Triazine as a promising scaffold for its versatile biological behavior

European Journal of Medicinal Chemistry 102 (2015) 39e57

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European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Triazine as a promising scaffold for its versatile biological behavior Prinka Singla, Vijay Luxami, Kamaldeep Paul* School of Chemistry and Biochemistry, Thapar University, Patiala 147004, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 June 2015 Received in revised form 19 July 2015 Accepted 20 July 2015 Available online 21 July 2015

Among all heterocycles, the triazine scaffold occupies a prominent position, possessing a broad range of biological activities. Triazine is found in many potent biologically active molecules with promising biological potential like anti-inflammatory, anti-mycobacterial, anti-viral, anti-cancer etc. which makes it an attractive scaffold for the design and development of new drugs. The wide spectrum of biological activity of this moiety has attracted attention in the field of medicinal chemistry. Due to these biological activities, their structureeactivity relationship has generated interest among medicinal chemists and this has culminated in the discovery of several lead molecules. The outstanding development of triazine derivatives in diverse diseases within very short span of time proves its magnitude for medicinal chemistry research. Therefore, these compounds have been synthesized as target structure by many researchers, and were further evaluated for their biological activities. In this review, we have compiled and discussed the biological potential of s-triazine derivatives, which could provide a low-height flying bird's eye view of the triazine derived compounds to a medicinal chemist, for a comprehensive and target oriented information for the development of clinically viable drugs. © 2015 Elsevier Masson SAS. All rights reserved.

Keywords: s-Triazine Antitumor Antimicrobial Antimalarial Antiviral

1. Introduction The designing, synthesis and evaluation of molecules with some human therapeutic values, remain one of the main objective of organic and medicinal chemistry. During the past decades, combinatorial chemistry has provided access to chemical libraries based on privileged heterocyclic motifs with utility in medicinal chemistry [1]. Synthesis of nitrogen containing heterocyclic compounds has been attracting increasing interest because of their utility for various biological receptors with a high degree of binding affinity. In the present review, the triazine moiety with a broad spectrum of biological profile has been matured into an indispensable heterocyclic scaffold that makes it one of the extensively studied heterocycle. The triazine structure is a heterocyclic ring analog to the six-membered benzene ring with three carbons replaced by nitrogens. The isomers of triazine are distinguished from each other by the positions of their nitrogen atoms, and referred to as 1,2,3-triazine (1), 1,2,4-triazine (2) and 1,3,5-triazine (3) (Fig. 1). 1,3,5-Triazine (s-triazine) has been widely used in organic reactions [2e7] that offers access to a multitude of useful molecules

* Corresponding author. E-mail address: [email protected] (K. Paul). http://dx.doi.org/10.1016/j.ejmech.2015.07.037 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

[8,9] due to its specific structure and electronic properties. Increased interest in this scaffold lies in the different reactivity of the chlorine atoms at 2-, 4- and 6-positions that are controlled by temperature, allows the sequential introduction of various substitutes for the preparation of mono-, di- and tri-substituted triazines [10,11]. Owing to the immense synthetic importance and varied bioactivities, efforts have been made from time to time to generate libraries of these compounds (Scheme 1). Nitrogen containing triazine heterocyclic motif is the ‘Master Key’, as acting at different targets to elicit varied pharmacological properties by inhibiting the action of an inducible membrane protein that normally function to increase the efflux of the cytotoxic agents. The triazine scaffold provides the basis for the design of biologically relevant molecules with widespread applications like antiprotozoal [12], anticancer [13e16], antimalarial [17], antiviral [18] and antimicrobial [19,20]. Triazine is also the basic structure of some herbicides like amitole, atrazine, cyanazine, simazine, trietazine, and resin modifiers like melamine and benzoguanamine [21,22]. There are also some compounds containing 1,3,5-triazine nucleus, that are available in the market as shown in Fig. 2. In the present review, we are intending to describe the structural and biological importance of this moiety in the development of drugs by investigating recent publications about the diverse range of triazine ring. These revealed that the substitution of various groups on the ring imparts different activity.

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Fig. 1. Various isomers of triazine.

2. Biological activities 2.1. Antitumor activity Triazine is widely explored for the development of anticancer agent due to its importance in various biological active molecules like triethylenemelamine, furazil and dioxadet [23]. Smith et al. [24] has been designed and synthesized a highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) that showed the dual PI3K/mTOR inhibitor 4. A structure-based approach was used to improve potency and selectivity. This resulted in the identification of compound 5, by the replacement of benzimidazole with pyridyl moiety and introduction of the methylsulphonylpiperazine group at 5-position of the pyridine ring [25]. It acted as a potent inhibitor of the class I PI3Ks with excellent selectivity over mechanistic target of rapamycin (mTOR) and a broad panel of protein kinase. Replacement of phenyl with pyridyl ring at 2-position of pyridyl moiety at triazine ring 6 showed potent, selective, and efficacious activities in both biochemical and cellular assays (Fig. 3). To pursue hybrid strategy for second generations, potent pan class I PI3K/mTOR inhibitors were exemplified by generic structure 8 that addressed the shortcomings of compound 6 and improved solubility over compound 7 [26]. The

chloropyridyl sulfonamide affinity pocket moiety of 7 has been replaced with 2-methoxypyridyl group of 6 to give a pan class I PI3K inhibitor 8 with a moderate (>10-fold) selectivity over the mammalian target of rapamycin [27]. 2-(Difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2yl]-1H-benzimidazole [28] (ZSTK474), 9a is a potent ATP competitive pan class I PI3K inhibitor [29e32]. Replacement of both morpholines in ZSTK474, a dual PI3K/mTOR inhibitor with 2,6-bridged morpholines (9b) was obtained, that led to 19-fold increase in mTOR selectivity due to the deeper binding pocket in mTOR relative to PI3K as compared to one bridged morpholine (9c). Substitution at 4- and 6-positions of the benzimidazole ring with 6amino-4-methoxy analog 10a displayed greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analog 10b (Fig. 4) against all three PI3K enzymes (p110a, p110b, and p110d) and also showed significant potency against two mutant forms of p110a isoform (H1047R and E545K) [33]. Peterson et al. [34] aimed at developing ATP-competitive mTOR inhibitors by transposing benzimidazole nitrogen (11) to imidazopyridine (12) that maintained the broader planarity between the triazine hinge-binder and the imidazopyridine ring, which was essential for good potency (Fig. 5). These s-triazine derivatives were screened for phototoxicity as well as the cytotoxic activities by interacting with DNA that caused extensive DNA damage, leading to induction of cell death against leukemia and adenocarcinoma derived cell lines in comparison to the normal human keratinocytes. Venkatesan and co-workers [35,36] have been reported a series of mono-morpholino triazine derivatives bearing 3-oxa-8azabicyclo[3.2.1]octane, as potent dual PI3K/mTOR inhibitors by increasing the clog P (Fig. 6). Morpholine in 13 was kept, as it formed a pivotal hinge region hydrogen bond interaction with

Scheme 1. Synthetic strategies for triazine derivatives.

Fig. 2. Drugs containing triazine nucleus.

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Fig. 3. Phosphatidylinositol 3-kinase inhibitors.

Fig. 4. Triazine bridged morpholines as PI3-kinase inhibitors.

Fig. 5. Substitution of benzimidazole and imidazopyridine.

Val851 and also urea appendage involved in vital hydrogen bond interaction with PI3Ka in the solvent exposed region [37e39]. Replacement of one of the bis-morpholine in lead compound 13 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane 14, resulted in an orally efficacious dual PI3K/mTOR inhibitor. Saczewski et al. [40] has been synthesized novel 2-amino-4(3,5,5-trimethyl-2-pyrazolino)-1,3,5-triazine derivatives that caused considerable growth inhibition on distinct tumor cell lines. Compound 16 with 5-nitrothienyl substituent is proved to be superior to 6-bromomethyl derivative (15) but elimination of the nitro group (17), yielded no anticancer activity. Metwally et al. [41]

worked on the synthesis and evaluation of some novel fused pyrazolotriazine derivatives with the hope of discovering new structural leads for serving as antitumor agents. Compound 18 exhibited a broad spectrum of in vitro antitumor activity to four human cancer cell lines viz., HepG2, WI 38, VERO and MCF-7 with IC50 values of 39.3, 40.3, 33.1 and 30.6 mg/mL respectively, while compound 19 showed very high cytotoxic activity due to the presence of fused pyridine ring with triazine moiety (Fig. 7). A new series of aromatic benzenesulfonamide incorporating 1,3,5-triazine moiety [42] has been investigated, for the inhibition of physiologically relevant carbonic anhydrase isozymes, that played a relevant role in tumorigenesis [43]. Compounds in which triazine ring (20) has been incorporated with amino, hydrazino, ethylamino, dimethylamino or amino acyl moieties, showed more activity but incorporation of bulky groups viz., n-propyl, n-butyl, diethylaminoethyl, piperazinylethyl, pyridoxal amine or phenoxy have shown less effectiveness towards hCA I, II and IX inhibitors. Raeppel et al. [44] has been identified new therapeutic agents (striazin-2-ylamino)methyl]-N-(2-aminophenyl)benzamides for the treatment of cancer that inhibited HDAC enzymes by arresting cell growth, that led to differentiation and apoptosis in tumor cell lines [45,46]. The structural diversification of s-triazine series (21) brought about by an increase in potency against HDAC with IC50 values of less than 0.2 mM with concomitant increase in antiproliferative activity (Fig. 8). Sa˛ czewski et al. [47] has been evaluated triazine derivatives of iminoacetonitriles (22) using human bladder cancer cell line 5637, human pancreatic cancer cell line DAN-G, human breast cancer cell line MCF-7 and human non-small cell lung cancer cell line LCLC103H to indicate whether a substance possessed enough activity at the concentration of 20 mM to inhibit 50% of cell growth. Iminoacetonitrile bearing (4-phenylpiperazin-1-yl) substituent (22a) at position 6 of triazine ring exhibited remarkable activity and selectivity for melanoma MALME-3M cell line. Substitution of the phenyl ring with either 4-nitro (22b) or 3-chloro (22c) resulted in decrease of activity (Fig. 9). Symmetrical trisubstituted trishaped triazine hydrazones [48] have been evaluated for their in vitro anticancer activity against the human liver carcinoma cell line HepG2 and human cervix carcinoma cell line HeLa and also acted as

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Fig. 6. Triazine bearing a 3-oxa-8-azabicyclo[3.2.1]octane.

Fig. 7. Pyrazole substituted triazine derivatives.

Fig. 8. hCA and HDAC inhibitors.

cytotoxic agents with the ability to prevent cell progression in cancerous cells [49]. Compounds 23a and 23b bearing p-fluoro and p-chloro substituents, exhibited a broad spectrum of antitumor activity against HepG2cells with percent inhibition of 4.32% and 6.41% respectively, while in case of HeLa cell line compounds 23c and 23d bearing p-nitro and p-methoxy substituents showed

percent inhibition of 8.36% and 9.37% respectively. The activity of quinoline substituted triazine compounds against prostate cancer cell (DU-145) proliferation suggested that the compound 24a, that is substituted with 3,5-dimethyl piperazine is the most active compound followed by 24b with 3trifluoromethylphenyl piperazine [50]. It has also been observed that higher inhibitory effects appeared to be dependent on the mono-chloro, di-chloro, acetyl, dimethyl, mono-fluoro, trifluoromethyl, trimethoxy and mono-methoxy functionality to the nitrogen atom of piperazine bases that condensed to the triazine nucleus. A series of tetrahydro-b-carbolines and s-triazine hybrids was evaluated for their cytotoxicity against a panel of eight human cancer cell lines and normal human fibroblasts (NIH3T3) that led to the discovery of racemic compounds 25aec, which has shown selectivity in cytotoxicity towards oral cancer cell lines; while their annuity pure, transforms are less active and non-selective [51]. Enantio pure compound 25d showed 2.5 times more selectivity towards MCF7 cells over normal fibroblast NIH3T3 cells (Fig. 10). Compound 26 with amino group at C2 position and benzyl amine at C6 position on the triazine moiety [52] was evaluated against tryptophan hydroxylase 1 (TPH1). The effect of either electron withdrawing group such as a trifluoromethyl or electron donating group such as methyl on the distal phenyl ring of

Fig. 9. Iminoacetonitrile-based inhibitors.

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Fig. 10. Quinoline and carboline-substituted inhibitors.

compound 26 has also shown four-fold increase in in vitro potency. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5] triazin-2-ol (27) [53] exhibited low nanomolar potency with in vitro selectivity against a panel of growth factor receptor tyrosine kinase and also demonstrated antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas (Fig. 11). Supuran et al. [54] has revealed moderate-weak inhibition of histone cytosolic isozyme, hCA III, IV, VA and XIII, moderate inhibition of hCA I, VI, and IX, and excellent inhibition of the physiologically relevant hCA II, VII and XII with triazinyl-substituted benzenesulfonamides compounds. The slow cytosolic isoform hCA I was moderately inhibited by compounds 28e30, with inhibition constant, KI values in the range of 81.5e250 nM, while difluoroand methylamino derivatives of sulfanilamide (28a and 30) with KI values in range of 83e88 nM, indicated the best hCA I inhibitors than to its longer congener difluoro derivative of 4aminoethylbenzenesulfonamide 29a, 2.3-fold less effective. Amongst the physiologically dominant isoform hCA II derivatives, 28e30 behaved as very strong inhibitors with KI values of 4.9e23 nM, dimethylamino derivative was less effective while poor inhibition of membrane-bound isoform hCA IV by compounds 28e30 with KI values of 603e3660 nM and cytosolic isoform hCA VII was also strongly inhibited by sulfonamides 28e30, KI values of 6.2e45 nM. The secreted isoform 3,6 hCA VI was poorly inhibited by 29a (KI of 1388 nM), and better inhibited by compounds 28, 29 (aec) and 30 with KI values of 130e274 nM. The least effective inhibitor was the dimethylamino compound 30 (KI of 45 nM) while remaining derivatives 28 (b,c), 29 (aec), 30 with bulkier substituents on the triazine ring were less effective to hCA IX inhibitors with KI values of 153e228 nM. The compounds possessing a longer spacer between the triazine and benzenesulfonamide rings (n ¼ 2), such as 28c and 29(aec), were more effective inhibitors compared to the sulfanilamide derivatives with n ¼ 0. The last transmembrane isoform, hCA XIV was poorly inhibited by compounds 28c and 30 (both of them incorporate one or two methylamino

moieties), with KI values of 3290e3407 nM and slightly better inhibited by the remaining derivatives, 28 (a,b) and 29 (b,c) (KI of 42e220 nM). The best hCA XIV inhibitor was the difluorotriazine derivative of 4-aminoethylbenzenesulfonamide 29a (KI of 42 nM) (Fig. 12). Seo and co-workers [55] have been attempted to discover and screen the antiproliferative activities of triazine as Hsp90 inhibitors (31aec, 32aec and 33aeb), against gefitinib-resistant H1975 cells. Compound 31a was the most effective for inhibition of cell proliferation among other derivatives and most compounds 31 (a,c), 32 (aec), 33a,b blocked cell proliferation in a dose-dependent manner with modest efficacies in a cell proliferative assay. Interestingly, the most toxic 31a did not induce the degradation of Her2 and Met, or upregulate Hsp70 protein that was not associated with Hsp90 inhibition, while 33b furnished a robust degradation of Her2, Met and Akt and induction of Hsp70 slightly better than 33a. Both 33a and 33b are phenoxy-triazines and structurally different from 31aec and 32aec with benzyloxy-triazine and a phenylamino-triazine scaffolds, respectively. The expression level of Her2 was substantially decreased upon the treatment of cells with 33b at a concentration of 50 mM, while the incubation with 100 mM of compound 33b almost completely depleted Her2 protein and significantly degraded Met and Akt. Thus, by introducing benzyloxy, phenylamino and phenoxy groups at the hydrophobic moiety of 2,6dimethylbenzyloxy group at 6-position of 2-amino-4-chloro1,3,5-triazine, led to the significant improvement in the potency. 2Amino-4-chloro-1,3,5-triazine moiety of 33b bound to the hydrophilic pocket of Hsp90 through hydrogen bonding, while 2,6dimethylphenyl moiety of 33b reached the hydrophobic region of Hsp90 for van der Waals interactions with antiproliferative activity against H1975 (Fig. 13). Suda et al. [56] described a novel series of 2-amino-1,3,5triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors, having strong anti-proliferative activity against human cancer cell lines (HCT116) with IC50 value of 0.46 mM. The transformation of methyl group on the sulfur atom with other

Fig. 11. Tyrosine-kinase inhibitors.

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Fig. 12. Human carbonic anhydrase isoforms.

Fig. 13. HSP90 inhibitors.

substituents, improved the affinity as well as physicochemical properties. While retaining the tricyclic moiety and introducing hydrogen bond acceptors like acetylamino (34a, IC50 ¼ 0.13 mM) and mesylamino (34b, IC50 ¼ 0.34 mM), increased affinity to Hsp90 by 4- to 8-folds in comparison with that of compound 35a CH5015765 showed high binding affinity for N-terminal Hsp90 with in vitro cell growth inhibition against human cancer cell line (HCT116, IC50 ¼ 0.46 mM). Introduction of the acetylamino group 35b (IC50 ¼ 1.2 mM) to compound 34a decreased in affinity by 10fold while methyl group (35c) slightly improved the affinity and chiral methyl group (35d) showed almost the same activity as the racemate (35c). These data suggested hydrophobic substituents are favored on a methylene carbon, but introducing the geminal dimethyl groups (35e, IC50 ¼ 6.3 mM) as a hydrophobic substituent, caused a significant decrease in affinity. Among these, CH5138303 35f showed strong in vitro cell growth inhibition against human cancer cell lines with HCT116, IC50 ¼ 0.098 mM and also excels in the series by its in vitro efficacy and physicochemical properties by reducing the phosphorylation and protein level of multiple Hsp90 client proteins by modifying the lead compound 35a (CH5015765, Fig. 14). Kononowicz et al. [57] synthesized and evaluated a series of novel triazine derivatives with different aryl substituents at 6position for histamine H4 receptor (H4R) affinity in Sf9 cells, expressing human H4R co-expressed with G-protein subunits. In this series, 4-methylpiperazinyl moiety acted as basic center and

the primary aromatic amino group as additional basic center or hydrogen acceptor/donor functionality. Substitution of chlorine in the para position (37a) of phenyl ring was the most potent and showing highest affinity with hH4R Ki value of 203 nM. By changing the substitute position from para to meta (37b, Ki ¼ 408 nM) and to ortho (37c, Ki ¼ 1261 nM) position, affinity has drastically been reduced. In addition, the change of chlorine, in the para-position for different substituents like fluoro, bromo or iodo, led to decrease in potency while unsubstituted analog (36, Ki ¼ 10 nM) had higher affinity. Two fluorine substituents in 2- and 6-positions (37d) are less beneficial than two (37e) or three atoms (37f) in respective 3,5positions and 3,4,5-positions (Fig. 15). Westwell and co-workers [58] has been synthesized a series of triazine substituted carbohydrazides and carboxamides as potential anticancer agents targeting Rad6B that led to the discovery

Fig. 15. Triazine derivatives as histamine H4 receptor.

Fig. 14. 2-Amino-1,3,5-triazines bearing a tricyclic moiety.

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of a number of compounds with low micromolar IC50 activity, specifically in Rad6B expressing human cancer cell lines MDA-MB-231 and MCF-7. Evaluation of newly synthesized compounds; 4-amino-N-phenyl-6-(arylamino)-1,3,5-triazine-2carbohydrazides (38) and 4-amino-N-benzyl-6-(arylamino)1,3,5-triazine-2-carboxamides (39) were carried out in human breast cancer cell lines MDA-MB-231 and MCF-7. For the triazine carboxamides compounds 39a, 39b and 39d were found to be essentially inactive in the MDA-MB-231 cell line, and 39a and 39b were inactive in MCF-7 cells. In contrast, 4-amino-N-(2methoxybenzyl)-6-(2-methoxy-phenylamino)-1,3,5-triazine-2carboxamide (39c, Fig. 16) was found to be the most active compound tested against the MCF-7 cell line with IC50 value of 1.97 mM, with moderate activity against MDAMB-231 having IC50 value of 32.9 mM. Paul et al. [59] synthesized a new series of triazineebenzimidazole hybrids with different substitution of primary and secondary amines at one of the position of triazine in moderate to good yields and evaluated for their inhibitory activities over 60 human tumor cell lines at one dose and five dose concentrations. Compounds 40, 41a and 41b showed a broad spectrum of antitumor activities with GI50 values of 9.79, 2.58 and 3.81 mM, respectively along with DHFR inhibition property. Among the series, compound 40 was depicted as the most active compound of DHFR inhibitor with IC50 value of 1.05 mM (Fig. 17). Joseph et al. [60] recently reported the design of pyrazolo[1,5-a]1,3,5-triazine (42a and 42b), constituted a new series of tubulin inhibitors that displayed micromolar antiproliferative activities towards colorectal cancer cell lines, having significantly higher biological potency. Compound 42b displayed higher antiproliferative activity in colorectal cancer cell lines and in CEM cells than 44a while Myoseverin 43 was active at low micromolar range in all the tested cell lines, being most active in the colorectal cancer cell lines (HCT116, SW48 and SW480, Fig. 18). 2.2. Antimicrobial activity In continuation of goal towards the discovery of potential bioactive leads, Singh et al. [61,62] deal with antifungal activity of triazine nucleus with phenylthiazole, to develop hybrid molecules and dwells upon structureeactivity relationship (SAR), along with physicochemical parameters to quantify the role of various electronic, steric and other factors to escalate the bioactivity. Compound 44a, with di-isopropyl amine, displayed no activity while a slight increase in activity was observed when a phenyl ring of thiazole motif was substituted with chlorine (44b), while the introduction of di-morpholine fragment led to a significant increase in activity 44(cee). Compound 44d with same di-morpholine fragment and 4-chloro phenyl thiazole amine exhibited moderate activity for all tested microorganisms (Fig. 19). Gahtori et al. [63] synthesized various triazine derivatives substituted with aromatic and heterocyclic amines as bioactive scaffold in search for exploring the potential as antibacterial drugs (45). Structureeactivity

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Fig. 17. Triazineebenzimidazole hybrids.

Fig. 18. Pyrazolotriazine derivatives.

relationship studies suggested that thiazole amine pendent is well tolerated at 6-position of tri-substituted triazine and electron withdrawing groups (NO2, Cl, Br, F) are necessary for compounds to be effective antibacterial activity. Further, the presence of nitro group (45b) led to increase in activity in comparison to the other electron withdrawing groups like chloro, bromo or fluoro; probably due to facilitated binding of nitro groups with the targets by increasing the membrane permeation. Solonkee et al. [64e66] reported the reaction of 2,4-bis-(phenylamino)-6-(4-acetylphenylamino)-triazine with different aldehydes to form chalcones. The inhibitory effect appears to be dependent on the substituent of chalcone. The introduction of different substituents like chalcones 46a, pyrazoline 46b, pyrimidine 46c and cyanopyridine 46d, played different roles in antibacterial activity and also point out the presence of a substituted benzene ring endowed with higher activity. For chalcone; the most active compound is 2-methoxyphenyl substituent 46a, for pyrazoline; 4-nitrophenyl (46b), while for pyrimidine; the most active derivative is 4-chlorophenyl substituent in aromatic ring (46c) and for cyanopyridines substitution with 5-member-ring heterocycle; 2-thienyl and 2-furanyl are important (46d, Fig. 20). Patel and co-workers [67] have been promoted the sequential introduction of various piperazine and piperidine substituents into the triazine ring that occupied a unique place in the realm of pharmacological activities [68e70]. To increase the biological activity by increasing the volume of the substituents attached to the

Fig. 16. Triazine substituted with carbohydrazides and carboxamides.

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Fig. 19. Phenylthiazoleetriazine hybrid.

Fig. 20. Chalcones based triazine derivatives.

piperazine ring system led to different biological potency, depending on the nature, position and number of the atoms or groups introduced. High potency has been observed in the scaffold 47 due to the presence of piperazine systems with fluoro, methoxy and piperidine entities having highest electronegativity, thermal stability and lipophilicity of fluorine atom. Introduction of fluorine substituents to biologically active piperazine ring can affect their biological properties associated with lipophilicity, absorption, and transportation [71]. Substitution of triazine ring [72] with 3- or 4fluorophenyl along with rigid diamine as one of substituent was preferred, since activity was increased by introducing rigidity at this position such as isopentyl (48a), cyclopentylmethyl (48b), cyclohexyl methyl (48c), benzyl amine (48d), piperidine (48e) and tetramethylpiperidine (48f). Among other rigid amines, compounds 48e or 48f showed most effective substituents against antimicrobial activity (Fig. 21). Menon et al. [73] reported a series of novel fullerene derivatives bearing s-triazine moiety by adopting 1,3 dipolar cycloaddition reaction of C60 and azomethineylides, generated from corresponding schiff bases that were screened for their antibacterial activity. One of the difficulties faced in using fullerene derivatives for biological application is its low solubility in water or water miscible solvents, but that can be solved by either introduction of (a) hydrophilic group or (b) ionic species in the molecule. Bacterial inhibition zones developed by fulleropyrrolidines (49) were found to be much bigger in size as compared to s-triazine based schiff base precursors, indicating the contribution of fullerene moiety towards antimicrobial activity. Compound 50 with ionic eNH3 group was found to be the most active followed by the derivative in which both eNH2 groups were free, but the activity was decreased

with increasing substitution on NH2 group due to reduced hydrophilicity of the molecule, that in turn decreased the disruption caused to the negatively charged bacterial cell membrane (Fig. 22). Designing of hybrid molecules through the combination of different pharmacophores in one structure, may lead to compounds with increased antimicrobial activity, has been prompted by Sarmah [74] and Kaswala [75]. They have synthesized some triazine derivatives carrying the biodynamic heterocyclic systems like 1,2,4triazole 51(aec), benzimidazole, benzotriazole [76] (52) and coumarin through an oxygen bridge (53) and having substituted urea or thiourea with the hope to achieve enhanced antimicrobial activity (Fig. 23). Compound 52 was found to be more active against other compounds because the aryl urea and benzimidazole moieties created structural crowding and various allosteric sites that provided sufficient electronic pressure to make it more active. The presence of electron withdrawing groups increased the antibacterial activities as compared to the electron donating group to the aromatic ring. The substitution at C-3 and C-4 positions of the phenyl ring showed effective antibacterial activity. The presence and position of oxo-linkage in the connecting linker between the aromatic rings were also seemed to be important for antibacterial effect like ureido linkage. Chloro (53a) and methoxy (53b) substituted compounds showed excellent activity, but thioureido linkage (53c) displayed better activity as compared to 53a or 53b. In one optimal configuration, two symmetrically positioned cis3,5-diamino-piperidine (DAP) moieties [77] are directly linked to a triazine core to form the di-DAP substituted triazine (DAPT) 54, a novel aminoglycoside mimetic that bind A-site within rRNA by acting as bacterial protein synthesis inhibitors. To improve the potency and establish antibacterial activity, optimization was

Fig. 21. Substitution of piperazine and piperidine.

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Fig. 22. Fullerene derivatives.

Fig. 23. Hybrids with heterocyclic rings.

focused around the phenyl tailpiece of 54 because phenyl linker in the tailpiece plays an important role in bacterial cell penetration. Aromatic tailpieces, 54 improved rRNA binding that resulted in potent translation inhibitors. Electron-withdrawing substitution on the phenyl ring improved inhibitory potency against bacterial translation 55a but electron-donating substitution 55b resulted in reduced potency. This is due to substituent-modulated changes in the electronic properties of the phenyl ring likely influence the stacking interactions with rRNA bases. The activity was also dependent upon the position of substitution e.g. ortho substitution universally correlated with weak antibacterial activity, while substitution at the meta and para positions often resulted with substantially improved antibacterial activity (Fig. 24). 4-[4-(4-Aminophenylamino)-6-dimethylamino[1,3,5]triazin-2yloxy]-1-methyl-1H-quinolin-2-one gave condensation reaction with different aldehydes to obtain schiff base derivatives, which after cyclization afforded thiazolidinones. Finally, they were reacted with N-ethylpiperazine to get target compound 56 that were evaluated for their antimicrobial activity. Compound 56a having electron donating methyl group on para position of phenyl ring, showed good ability to inhibit Staphylococcus aureus and Bacillus cereus but compound 56b having electron withdrawing fluoro and chloro substituents on phenyl ring attached to thiazolidinone

Fig. 24. Diaminopyridine substituted triazine derivatives.

moiety exerted greatest activity and showed the highest zone of inhibition as compared to bromo substituted compounds. Thiazolidinone 56c having para substituted NO2 or OH group on phenyl ring depicted better activity [78]. To find out the effect of schiff base on biological system, an attempt was made to synthesize novel schiff base derivative (57) derived from 4,40 -((6-(4-(diethylamino) phenyl)-1,3,5-triazine-2,4-diyl)bis(oxy))dibenzaldehyde (DIPOD), with very poor antimicrobial activity as compared to schiff base (Fig. 25) [79]. Far et al. [80] screened a chemical library of atriamino-triazine inhibitors having good antibacterial activity with significant reduction in cytotoxicity towards mammalian cells. Triaminotriazine 58a acted as a low micromolar inhibitor of the enzyme, but it did not display antibacterial activity against gram-negative organisms, along with moderate activity against gram-positive organisms. In an effort to form a scaffold that can be used to generate helicase inhibitors with antibacterial activity and reduced cytotoxicity, a correlation between the electron-withdrawing substituents on the aryl rings and its inhibitory activity was established. Indeed, compound lacking substituents (58b), fluorine atoms on aryl rings (58c) and having electron-rich substituents (58d), were completely inactive, whereas the replacement of the nitro in 58a by a chlorine atom (58e) resulted in a reasonable inhibitory activity (Fig. 26). Singh et al. [81] reported a novel series of triazineepyrazole conjugates to bring diversity around the core skeleton tested against gram-positive and gram-negative microorganisms. Compounds 59(aee) having p-Cl on both the rings connected to triazine core along with 6-substituted phenyl of pyrazole, showed significant to substantial activity against tested pathogens. Especially, in the case of compound 59a, having unsubstituted phenyl on pyrazole ring, showed significant activity while the introduction of 2NO2 (59b) on phenyl ring, led to a drastic decline in activity but no significant change in activity with isomeric replacement of NO2 (59c). A marked inhibition pattern was reported by insertion of 2-Cl (59d) against the entire set of testing organisms except Proteus vulgaris, while no major shift in antibacterial activity was reported

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Fig. 25. Schiff based derivatives.

Fig. 26. Atriamino and pyrazoleetriazine conjugates.

by changing the substitution pattern of Cl (59e), except it makes the compound twofold more active against B. cereus, while the introduction of 2-Cl (59i) disclosed improvement in antibacterial activity. The presence of 3-NO2 on the phenyl of triazine 59f also showed improvement in antibacterial activity and render molecule potent against S. aureus, B. cereus and P. vulgaris but compound 59g with 3-NO2 groups at the phenyl of pyrazole, made the molecule almost inactive and no drastic change in activity was observed upon isomeric replacement of NO2 from second to fourth position 59h. Compounds 59l and 59m having NO2 on respective second and fourth positions presented considerable activity but introduction of Cl on second 59n and fourth 59o positions marked with increase in activity. The antibacterial results corroborated that the presence of halogen atoms would drastically manipulate the activity of the molecules, but more pronounced activity was disclosed by the analogs having the fluoro substitution on the phenyl ring connected to triazine. The chloro group served as the next prominent molecule in the antibacterial assay, but least to moderate activity was observed by NO2 substituted compounds. The most pronounced activity was kept with the intact phenyl, in contrast to their substituted counterparts (59a, 59f and 59k), but contribution of lesser activity of substituted phenyl derivatives was shown due to generation of steric hindrance on the probable binding site. 2.3. Antimalarial activity Chemical

modification

of

quinine

nucleus

led

to

the

development of other therapeutic agents such as chloroquine [82] (60), pamaquine [83] (61) and mefloquine [84] (62, Fig. 27). In spite of drug resistance, chloroquine has been the compound of choice that remained a front line drug for the malaria treatment. Hence, there is still scope for structural manipulation of chloroquine molecule in such a way that the problem of drug resistance can be sorted out. Rawat et al. [85] described the importance of substitution of triazine nucleus with quinoline moiety for antimalarial activity. 7Chloro and 4-amino groups in quinoline nucleus are essential for antimalarial activity by inhibiting the b-hematin formation that helps the drug to accumulate in the acidic food vacuole of the parasite [86e89]. Substitution of 7-chloro of quinoline moiety by electron donor or electron withdrawing groups reduced the antimalarial activity [90]. 4-Aminopyridine substructure of 4aminoquinoline also helped in binding with the heme [91]. The presence of linker alkyl chain between triazine and quinoline nucleus is essential, but both shortening (2e3 carbon atoms) and lengthening (10e12 carbon atoms) of the alkyl chain led to compounds with retained antimalarial activity [92,93]. Substitution of diethyl group by metabolically stable side chain of tert-butyl group as well as the heterocyclic functionality such as morpholinyl, piperidinyl or pyrrolidinyl groups led to increase in antimalarial activity [94]. Triazine derivative 63 or 64 has been found to be the most active against chloroquinoline sensitive strain [95] (Fig. 28). The combination of piperidine, cyclohexylamine, p-fluoroaniline, aniline and morpholine as substituents on triazine nucleus at

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49

Fig. 27. Quinine nucleus drugs.

Fig. 28. Quinoline substituted triazine derivatives.

4- or 6-position was well tolerated for the antimalarial activity while bulky phenyl group e.g. o-toluidine exerted negative effect on the antimalarial potency, but p-toluidine 65 at both positions proved to be active [96]. Chahuan et al. [97] has developed and evaluated a new series of 9-anilinoacridine triazine hybrid molecules as more potent and efficacious antimalarial agents. Compounds 66a and 66b with respective IC50 values of 4.21 and 4.27 nM, displayed two times higher potency than chloroquinoline (Fig. 29).

2.4. Antiviral activity HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) with high antiviral potency, specificity and low cytotoxicity have become an indispensable component in HAART regimen [98]. Therefore, it is an urgent need to design and develop new anti-AIDS drugs with improved potency to halt the spread of HIV. Among the non-nucleoside reverse transcriptase inhibitors, diarylpyrimidine (DAPY) derivatives such as dapivirine (67), etravirine (68) and rilpivirine (69) and diaryltriazine (70) [99,100] with superior activity profiles against HIV-1 have attracted considerable attention over the past few years (Fig. 30). Liu et al. [101] has developed a novel series of DAPY analogs with piperidine-substituted triazine moiety, which is structurally similar to the piperidine-linked aminopyrimidine derivatives for anti-HIV

activities in MT-4 cells [102,103] and even better than that of nevirapine, delavirdine, zidovudine and dideoxycitidine. Compounds 71 (aed) and 72 (aed) exhibited highest inhibitory activity while compounds 73 (aed) and 74 (aed) showed moderate inhibitory activity against HIV-1, of which 73b and 73c showed more potency than dideoxycitidine. N-Benzyl analogs with Y ¼ NHMe 71 (aed) were slightly more potent than their corresponding compounds with Y ¼ OMe 72 (aed). In the N-benzoyl analogs, 73c and 74c were more active than 4-hydroxy (73b and 74b), 4-nitro (73d and 74d) and 4-carboxyl (73a and 74a) derivatives while among the Nbenzyl analogs, 71a and 72a were the most potent derivatives (Fig. 31). To pursue the anti-HIV studies, structural modification of piperidine-substituted triazine derivatives in which amino group was introduced to the triazine ring like etravirine that improve hydrogen bond interaction with amino acid residues inside the binding pocket of HIV-1 NNRTI [104]. Introduction of eNH2 group at the triazine ring improved the activity compared to the eNHMe and eOMe series except 4-carbamoylphenyl group (75a) while compound 75b with pyridyl ring showed more potency due to the presence of polar hydrophilic substituents at the para phenyl such as sulfamoyl, methylsulfonyl, cyano and nitro groups [105] (Fig. 32). Jorgensen et al. [106] has reported non-nucleoside inhibitors of HIV-1 reverse transcriptase with greater solubility and high antiviral activity than the structurally related drug etravirine and

Fig. 29. Quinoline and acridine nucleus derivatives.

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Fig. 30. NNRTIs derivatives.

Fig. 31. DAPY derivatives.

Fig. 32. Hybridization of piperdine-linked aminopyrimidine and etravirine.

rilpivirine. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent at 6-position in the azine ring in the entrance channel of the NNRTI binding site [107]. The final intermediate 76a was also reduced to obtain the corresponding analog 76b lacking the morpholinoalkoxy group with EC50 values of 2.3, 47 and 90 nM against respective strains of WT, Y181C, K103N/Y181C along with low aqueous solubility. The corresponding triazine 76c with a strategically added morpholinopropoxy group enhanced solubility like dapivirine (48) with EC50 values of 8, 310 and 31 nM. Replacement of 4-Me substituent of the

mesityl group by cyano and cyanovinyl, provided the remarkably potent molecules 76d and 76e with EC50 values of 1, 12 and 1 nM against WT, Y181C, K103N/Y181C strains. However, 4-methyl analog 76f was strikingly potent, 190 pM, in the WT assay. These triazine analogs 76 (cef) were turned out to be 2e3 fold more potent than their corresponding piperidine analogs 77 (Fig. 33). The interest in the morpholine containing triazine compounds was particularly high that would likely to improve the solubility of the compounds. So, extending into the entrance channel for parent analog 78 would require attachment of substituent at C6 position of

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51

Fig. 33. Morpholinylalkoxy substituted triazine derivatives.

the triazine ring with some loss of potency. Thus, compounds 78a (92 nM) and 78b (95 nM) showed good activity by addition of the morpholinoalkoxy substituent that represents a significant improvement in solubility and potencies over the methylpiperazinyl analog 78c (0.32 mM) [108]. 2.5. Anti-inflammatory activity The aromatic side chains of the hydrophobic core dipeptide Phe132-Tyr133 of protein A are able to bind the Fc portion of IgG that taken into consideration while designing of protein A mimetic [109]. Aniline and tyramine substituents may mimic the side chains of Phe132-Tyr133, while triazine ring was used as a core structure to maintain optimal orientation of the two mimetic groups. Zacharie et al. [110] has been synthesized and evaluated a number of bis-triazine derivatives of structural type 1 as protein A mimetic and displayed significant activity comparable to protein A. Amino function of 3-aminoaniline group appeared to be essential, and activity declined upon replacement of 3-aminoaniline with other groups such as 2-fluoroaniline (79a) or aminoethylamidine (79b) or 3-methylsulfonamidoaniline (79c). With 3-aminoaniline group at one of the triazine and substitution of 3-fluoroaniline (80a), 4fluoroaniline (80b), 4-chloroaniline (80c), 3-methylsulfonylaniline (80d), ethylenediamine (80e) at another triazine ring, displayed less activity than compounds 3-aminoaniline (80f) and ethanolamine (80g, Fig. 34). Thus, aliphatic linkers with two- or three-carbon spacers 81 (aec) demonstrated good activity as compared to protein A. Selection of the linker is critical, since activity is dependent upon the distance between two triazine rings. 4-Aminoaniline (81d) demonstrated better activity than 3-aminoaniline (81e, Fig. 35). 4-

Aminophenethylamine as a linker at this position has been enhanced in vitro antibody binding activity, but 3aminophenethylamine or 4-amino-R-methylbenzylamine displayed a decrease in activity and also phenethylamine group resulted in a loss of activity. In this context, screening of Gewald [111] communication describes their efforts to optimize s-triazine compound library that resulted in the identification of potent, selective and orally active PDE4 inhibitors. Interestingly, the attachment of a cyano function 82b (IC50 ¼ 40 nM) enhanced the activity as compared to the analog 82a (IC50 ¼ 245 nM), while the size of the cycle and prolongation of the ethyl chains showed barely any influence on the inhibitory activity (82c, IC50 ¼ 44 nM). A sharp drop in potency was caused by omitting the methyl group (83a, IC50 ¼ 1040 nM), but

Fig. 34. Bis-triazine derivatives.

Fig. 35. Bis-triazine with aliphatic linkers.

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adding size at this position (83b, IC50 ¼ 126 nM) was not well tolerated. In addition, the hydrogen bond donor elements were identified as crucial structural features required for potent inhibition (83c, IC50 ¼ 563 nM). Although, the impact of a small carbon linked group (84a, IC50 ¼ 19 nM), cyano substituent (84b, IC50 ¼ 38 nM) or methoxy substituent (84c, IC50 ¼ 19 nM) were slightly improved and maintained inhibitory activity, while a ninefold increase in potency was detected for methylthio derivative (84d, IC50 ¼ 4.4 nM). Triazines bearing an alicyclic moiety (85a, IC50 ¼ 0.15 nM) behaved metabolically less stable than their open-chain counterparts by stepwise reduction of the chain length (85b, IC50 ¼ 1.1 nM), led through an affinity maximum for derivative 85c (IC50 ¼ 0.81 nM). The SAR optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 85c as a potent, selective and orally active PDE4 inhibitor (Fig. 36). 2.6. Antileishmanial and antiamoebic activities A real advancement in chemotherapy of protozoan infections was made more than four decades ago with the introduction of pentamidine for leishmania [112e114] and metronidazole for amoebiasis [115,116] that demands a renewed effort seeking the development of new antileishmanial and antiamoebic agents effective against the pathogenic parasite and non toxic to the human cells by considering the need for a new molecule. Earlier, pyrimidines were synthesized and evaluated as inhibitors of leishmanial and trypanosomal dihydrofolate reductase (DHFR) [117] that has been successfully used as a drug target in the area of parasitic diseases, but clinically showed less selectivity [118] due to the over expression of gene pteridine reductase (PTR1), that has ability to provide reduced pterins and folates. Triazine being the inhibitors of DHFR [119,120] has also been identified as potential antileishmanial agents [121]. Based on these observations, Chauhan et al. [122] has been devoted to the synthesis of diverse heterocycles such as pyrimidines [123e128], indole [129], quinolines [130], pyridines [131,132] and triazines [119,120] as anti-infective and antiparasitic agents. 3,4-Dimethoxyphenyl group at the fourth position of pyrimidine and N-methylpiperazines at 4- and 6positions of 1,3,5-triazine gave 86b, that showed several folds better activity than pentamidine while 3,4,5-trimethoxyphenyl group at the fourth position of pyrimidine and piperidine at the 4- and 6-positions of 1,3,5-triazine (86a) showed less cytotoxicity in comparison to compound 86b with enhancement of the

antileishmanial activity. Hybrids of [1,2,4]triazino[5,6-b] indole with 1,3,5-triazine were screened for their antileishmanial profile [133]. Atriazino[5,6-b]indol-3-ylthio-1,3,5-triazine derivatives (87a and 87b) have been found to be the most active and less toxic with 20- & 10-fold more selectivity as compared to that of pentamidine (Fig. 37). Triazine derivative (88) with 5-aminopentan-1-ol linker [134] was found to be inactive as compared to shorter chain length like 4-aminobutan-1-ol linker (89aeh) against Leishmania donovani. Substitution of 6-chloro with morpholine (89a) and amino ethyl morpholine (89b) groups showed successive increase in the antileishmanial activity with concomitant reduction in cytotoxicity. Aliphatic amines such as n-pentylamine (89c) also showed good anti-amastigote activity and selectivity, while decreasing the chain length by one carbon (R1 ¼ R2 ¼ n-butyl) enhanced the activity in case of compound 89d but further decrease in chain length by one carbon (R1 ¼ R2 ¼ n-propyl, 89e) demonstrated further enhancement in anti-amastigote activity and selectivity. Surprisingly, tertbutyl substituted derivative 89f exhibited better activity (IC50 ¼ 0.77 mM) among all the synthesized analogs (Fig. 38). Athar et al. [135] has synthesized and evaluated a series of compounds bearing a tetrazole 90 (aec) and triazine ring motif conjugated with SO2NH function as their antiamoebic potency. The cytotoxic activity of these compounds has been checked on human hepatocellular carcinoma cell line HepG2 that additionally efforts to the development of new chemotherapeutic agents which are antiamoebic and non toxic to human cells. Incorporation of triazine ring in place of tetrazole (92), resulted in precipitous increase in the antiamoebic activity of the compounds. The substituted phenyl groups of the sulfonamide fragment also have a marked effect on the activity of the compounds. Modification at 4-position of the phenyl ring of the sulfonamide fragment of the triazine ring with some electron withdrawing substituents like chloro (91b) or nitro (91c) group, allowed optimization of these compounds for an effective and probably selective for better antiamoebic therapy but electron releasing group like methyl group (91a) or isopropyl group decreased the activity (Fig. 39). Antiamoebic and cytotoxicity studies of these compounds resulted in the binding of two compounds 91b and 91c, as stronger inhibitor with least cytotoxicity to human cells (HepG2) than the standard drug metronidazole. 2.7. Antitubercular activity Chauhan et al. [136] has been discovered a new series of triazine as a potent inhibitors of Mycobacterium tuberculosis H37Rv using

Fig. 36. PDE4 inhibitors.

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53

Fig. 37. Pyrimidine and indole thio-pyrimidine substituted analogs.

Avupati [137] et al. have been observed inhibitory property of 1,3,5-triazineeazomethine conjugates against Mycobacterium tuberculosis revealed the importance of the nature of substituted aromatic/heteroaromatic aldehyde or ketone from which the corresponding schiff bases were obtained. The mycobacterial activity screening data revealed that electron releasing groups were found to be biologically relevant in case of compound 96a, demonstrated comparatively the most potent inhibitory activity, with MIC value 3.125 mg/mL and hydroxyl group substitution at different positions on the phenyl ring also showed appreciable inhibitory activity in case of compounds 96b and 96c with MIC values of 6.25 mg/mL. 2.8. Miscellaneous

Fig. 38. Effect of linker on the activity.

Fig. 39. Triazine substituted with Tetrazole.

the hits obtained from the pyrimidineetriazine derivatives (93aec), along with some substituted pyrimidines (94) as potential drug candidates. In pyrimidineetriazine derivatives, compound 93a having methoxy and t-butylamine groups decreased the activity as compared to their unsubstituted analog at one of the position 93b. These pyrimidineetriazine compounds were found to have moderate anti-tubercular activity, while substituting pyrimidines (94) showed deprived in activity that confirmed, hybrids may be active due to the presence of triazine moiety. For this purpose, triazine has been monosubstituted with 1,2,3,4tetrahydroquinoline, piperidine and disubstituted with 1,2,3,4tetrahydroquinoline or tetrahydroisoquinoline, resulted in moderate anti-tubercular activity. So, in an effort to increase the activity, isoniazid with triazine moiety (95, Fig. 40) has been incorporated that showed promising anti-tubercular activity.

One of the hit series for structure 97 was subsequently demonstrated to possess excellent cell based activity in a Monocyte Chemotactic Protein-1 (MCP-1) induced THP-1 cell migration assay [138]. Xia et al. [139] evaluated a series of substituted triazine for cholesteryl ester transfer protein (CETP), that transfers cholesteryl ester (CE) from HDL to LDL and in return transfers triglyceride (TG) back to HDL and inhibition of CETP, presented a potential therapeutic approach for treating atherosclerosis. Initial lead structure (98a) was discovered by random screening and replacing the hydrazone group in 98a with a variety of isosteric substituents that displayed a range of in vitro CETP inhibitory activities with the most potent ones. There is a size requirement for activity at this hydrazone substitution site; H and OH substituted compounds (98b and 98c) showed little inhibition whereas increasing size resulted in increasing inhibition (98d). For nitrogen substituted compounds, secondary amine substitution (98e) has been demonstrated more potent inhibition than primary amine (98f, Fig. 41). Supuran et al. [140] has been reported sulfonamides incorporating triazine moieties (99aec, Fig. 42), selectively and potently inhibition of tumor-associated carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II. The longer spacer compound (n ¼ 2) has been shown more effectiveness as an inhibitor than the intermediate spacer (n ¼ 1), which in turn was more effective than the shorter spacer derivative (n ¼ 0). The short amino alcohol derivative (100a) has also been shown more effective than the bulkier compound 100b (with a longer spacer between the amino and OH moieties). Moro et al. [141] reported a new series of triazolotriazines with different substitution at C5 and N7 positions that were fully characterized at the four adenosine receptor (AR) subtypes. In particular, arylacetyl and arylcarbamoyl moieties were introduced at the N7 position with enhanced affinity at the hA2B and hA3 ARs respectively. Compound with a free amino group at the 7-position (101) has shown good affinity and potency that could represent a starting point for searching new non-xanthine hA2B AR antagonists, while the introduction of a phenylcarbamoyl moiety at N7 position (102, Fig. 43) slightly increased the affinity at the hA3 AR with respect to the unsubstituted derivatives. Marino et al. [142] has identified 1-(1,3,5-triazin-yl)piperidine-

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Fig. 40. Pyrimidine and azomethine substituted triazine conjugates.

Fig. 41. MCP-1, CETP and PDE4 inhibitors.

Fig. 42. Carbonic anhydrase transmembrane isoforms.

(104a, IC50 ¼ 1 nM) proved 100-fold reduction in potency relative to meta- (104c) or para-positioning (104d). Polarized, electronwithdrawing groups like cyano-analog (104e) were also found to be 10-fold less optimal as compared to non-polarized electronwithdrawing groups like trifluoromethyl (104f) or trifluoromethoxy (104a). By combining 2-trifluoromethyl- or 2trifluoromethoxy substituent with a variety of 4-substituents like F (104g, IC50 ¼ 3 nM), OCH3 (104h, IC50 ¼ 1 nM), Br (104i, IC50 ¼ 0.5 nM), resulted in no loss of enzyme activity (Fig. 44). Barth and co-workers [143] described a new potent and brain penetrating Cannabinoid CB2 ligand expressed in CHO cells (105b, IC50 ¼ 1.4 nM) that was selective versus human CB1 receptors (IC50 ¼ 180 nM). The triazine 105a was selected from a proprietary library of cannabinoid CB2 ligand as a starting point for the development of a CB2 PET tracer due its high affinity for hCB2 receptor (105a, IC50 ¼ 0.58 nM), good selectivity versus hCB1 receptor (IC50 ¼ 300 nM) with moderate lipophilicity (Fig. 44).

3. Conclusion Fig. 43. Triazolotriazine derivatives.

4-carboxamide as inhibitor of soluble epoxide hydrolase. There is no improvement in potency when N-4-methyl-piperazine (103b, IC50 ¼ 20 nM) was replaced with other amine groups (103a, IC50 ¼ 40 nM), while an alkyl or aryl substituent (103c IC50 ¼ 1 nM) showed improvement in potency due to the extremely high plasma protein binding. The phenyl core replacements with pyridines (103d, IC50 ¼ 10 nM) and pyrimidines (103e, IC50 ¼ 5 nM) led to a decrease in CYP2C9 activity as compared to triazine analog 103c. The preference for an electron withdrawing substituent on the benzyl ring is evident if one compares the activity for leads (103c) to analogs which contain electron donating groups such as methyl or methoxy (104b) that resulted in 2e3 order of magnitude loss in potency. Ortho substitution on the phenyl ring of the benzyl group

s-Triazine is a versatile building-block in many biologically active compounds and is found in many clinically used drugs such as altretamine, atrazine, melamine etc. Some new triazine-based drugs such as azacitidine, decitabine and metformin were also introduced recently in the market. In this article, we intended to review the comprehensive description of the biological and pharmacological properties of triazine scaffold based derivatives and highlight their role in new leads identification and drug discovery. This article is endeavoring to find potential future directions in the development of more potent and specific analogs of triazine-based compounds for various biological targets. It is believed that the information compiled in this article will not only update scientists with recent findings of biological activities of s-triazine but also encourage them to use this promising moiety for the design of novel molecules with enhanced medicinal properties, that are leading to new treatments and therapeutic agents for the benefit of humanity.

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Fig. 44. Epoxide hydrolase and cannabinoid CB2 ligands.

Acknowledgments K.P. thanks the SERC Fast Track Research Grant (SR/FT/CS-40/ 2010), Department of Science and Technology, New Delhi. PS is grateful for a DST/Inspire Fellowship (Fellow Code-IF110542).

CYP2C9 activity cytochrome P450 2C9 encoded by the CYP2C9 gene CB2 Cannabinoid receptors hCB1 human cannabinoid 1 PET positron emission tomography References

Abbreviations PI3Ks class I phosphatidylinositol 3-kinases mTOR mammalian target of rapamycin ZSTK474 2-(Difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5triazin-2-yl]-1H-benzimidazole ATP Adenosine triphosphate DNA Deoxyribonucleic acid clog P calculated lipophilicity Val851 valine851 Hdac Histone deacetylases TPH1 tryptophan hydroxylase 1 KI Inhibition constant H4R histamine H4 receptor SAR structure activity relationship DAP 2,3-diaminopyridine rRNA ribosomal ribonucleic acid DIPOD 40 -((6-(4-(diethylamino) phenyl)-1,3,5-triazine-2,4 diyl) bis(oxy)) dibenzaldehyde HIV-1 human immunodeficiency virus 1 HAART highly active antiretroviral therapy DAPY diarylpyrimidine analogs AIDS acquired immune deficiency syndrome nM nanomolar Fc crystallizable fragments IgG immunoglobulin PDE4 inhibitors phosphodiesterase-4 inhibitors PTR1 gene pteridine reductase MCP-1 Monocyte Chemotactic Protein-1 CETP cholesteryl ester transfer protein THP-1 human monocytic cell line CE cholesteryl ester HDL high density lipoprotein LDL low density lipoprotein TG triglyceride AR adenosine receptor

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