cancer cell lines, and a QSAR model to predict or facilitate the discovery of new compounds [134]. Oroxylin A is an isomer of wogonin and an O-methylated derivative of baicalein. Oroxylin A has been shown to inhibit Akt and ERK activation, reduce the downstream phosphorylation level of mTOR and STAT3, and inhibit the proliferation of malignant glioma cells by inducing autophagy in a dose- and time-dependent manner [135]. To improve its very low oral bioavailability a nitrogen-containing hydrophilic heterocyclic ring was introduced to block 7-OH glucuronidation (Fig. 2.47). Compounds containing a tetramethylene spacer between the oxygen and the heterocyclic ring have been found to be particularly potent with respect to cellular inhibition in HepG2, HCT-116, and BCG-823 cells, with IC50 values ranging from 1.42 to 9.52 mM, c. 5–20-fold more potent than oroxylin A [136]. Casein kinase 2 (CK2) is a pleiotropic and constitutively active Ser/Thr kinase involved in many oncologic processes. It is considered a promising drug target. Several natural flavones have been identified as CK2 inhibitors (e.g., chrysin and morin have IC50 values 10 times lower than apigenin and quercetin) [137]. Based on these structures, various 3-hydroxy-40 -carboxyflavones have

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FIG. 2.47 5-Hydroxy-6-methoxy-7-[4-(1-piperidyl)butoxy] flavone.

FIG. 2.48 6,8-Dibromo-30 -chloro-40 -hydroxy-50 -methoxy flavone.

FIG. 2.49 PD98059.

been synthesized and tested in vitro toward CK2, all of them with submicromolar IC50 values [138]. Further research has led to a large series of 40 -hydroxyflavones being synthesized and tested. SAR analysis revealed that increasing the hydrophobic character of 6-substituents leads to better inhibitory activity. The introduction of additional hydrophobic substituents at position 8 also has a positive effect. One derivative containing a 6,8-dibromo substitution (Fig. 2.48) has been shown to be nearly 100 times more potent than fisetin, the most active natural flavone known to inhibit CK2 [139]. The Ras–Raf–MEK–ERK signal transduction cascade is involved in regulation of a large variety of processes, including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription [140]. PD98059 (Fig. 2.49), or 20 -amino-30 -methoxyflavone, has been shown to specifically and potently inhibit MEK1 and MEK2 activity [141].

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FIG. 2.50 20 -Chloro-40 -aminoflavone.

FIG. 2.51 40 -Bromophenol-3-hydroxyflavone.

Inhibition of the ERK–MAPK pathway was improved by isosteric replacement of an oxygen atom by a sulfur atom [142]. Structurally related 20 -chloro-40 nitroflavone (Fig. 2.50) and the corresponding 20 -chloro-40 -aminoflavone derivative have been synthesized and demonstrated notable antiproliferation activity and proapoptosis effect against HepG2 cells. Substitution by an alkyl group on the A ring is correlated with enhanced antiproliferation activity [143]. ERK enzymes have been shown to be inhibited by quercetin 3-methyl ether tetracetate in human leukemia HL-60 and U937 cell lines, resulting in G2/M phase cell cycle arrest and apoptosis induction [144]. Based on these results a series of flavonols and 3-methyl ether derivatives have been synthesized and assessed for cytotoxicity against human leukemia cells. 40 -Bromophenol-3-hydroxyflavone (Fig. 2.51) produced the best cytotoxic effects of this series (associated with the activation of apoptosis) [145]. Further research investigating these types of derivatives resulted in the generation of 30 ,40 -dibenzyloxy-3-hydroxyflavone (Fig. 2.52). It has been shown to possess potent cytotoxic properties, inducing S phase cell cycle arrest and apoptosis on human leukemia HL-60, U-937, and MOLT-3 cells through ERK1/2 and p38MAPK, independent of the generation of ROS [146].

Tubulin Inhibitors Microtubules play essential roles in mitosis and are important targets for the development of anticancer drugs. Antitubulin agents can bind to one of the three established drug domains on the tubulin heterodimer: the colchicine, paclitaxel, and vinca alkaloid binding sites. A very large series of chalcones have been

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FIG. 2.52 30 ,40 -Dibenzyloxy-3-hydroxyflavone.

FIG. 2.53 MDL-27048.

synthesized and evaluated as antimitotic agents. One of the first important antimitotic chalcones proved to be (E)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino) phenyl]-2-methyl-2-propen-1-one, also known as MDL-27048 (Fig. 2.53). It is an effective antimitotic agent at a concentration of 4 nM against HeLa cell lines, and has proven in vivo antitumor activity against L1210 leukemia and B16 melanoma [147]. Based on this compound, (E)-1-(3,4,5-trimethoxyphenyl)3-[30 -hydroxy-40 -methoxy-phenyl]-2-methyl-2-propen-1-one has been obtained and proven to be more active. Moreover, the importance of the 2-methyl group on the 2-propen-1-one template has been highlighted and emphasis placed on its ability to adopt a s-trans conformation [148]. Replacing the methyl group with a nitrile group resulted in a very poor cytotoxic effect, whereas doing so with a fluorine group significantly improved tubulin inhibition and consequently the cytotoxic effect. SAR analyses have revealed that the spatial relationship between the two aromatic rings of chalcones (combretastatin A-4 and colchicine) is a prerequisite to binding to tubulin [149]. To improve the solubility of this type of derivative, several nitro-substituted chalcones have been synthesized and then transformed into corresponding amino-derivatives. Aminoflavones have been proven to be more active than their nitro-analogues, and the most active compound of the series contains a 2,3,4,5-tetramethoxy substitution [150]. Millepachine is a 2,2-dimethylbenzopyran chalcone isolated from Millettia pachycarpa and has potent apoptosis-inducing effects that prompted the design and synthesis of novel derivatives. Such derivatives have been evaluated for their antitumor activity. The cytotoxicity of compounds was

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evaluated against HepG2, K562, SK-OV-3, HCT116, HT29, and SW620 cell lines using MTT assay. Analysis into the nature of the R-substituent of the 3-(R-phenyl)-prop-2-en-1-one structure indicated that electron-withdrawing groups (F, Cl, Br, NO2, CF3) are detrimental to antitumor activity, while the introduction of electro-donating dimethylamino or diethylamino groups significantly improved antiproliferative activity. The cytotoxic effect is a direct consequence of microtubule polymerization and spindle formation suppression [151]. The SARs deduced were used to improve the anticancer effect and the 30 -amino-derivative of millepachine (Fig. 2.54) to determine G2/M cell arrest, cellular apoptosis, and antivascular activity. Microtubule dynamics confirmed the compound to be a novel tubulin polymerization inhibitor by binding at the colchicine site [152]. Hybrid structures are widely used as a strategy in drug design to achieve better effects. A series of chalcone–coumarin hybrids linked by a triazole ring have been shown to demonstrate dual inhibition of a- and b-tubulins and to have promising cytotoxic effects on HuCCA-1, HepG2, A549, and MOLT-3 cancer cells [153]. Two tubulin inhibitors—phenstatin (Fig. 2.55) and isocombretastatin (Fig. 2.56)—have been joined in a chalcone scaffold using the aforementioned strategy to obtain synergic hybrids. The best results were registered for the 3,4-dimethoxy, 3,4-methylenedioxy, and 3-amino-4-methoxy analogues of phenstatin [154]. Resveratrol, a natural stilbene derivative with chemopreventive, antiproliferative and proapoptotic effects, has been used to prepare a series of chalcone hybrids. Most of the resulting compounds exhibited

FIG. 2.54 30 -Amino millepachine.

FIG. 2.55 Phenstatin.

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FIG. 2.56 Isocombretastatin.

potent tubulin polymerization-inhibitory activity and antiproliferative activities against HepG2, B16-F10, and A549 tumor cell lines [155]. Research investigating chalcone derivatives as tubulin inhibitors was soon extended to flavonoid derivatives, their cyclic congeners. Centaureidin is an O-methylated flavonol and the first known flavone with antimitotic activity, inhibiting tubulin polymerization by binding to the colchicine site [156]. To find better tubulin inhibitors a series of 79 flavones related to centaureidin was tested in vitro in the NCI 60 human tumor cell lines screen and then their effect on tubulin polymerization was evaluated. The study highlighted the importance of 3-methoxy substitution for interference with tubulin polymerization, since compounds with a 3-hydroxyl or hydrogen substituent had no significant effect on tubulin polymerization. 30 -Hydroxy-40 -methoxy substitution also appears to be critical [157]. A study investigating the semisynthesis of flavones sharing the aforementioned features has found casticin to be a potent inhibitor of tubulin polymerization, whereas its synthetic derivative, 8-dimethylaminocasticin, was inactive. The 6,8-dibromo analogue of ayanin has been shown to have significant antiproliferative and moderate inhibitory effects on tubulin polymerization [158]. Subsequent synthesis provided 30 -amino-substituted flavones. A SAR study indicated that 5-hydroxy6,7,8-trimethoxy substitution was mandatory. A 3-chloro-substituted derivative was shown to have the highest antiproliferative effect [159]. Various oxime-bearing flavone and isoflavone derivatives have been synthesized and tested against human cancer cell lines. WTC-01 (Fig. 2.57), chemically known as (Z)-6-[2-hydroxyimino-2-(4-methoxyphenyl)-ethoxy]2-phenyl-4H-1-benzopyran-4-one, had the greatest antiproliferative effect. The effect is brought about by its capacity to interfere with microtubule assembly by binding to the colchicine-binding site of tubulin, resulting in G2/M cell arrest and the activation of apoptotic pathways [160]. Using methoxylated flavones as lead compounds a series of 2-aryl-trimethoxyquinoline analogues has been designed and synthesized as tubulin inhibitors. A compound with a 2-trimethoxyphenyl-quinoline substitution demonstrated the highest cytotoxicity. It was also the most potent tubulin inhibitor from this group [161].

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FIG. 2.57 WTC-01.

FIG. 2.58 7-O-benzyl glaziovianin A.

FIG. 2.59 6-O-benzyl glaziovianin A.

Glaziovianin A is an isoflavone first isolated from the leaves of the Brazilian tree Ateleia glazioviana. It has been shown to exhibit a broad spectrum of cytotoxic activities by inhibiting tubulin polymerization. Several glaziovianin A analogues have been synthesized and tested against HeLa S3 cells. 7-O-benzyl (Fig. 2.58) and 7-O-propargyl analogues have been proven to be more potent cell cycle inhibitors than glaziovianin A [162]. It was later discovered that 6-O-benzyl-glaziovianin A (Fig. 2.59) inhibited microtubule polymerization to a greater degree (IC50 2.1 mM). The 6-O isomer has a specific a,b-tubulin affinity, while the 7-O isomer specifically inhibits g-tubulin [163].

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Other Enzyme Inhibitors Topoisomerase enzymes are key to cell transcription and replication and important anticancer targets. Camptothecin is a well-known anticancer drug that works on topoisomerase I, while doxorubicin and etoposide are clinically important anticancer drugs targeting topoisomerase II. A number of natural flavones, flavonols, and isoflavones have been tested against human topoisomerase IIa and IIb as potential anticancer agents. Genistein was found to be the most active, stimulating enzyme-mediated DNA cleavage 10-fold. SAR studies have indicated that DNA cleavage by both isoforms required a 5-OH and a 40 -OH group and was enhanced by the presence of additional hydroxyl groups on the pendant ring [164]. A chemically diverse series of chalcone compounds have been synthesized and tested against two human cancer cell lines, T47D and SNU638 [165]. A series of thiophene- or furan-based chalcone derivatives substituted with epoxide or thioepoxide have been designed and synthesized to target topoisomerase activity. The presence of a 2-furan ring in the B ring position of the chalcone system coupled with thioepoxide substitution provided the greatest topoisomerase-inhibitory activity, the corresponding compounds demonstrating good antiproliferative effects on T47D cancer cells and moderate inhibition on MDA-MB468 cancer cells [166]. Nuclear enzyme poly(ADP-ribose)polymerase (PARP) has been shown to be involved in cancer pathology and became an attractive target for cancer therapy. Natural and synthetic flavonoids, such as quercetin, rutin, monoglucosyl rutin, and maltooligosyl rutin, have been shown to inhibit PARP activity and induce synthetic lethality in BRCA2-deficient Chinese hamster cells [167]. Semisynthetic water-soluble isoquercetin and rutin glycosides, such as maltooligosyl isoquercetin, monoglucosyl rutin, and maltooligosyl rutin, have been developed to overcome solubility challenges, but bioactivity evaluations using PARP showed they were less effective at inhibiting than the natural analogues [168]. Recent studies have identified human carbonic anhydrase (hCA) isoforms IX and XI as a novel research direction regarding the way in which several naturally occurring flavonoids interact with molecular targets involved in cancer progression and response to therapy. Such a direction might be of interest to researchers seeking to develop new synthetic flavonoid derivatives. Isoforms IX and XII of hCA are overexpressed in cancer cells as a result of their involvement in pH regulation in poorly vascularized and hypoxic tumoral microenvironments. Some naturally occurring (iso)flavonoids have been proven to interact with the active site of hCA [169,170].

CONCLUSION Research investigating synthetic and semisynthetic flavonoid derivatives has been focused on improving and broadening the activity spectrum of corresponding natural flavonoids and on obtaining multitarget-directed agents. Generally,

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these attempts have been proven to be successful, whether regarding decreased side effects or increased bioavailability, activity, and selectivity. Although the number of studies available in the literature is impressive, only a few synthetic flavonoid derivatives have entered clinical trials, including FAA, flavone 8-acetic acid dimethylaminoethylester, ASA404, flavopiridol, P276-00 for several types of cancer, and flavodilol as an antihypertensive agent. None of these compounds has been proven to have the expected clinical efficacy. However, they have displayed generally favorable safety profiles (with the exception of flavopiridol, which is highly active in relapsed and refractory CLL, but also causes serious side effects), which justify their further study. Therefore, further efforts must be made toward obtaining new therapeutic agents based on the flavonoid scaffold.

LIST OF ABBREVIATIONS Ab ACE ACh AChE AD ADs AGEs AIDS Akt/PKB AMPK/ACC Ang AP-1 ATP BACE1 BBB BDNF BSA BuChE CAS CDK CK2 COX CVB3 CXCL1 DA DKA DMC

amyloid-b peptide angiotensin converting enzyme acetylcholine acetylcholinesterase Alzheimer’s disease antidepressant drugs advanced glycation end-products acquired immunodeficiency syndrome Akt/protein kinase B 5’-monophosphate-activated protein kinase/ reduced acetyl-CoA carboxylase angiotensin activator protein-1 adenosine triphosphate beta secretase 1 blood–brain barrier brain-derived neurotrophic factor bovine serum albumin butyrylcholinesterase catalytic active site cyclin dependent kinases casein kinase 2 cyclooxygenase coxsackievirus B3 chemokine (C-X-C motif) ligand 1 dopamine b–diketo acids 2’,6’-dihydroxy-4’-methoxychalcone

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DNA 3D-QSAR EV71 FAA FDA FST FXR GABA GSK-3b hCA HCMV HCV 5-HIAA HIV 5-HT IBD IC50 IκBa IL-6 IN IR JAK KAS LEDGF LPS MAO MAPKs MIC MRSA MTDL NA NADPH NF-kB NMU2R iNOS NSAIDs 3’-P PARP PAS PGE2 PI3K PMNs POM

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deoxyribonucleic acid 3D quantitative-activity relationship enterovirus 71 flavone 8-acetic acid Food and Drug Administration forced swimming test farnesoid X receptor gamma-aminobutyric acid glycogen synthase kinase-3b human carbonic anhydrase human cytomegalovirus Hepatitis C virus 5-hydroxyindoleacetic acid human immunodeficiency virus 5-hydroxytryptamine inflammatory bowel disease half maximal inhibitory concentration nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha interleukin 6 HIV integrase insulin resistant Janus kinases b-ketoacyl carrier protein synthase lens epithelium-derived growth factor lipopolysaccharide monoamineoxidase mitogen-activated protein kinases minimum inhibitory concentration methicillin resistant S. aureus multi-target directed ligand noradrenaline nicotinamide adenine dinucleotide phosphate nuclear factor-kB neuromedin U2 receptor inducible nitric oxide synthase nonsteroidal anti-inflammatory drugs 3’-processing poly(ADP-ribose)polymerase peripheral anionic site prostaglandin E2 phosphatidylinositol 3-kinase polymorphonuclear neutrophils Petra/Osiris/Molinspiration (computational analysis)

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PPAR PZ QRSA QTME RAAS RNA ROS SAR SHR SVM ST TNF-a TST XO

peroxisome proliferator-activated phloridzin quinolone resistant S. aureus quercetin tetramethyl ether renin angiotensin aldosterone system ribonucleic acid reactive oxygen species structure-activity relationship spontaneous hypertensive rats support vector machine strand transfer tumor necrosis factor-a tail suspension test xanthine oxidase

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