Recent developments in biological activities of indanones

European Journal of Medicinal Chemistry 138 (2017) 182e198

Contents lists available at ScienceDirect

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

Review article

Recent developments in biological activities of indanones Siddappa A. Patil a, **, Renukadevi Patil b, Shivaputra A. Patil b, * a

Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Kanakapura, Ramanagaram, Bangalore 562112, India Pharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 April 2017 Received in revised form 17 June 2017 Accepted 20 June 2017 Available online 21 June 2017

Indanone is one of the privileged structures in medicinal chemistry and it's commonly associated with various pharmacologically active compounds. The indanone moiety is found in several natural compounds and also, it can be used as intermediate in the synthesis of many different types of medicinally important molecules. Among the medicinally important indanones, the most significant drug probably is donepezil (IV), an acetylcholinesterase (AChE) inhibitor, which has been approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Along with donepezil, the indanone moiety can be seen in a number of other pre-clinical and clinical candidates which belong to different categories with diverse therapeutic activities. In summary, the present review article encompasses the recent biological applications such as antialzheimer, anticancer, antimicrobial and antiviral activity of various indanone derivatives. © 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Antialzheimer Anticancer Antimicrobial Antiviral Indanone Pharmaceutical agent

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Pharmacological activities of the indanone analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 3.1. Indanones as antialzheimer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 3.2. Indanones as anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.3. Indanones as antimicrobial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 3.4. Indanones as antiviral agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Conclusion and future aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

1. Introduction Indanone is one of the privileged structures in medicinal chemistry and is commonly associated with various

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (S.A. Patil), shivaputra.patil@ rosalindfranklin.edu (S.A. Patil). http://dx.doi.org/10.1016/j.ejmech.2017.06.032 0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.

pharmacologically active compounds. Indanones have demonstrated a broad spectrum of biological activity. Moreover, they are very useful synthons for the synthesis of various carbocyclic and heterocyclic molecules as synthetic intermediates for several drugs and natural products [1e8]. Their important biological activities include antiinflammatory [9e13], analgesic [14], antimicrobial [15,16], anticholinergic [17,18], dopaminergic [19], anticancer [20] and antimalarial [21] activities. The indanone moiety is present in various bioactive natural products. The important natural products

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

Abbreviations AD AChE BChE BACE1 SAR HDACs ACh IC50 MAO-B BBB mM nM GI50

Alzheimer's disease Acetylcholinesterase Butylcholinesterase b-Site amyloid precursor protein cleaving enzyme 1 Structure-activity relationship Histone deacetylases Acetylcholine Half maximal inhibitory concentration Monoamine oxidases B Blood brain barrier Micromolar Nanomolar The concentration of drug to cause 50% reduction in proliferation

such as 1-methoxy-6-methyl-3-oxo-2,3-dihydro-1H-indene-4carbaldehyde (I) and Pterosin B (II) were isolated from marine cyanobacterium and Pteris ensiformisburm (Fig. 1) [22,23]. Another important natural product having the indanone ring system is a potential anti-viral polyphenolic derivative Paucifloral F (III) (Fig. 1) and its isomer isopaucifloral F is a potential anti-osteoporosis agent [24,25]. Because of the biological importance of the indanone core, past several years researchers have produced library of pharmacologically active indanones. Very recently, our laboratory reported the novel indonone analogs as antiviral and antimicrobial agents [26,27]. Among them the most significant drug that bears an indanone moiety is probably donepezil (IV), an acetylcholinesterase (AChE) inhibitor, which has been approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Along with donepezil, the indanone moiety can be noticed in a number of other pharmacologically active molecules that belong to different categories with diverse therapeutic activities [28e32] (Fig. 1).

S. aureus Staphylococcus aureus E. coli Escherichia coli K. pneumonia Klebsiella pneumonia A. baumannii Acinetobacter baumannii P.aeruginosa Pseudomonas aeruginosa C. albicans Candida albicans C. neoformans Cryptococcus neoformans A. clavatus Aspergillus clavatus B. subtilis Bacillus subtilis M. luteusgenes Micrococcus luteusgenes L. Monocytogenes Listeria monocytogenes A. Niger Aspergillus niger T. mentagrophites Trichophyton mentagrophites RBV Ribavirin

Fig. 2. 1-Indanone thiosemicarbazone derivatives.

Fig. 1. Pharmacologically active important natural and unnatural products bearing indanone moiety.

183

184

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

Inspired by the success of donepezil several academic and industrial laboratories commenced the active research to develop novel indone analogs as therapeutic agents. This article reviews synthesis and biological activities of important indanone derivatives as antialzheimer, anticancer, antimicrobial and antiviral agents. In addition, we have also tabulated important patents on indanones in the supporting information (Table S1).

for the total synthesis of (7b-9ab)-1,4-dichloro-2-hydroxygibba1(10a),2,4,4b-tetraen-6-one [43]. 2-Indanone was used for the synthesis of indenochromones and indeno-thiochromone [44]. Very recently, Tang et al. have reported the synthesis of enantiomerically pure (þ)-isopaucifloral F [45].

2. Chemistry

Indanone is considered as privileged scaffold in drug discovery and development and it has been featured in a number of pharmacologically active agents. In view of this, the present review provides a comprehensive overview of current developments of indanone based compounds as potent antialzheimer, anticancer, antimicrobial and antiviral agents in the following sections.

Over the years, a considerable amount of effort has been made to synthesize biologically active indanones. The literature survey revealed that various methods have been developed for the synthesis of indanones [33e37]. Indanone and its derivatives can be used as useful intermediates in the synthesis of (R) and (S)2ehydroxyeindanone [38], 6-substituted 3,4-benzotropolones [39], dimer of 2-(4-pyridylmethyl)-1-indanone [40], biphenylcarboxylic acid indanones [41] and 1-indanone thiosemicarbazone derivatives [42]. The critical intermediate 4-chloro2-(2-fluoroethyl)-5-methoxy-2,3-dihydro-1H-inden-1-one used

3. Pharmacological activities of the indanone analogs

3.1. Indanones as antialzheimer agents Alzheimer's disease (AD) is age related incurable neurodegenerative disease and most common form of dementia. Its prevalence is estimated to rise up to 130 million by 2050 [46e49]. Aging

Scheme 1. 5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl-1-benzylpiperidine-4-carboxylate.

Scheme 2. Synthesis of 4-amino substituted indanone analogs.

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

population expected to rise in the USA and worldwide, thus age dependent AD represents very serious economic and medical challenge to the society [50]. Over the past decades, a great amount of research has been focused on deciphering the fundamental mechanisms of AD. We have seen a dramatic change in AD drug development in recent years. Remarkable progress has been made in the treatment of AD with the advent of tacrine, rivastigmine, and galantamine [51e53] along with most important indanone class of drug, donepezil (IV) [54e56]. Despite the progress in AD treatment, there are no drugs or treatment that could entirely cure AD, therefore, there is still a strong demand for the discovery and development of novel drugs

185

for complete cure. Recently, researchers from academia as well as pharmaceutical industries are trying to find new drugs with novel chemical entities that affect the underlying disease process. Although AD pathogenesis is complex and multiple factors such as b-amyloid (Ab), tau-protein, oxidative stress and low levels of acetylcholine (ACh) are likely to play vital roles in the development of AD. Among these factors, the most important one is cholinergic hypothesis [57,58] that postulates the cognitive decline which can be linked to a decrease in the amount of the neurotransmitter acetylcholine. The enzyme acetylcholinesterase (AChE) regulates ACh levels in the brain and it also been shown to bind to Ab and play a role in the formation of Ab plaques [59]. Majority of

Scheme 3. Synthesis of benzylpiperidine substituted indanone analogs.

Scheme 4. Synthesis of phenylmethyl-piperazine substituted indanone analogs.

186

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

preclinical and clinical indication points towards a diseasemodifying role by the marketed AChE inhibitors. In an effort to identify the novel potent AChE inhibitor Greunen et al. [60] designed and prepared a series of donepezil based derivatives as acetylcholinesterase inhibitors. Their detailed structure-activity relationship (SAR) study revealed that the piperidine ring system with reversed ester linker contributed the best results. Their molecular modelling studies with new analogs using crystal structures (pdb IDs: 4EY7 and 1EVE) well correlated with activities obtained. Their study provided the very potent acetylcholinesterase inhibitor 5,6-dimethoxy-1-oxo-2,3-dihydro1H-inden-2-yl-1-benzylpiperidine-4-carboxylate (3) (IC50 ¼ 0.03 ± 0.07 mM) and it exhibited selectivity towards SHSY5Y cell line (IC50 ¼ >100 mM) (Scheme 1). The modification of existing drugs is an important approach in

the development of new agents in drug discovery. Stimulated by
lık et al. [61] synthesized 38 novel indanone anthis approach Sag alogs based on donepezil and examined their inhibitory activity towards cholinesterase enzymes (AChE and BChE). The detailed SAR of all these analogs identified a new anticholinesterase agent, compound (5a) (IC50 ¼ 0.2197 ± 0.06 mM) (Scheme 2). Costanzo et al. [62] designed and developed eco-friendly synthetic method for the synthesis of donepezil derivatives (Scheme 3). Their synthetic method uses a green ultrasound assisted condensation of the indanone nucleus and N-benzylpiperidine-4carboxaldehyde derivatives. They screened all the newly synthesized compounds for the enzymatic inhibition on AChE and BuChE and b-Site amyloid precursor protein cleaving enzyme 1 (BACE-1) activities along with the cell viability in SHSY-5Y neuroblastoma cells. Their SAR revealed that compounds (8a)

Scheme 5. Synthesis of benzylideneindanone derivatives.

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

(IC50 ¼ 0.058 ± 0.033 mM) and (8b) (IC50 ¼ 0.043 ± 0.007 mM) exhibited the greatest inhibitory activity on AChE and were about two orders of magnitude more selective for AChE than BuChE. These compounds also displayed the highest inhibition activity towards BACE-1. The selectivity in cholinesterase inhibition and the effect on BACE-1 activity indicates that these two compounds could be developed as dual inhibitors for AD treatment. In continuation of their work on the development of new molecules as potential drug candidates for AD Rampa's research group [63] identified the compound (10a) (IC50 ¼ 2.49 ± 0.08 mM), bearing the bulky bis(4-fluorophenyl)methyl)piperazine substituent, as the most potent BACE1 inhibitor (Scheme 4). All the compounds were screened against human recombinant AChE (hAChE) and human recombinant BACE1 (hBACE1) and screening results produced the compound (8b) as potent BACE1 inhibitor. Their detailed SAR studies revealed that increasing the size of the amine backbone would also increase the inhibitory activity on BACE1, while decreasing the potency on AChE. Later Rampa's research group has been involved in developing dual-binding AChE inhibitors that simultaneously inhibit AChE and AChE-induced Ab aggregation [64]. In extension of their work on the development of novel indanone hybrids bearing a pharmacophoric fragment of AP2238, they designed and synthesized new indanone analogs based on donepezil and AP2238. They evaluated the new analogs for the inhibitory activity against AChE along with the inhibition of AChE-induced Ab aggregation [65]. All novel indanone hybrids have been screened for their inhibitory activity against AChE and they found a highly potent compound (10b) (IC50 ¼ 0.18 ± 0.02 mM). Indanone hybrid (compound 10c) with a 5carbon alkyl chain, remarkably improved the inhibition of AChEinduced Ab aggregation (46.8 ± 2.0%). One molecule, multiple targets paradigm stimulated the interest of Li research group [66] to design and synthesize new indanone analogs as multi-target-directed ligands towards AD. Their initial research efforts have identified highly potent both AChE inhibitor (compound A) [67], and Ab aggregation inhibitor (compound B), [68]. The compound A, piperidine group linked to indone ring by a two-carbon spacer, demonstrated highest potency towards AChE

187

inhibition (IC50 ¼ 0.0018 mM) and it is almost 14-fold more potent than the clinical drug donepezil. The compound B, benzylideneindanone derivative had displayed greatest inhibitory potency toward self-induced Ab aggregation (80.1%, 20 mM). Additionally, this compound shown monoamine oxidases B (MAO-B) inhibition (IC50 ¼ 7.5 mM) along with excellent antioxidant property. They wanted to rationally combine the functionalities of these two molecules (A and B) to obtain the multi-target-directed indanones. Thus, following the one molecule, multiple targets idea, they designed and synthesized new series of indanones. Their detailed SAR produced two new indanones (compounds 13a and 13b) as potent multi-functional anti-AD agents (Scheme 5). Both compounds exhibited higher inhibitory activity towards AChE (13a:

Scheme 7. Synthesis of donepezil-tacrine hybrids.

Scheme 6. Synthesis of hydrazinonicotinamide substituted indanone analogs.

188

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

IC50 ¼ 14.8 nM and 13b: IC50 ¼ 18.6 nM) and Ab aggregation activity (13a: 85.5% and 13b: 83.8%). More interestingly both compounds (13a and 13b) can cross the blood brain barrier (BBB) in vitro. Following the above principle Bukhari et al. [69] prepared three new indanone derivatives along with a,b-unsaturated carbonyl analogs using a simple and eco-friendly method. All three analogs found to be inactive towards both acetylcholinesterase (IC50 ¼ >100 mM) and butylcholinesterase (IC50 ¼ >100 mM) but their study identified interesting a,b-unsaturated carbonyl analogs as anti-AD agents instead of indanone analogs. With the aim of identifying the active cholinesterase inhibitors _ Zurek et al. [70] prepared Donepezil-hydrazinonicotinamide hybrids by the reaction of indanone derivatives and the hydrazine nicotinated moiety. All the compounds were screened for their anticholinesterase activities and most of the compounds were demonstrated higher affinity to AChE than for BChE. Among the all hybrid molecules, N-{5-[2-(4-benzylpiperidin-1-ylmethyl)-1oxoindan-5-yloxy]-pentyl}-6-hydrazinonicotinamide hydrochloride (19a) was most effective and selective inhibitor of acetylcholinesterase (IC50 ¼ 1.087 mM) (Scheme 6). Camps et al. [71,72] designed and synthesized a novel series of donepezil-tacrine hybrids as AChE inhibitors (Scheme 7). All newly prepared hybrids have been screened for acetylcholinesterase, butylcholinesterase, and AChE-induced Ab aggregation. They demonstrated high potency towards bovine and human AChE and

BChE. The compound (21a) turned out be the most potent analog among the series (bAChE: IC50 ¼ 90 pM and hAChE: IC50 ¼ 270 nM) and it binds well in the catalytic site of hAChE. Similarly Alonso et al. [73] reported a new series of donepeziletacrine hybrids as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. With the goal of identifying novel indanone analogs as AChE inhibitors Ali research group [74] reported the synthesis of substituted phenyl-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2indenylmethanone derivatives. They screened all newly prepared analogs for AChE inhibition. They observed moderate to high AChE inhibitory activities within the small set of indanones, and 5,6dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4,5trimethoxyphenylmethanone (23a) turned out be the best inhibitor of AChE (IC50 ¼ 2.7 ± 0.01 mM) (Scheme 8). Zhang et al. [75] developed the dual-binding-site acetylcholinesterase (AChE) inhibitor, a indanone analog (BZYX) to examine the cognition-enhanced, anticholinesterase, and neuroprotective effects. This compound demonstrated the comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO2 and ethanol, respectively and it displayed high inhibition on AChE activity (IC50 ¼ 0.058 ± 0.022 mM). Sheng et al. [76] were also developed dual-site binding indanone based AChE inhibitors. All newly synthesized indanone

Scheme 8. Synthesis of indenylmethanone analogs.

Scheme 9. Synthesis of aminomethyl-benzylidene subsituted indanone analogs.

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

analogs were screened for the ChE inhibitory activities in vitro and majority of indanones were demonstrated selective inhibition towards AChE whereas almost no activities were observed against BChE. Intermediate indanone derivative (25a) displayed high potency towards AChE (IC50 ¼ 0.035 mM) and very interestingly this compound improved the memory deficits induced by scopolamine in mice by step-down passive avoidance test (Scheme 9). Their docking studies demonstrated that it was very well accommodated by AChE.

189

The same group previously reported [77] 2-phenoxy-indan-1one derivatives as acetylcholinesterase inhibitors. Their SAR identified compound 27a as the most potent towards AChE inhibitory activity (IC50 ¼ 50 nM) (Scheme 10). This high inhibitory activity prompted them to perform molecular docking study to understand the ligandeprotein interactions. The molecular docking study indicated that it was nicely accommodated by AChE. Diagnostically, imaging has played a vital role in AD and is an established tool in drug discovery. Zhou research group [78,79]

Scheme 10. Synthesis of 2-phenoxy-indanone analogs.

Scheme 11. Synthesis of (E)-5-iodo-6-methoxyl-2-(4-(dimethylamino)benzylidene)indan-1-one.

Scheme 12. Synthesis of 3-aryl and heteroaryl substituted indaone analogs.

190

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

successfully designed and synthesized a new series of indanone derivatives as potential imaging probes for the in vivo imaging of AD brain amyloid plaques. Compound [125I] (30) showed an excellent initial uptake in brain and a rapid clearance from the brain (Scheme 11). Very interestingly, [125I] (30) has shown the capacity of binding to Ab deposits in living transgenic mouse brain in the ex vivo.

3.2. Indanones as anticancer agents Cancer is a complex class of diseases characterized by abnormal cells that grow in the body. Cancer is the second leading cause of death globally and it remains a major threat to people's health [80]. Nowadays, different types of methods have been used to recognize cancer cells, such as biosensors [81], microfluidic devices [82], immunocytochemistry [83] and electrochemical methods [84]. There are various classes of compounds have been used for the treatment of this lethal disease. In the midst of diverse known moieties, indanone based compounds are known to have significant cytotoxic effect. Numerous indanone based anti-proliferative compounds have been developed by various research groups across the globe. Novel indanones analogs (32) and (34) were synthesized by

Bałczewski research group using Nazarov cyclization in the final step in moderate to good yields (Scheme 12) [85]. All final indanone derivatives along with intermediates were screened for in vitro cytotoxic activity towards HeLa and K562 cell lines. Their detailed SAR identified the final indonone analog (34a) as the most potent anticancer agent and it demonstrated significant activity against HeLa and K562 cancer cells with half maximal inhibitory concentration (IC50) values of 60 mM and 10 mM, respectively. Negi research group [86,87] designed and synthesized a series of benzylidene indanones (37a-g) and evaluated them for their in vitro anticancer activity against a panel of human cancer cell lines (Scheme 13). Compound 37a with 4-nitro group and compound 37e with 4-carboxylic ester showed good cytotoxicity towards MCF7 cell line with IC50 values of 4 mM and 24 mM, respectively. On the other hand, compound 37f with a 4-carboxylic acid group exhibited weak cytotoxicity of IC50 value 48 mM towards the same cell line. Furthermore, high cytotoxicity has been observed (IC50 values < 10 mM) for several compounds 37a, 37c, 37e, and 37f. However, the best compound of the series, compound 37a, exhibited highest cytotoxicity towards all the cell lines with IC50 values in the range 3e10 mM. In their previous studies on gallic acid-based indanone derivatives they reported the detailed SAR and anticancer effects of

Scheme 13. Synthesis of benzylidene indanones.

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

novel lead indanone derivatives (compounds 38 and 39) [88e90]. Compound 38 exhibited effective cytotoxicity (IC50 ¼ 0.010 mM) towards numerous human carcinoma cells. In cell cycle analysis the compound 38 induced G2/M phase arrest in both MCF-7 and MDAMB-231 cells. In sub-acute toxicity experiments compound 38 did not show toxicity up to 100 mg/kg dose for 28 days. Their other lead compound 39 demonstrated nice cytototxicity towards MCF-7 cell line (IC50 ¼ 2.2 mM) and it inhibited tubulin polymerization (IC50 ¼ 1.88 mM). The compound 39 was inferior to the 2benzylidene indanone analog (compound 38) in terms of in vitro and in vivo activities. Hu and co-workers [91] designed and synthesized a series of new benzylideneindanone derivatives (42a-i) and (44a-e) and evaluated them for anticancer activity in vitro (Scheme 14). Compound 42a contains hydroxyl moiety showed high potent inhibitory activity, with GI50 values from 0.17 to 0.57 mM towards five cancer cell lines. Additional study confirmed that compound 42a could effectively inhibit the microtubule polymerization and induces G2/M phase arrest and apoptosis in A549 cells. In an effort to identify the histone deacetylases (HDACs) inhibitors, a series of indanone derivatives have been synthesized by Bertrand and co-workers [92]. All the synthesized indanone analogs (46 and 47) were screened towards non-small lung cancer cell line H661tumour cells (Scheme 15). Two alkyl substituted compounds 46c and 47c showed moderated activity (IC50 ¼ 20 mM). Shih et al. [93] synthesized 5,6-dimethoxy-1-indanone derivatives (48 and 50) and evaluated for their cytotoxicity against Jurkat cell line (Scheme 16). Their detailed SAR identified a very potent compound, indanocine 50a with IC50 value 1.0 nM. Indanocine interacts with tubulin at the colchicine-binding site, potently inhibits tubulin polymerization in vitro and induces apoptotic cell death in multidrug resistant cell lines (MCF-7/ADR, MES-SA/DX5, and HL-60/ADR) [94]. Their detailed biological study suggests that indanocine could be developed as chemotherapeutic agent for drug-resistant malignancies.

191

3.3. Indanones as antimicrobial agents An agent that destroys micro-organisms growth or kills microorganisms is called an antimicrobial agent. The fast development of microbial resistance to the present spectrum of antimicrobial drugs emphasises the development of new antimicrobial agents. Heterocyclic compounds bearing indanone moiety have drawn considerable attention over the last few years due to their valuable antimicrobial activities. Indanone bearing antimicrobial agents are shown in Schemes 17e19. In an effort to identify new indanones as antimicrobial agents, very recently, we have reported the synthesis and antimicrobial evaluation of series of new indanone derivatives (52a-g) (Scheme 17) [27]. Preliminary in vitro antibacterial evaluation was accomplished for all the synthesized compounds against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Klebsiella pneumonia (K. pneumonia), Acinetobacter baumannii (A. baumannii),

Scheme 15. Synthesis of 2-substituted indanone analogs.

Scheme 14. Synthesis of benzylideneindanone derivatives.

192

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

Scheme 16. Synthesis of 5,6-dimethoxy-1-indanone derivatives.

Scheme 17. Synthesis of 5,6-dimethoxy-1-indanone derivatives.

Pseudomonas aeruginosa (P.aeruginosa), Candida albicans (C. albicans) and Cryptococcus neoformans (C. neoformans) through whole cell growth inhibition assays. All the compounds (52a-g) have shown medium to good antibacterial activity against gram-positive

bacteria S. aureus and the two gram-negative bacteria E. coli and P. aeruginosa. Weak to medium antibacterial activity was observed for the compounds (52a-g) against gram-negative bacteria K. pneumonia. In contrast, compounds (52a-g) did not show

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

193

Scheme 18. Synthesis of derivatives of 5,6-dimethoxy-1-indanone coupled with substituted pyridine.

Scheme 19. 1-Indanone thiosemicarbazone derivatives.

antimicrobial activity against gram-negative bacteria A. Baumannii and the two fungi: C. albicans and C. Neoformans. Patel et al. synthesized several novel derivatives of 5,6dimethoxy-1-indanone coupled with substituted pyridine (Scheme 18) and evaluated them for antimicrobial activity through agar disc-diffusion method towards Gram-positive bacteria S. aureus, Streptococcus pyogenes (S. pyogenes) and Gram negative bacteria including E. coli, P. aeruginosa and yeast including C. albicans and fungi Aspergillus clavatus (A. clavatus) [95]. Their structure-activity relationship studies revealed that the compounds (56c), (56d), (56i) and (56k) demonstrated good antibacterial activity whereas compounds (56c), (56h), (56i) and (56j) emerged as the best antifungal agents. 1-Indanone thiosemicarbazone derivatives (59a-c) synthesized by Brousse et al. were evaluated for antimicrobial activity (Scheme 19) [96]. All the compounds (59a-c) have shown weak to medium antibacterial activity against Bacillus subtilis (B. subtilis), E. coli, Micrococcusluteusgenes (M. luteusgenes), Listeria monocytogenes (L. Monocytogenes), P. aeruginosa and S. aureus. On the other hand strong antifungal activity was observed against C.albicans, Aspergillus niger (A. Niger), Trichophyton mentagrophites (T. mentagrophites) and Mucor sp. by 1-indanone thiosemicarbazone derivatives (59a-c). 3.4. Indanones as antiviral agents Viral infection continues to threaten human life globally. Discovery of novel small molecules as antiviral agents is always the top

priority for medicinal chemists. Small number of antiviral drugs available for the treatment of life threatening viral diseases such as HIV and hepatitis are available but their efficacy is very limited. Therefore, the design and development of highly potent and selective antiviral drug candidates is one of the primary reasons of the modern drug discovery and development research. In an effort to develop new efficacious antiviral drug candidates for hepatitis C virus (HCV), Sosnik research group [97e99] identified 1-indanone thiosemicarbazones (TSCs) with hydroxypropyl-b-cyclodextrin as best antiviral agents. The details about the design and synthesis of various thiosemicarbazones have been described by Brousse et al. [100e102]. The low aqueous solubility and high self-aggregation tendency of thiosemicarbazones prevent their reliable biological evaluation in vitro even though they have demonstrated antiviral activity against a wide range of DNA and RNA viruses. TSC1 (60) and TSC2 (61) (Fig. 2) with hydroxypropyl-b-cyclodextrin (HPb-CD) complexes showed more physically stable than free TSCs (60 and 61) that precipitated rapidly in the culture medium. Authors compared TSC1 (60) and TSC2 (61) and their inclusion complexes with hydroxypropyl-b-cyclodextrin (HPb-CD) in Huh-7.5 cells. Their study revealed that free TSCs demonstrated remarkable antiHCV activity whereas complexes have shown moderate declines than the free TSCs. They showed that the TSC1 improves its activity against a Hep C surrogate model (bovine viral diarrhea virus BVDV). BVDV is an easy cultivable virus and one of the best characterized members of the Pestivirus genus. The genomic organization, translation, replication pathway and protein functions of

194

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

Table 1 Biological activities of lead indanone analogs identified in each series. I: Antialzheimer lead indanones S. No.

Structure of leads

S. No.

1.

2

3.

4.

5.

6.

7.

8.

9.

10.

11.

II: Anticancer lead indanones 12.

13.

Structure of leads

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

195

Table 1 (continued ) I: Antialzheimer lead indanones S. No.

Structure of leads

14.

S. No.

Structure of leads

15.

III: Antimicrobial lead indanones 16.

17.

IV: Antiviral lead indanones 18

pestiviruses is very closely resembles with HCV. Thus, Castro et al. [103] demonstrated that TSC1 (60) inhibited BVDV replication in cell culture synergistically with ribavirin (RBV), this synergic activity could be utilized for the combination therapies to combat HCV replication.

19

Conflict of interests The authors declare that there is no conflict of interests regarding the publication of this paper. Acknowledgment

4. Conclusion and future aspects With the advent of acetylcholinesterase (AChE) inhibitor a novel indanone analog, donepezil as therapeutic agent for the treatment of Alzheimer patients invigorated the several research groups to develop new indanone derivatives as antialzheimer agents. Various substituted indanones have been mainly developed based on the structure of donepezil and have shown excellent antialzheimer activity in vitro. In addition to this, various indanone based compounds have been developed as anticancer, antimicrobial and antiviral agents. Several indanone derivatives demonstrated significant cytotoxic effect in different cancer cell lines including few resistant cell lines. Recent efforts have also been made to develop antimicrobial and antiviral indanones by researchers working in the field. The future research will continue to identify new therapeutic indanone derivatives using drug design and discovery process. The therapeutic usefulness of highly potent and selective indanone analogs (Table 1) from the present review have suggested that several leads could be further developed as potential drug candidates whereas others may serve as motivation to develop new effective therapies for the disease of interest such as alzheimer, cancer, fungal, bacterial and viral infections.

Siddappa Patil thanks DST-SERB, India (SERB/F/7013/2015-16), DST-Nanomission, India (SR/NM/NS-20/2014), and Jain University, India for financial support. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmech.2017.06.032. References [1] C. Wu, H. Nakamura, A. Murai, S. Inouye, Chemical studies on the chiral indanonederivativesas the inhibitor of Renilla luciferase, Tetrahedron 57 (2001) 9575e9583. [2] D.J. Kerr, E. Hamel, M.K. Jung, B.L. Flynn, The concise synthesis of chalcone, indanone and indenone analogues of combretastatin A4, Bioorg. Med. Chem. 15 (2007) 3290e3298. [3] R. Bansal, G. Narang, C. Zimmer, R.W. Hartmann, Synthesis of some imidazolyl-substituted 2-benzylidene indanone derivatives as potent aromatase inhibitors for breast cancer therapy, Med. Chem. Res. 20 (2011) 661e669. [4] A.J. Byrne, J.W. Barlow, J.J. Walsh, Synthesis and pharmacological evaluation of the individual stereoisomers of 3-[methyl(1,2,3,4-tetrahydro-2naphthalenyl)amino]-1-indanone, a potent mast cell stabilizing agent, Bioorg. Med. Chem. Lett. 21 (2011) 1191e1194.

196

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

[5] V.M. Patel, N. Bhatt, P. Bhatt, H.D. Joshi, Synthesis and pharmacological evaluation of novel 1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one derivatives as potential antimicrobial agents, Med. Chem. Res. 23 (2014) 2133e2139. [6] H. Schumann, O. Stenzel, F. Girgsdies, (e)-2-Menthylindenyl and (e)-2menthyl-4,7-dimethylindenyl complexes of rhodium, iridium, cobalt, and molybdenum, Organometallics 20 (2001) 1743e1751. [7] M.N. Herzog, J.C.W. Chien, M.D. Rausch, Novel 2-indenyl ansa-zirconocenes for the polymerization of a-olefins, J. Organomet. Chem. 654 (2002) 29e35. [8] L.M. Leoni, E. Hamel, D. Genini, H. Shih, C.J. Carrera, H.M. Cottam, D.A. Carson, Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug resistant cancer cells, J. Natl. Cancer Inst. 92 (2000) 217e224. [9] V.S. Saravanan, P.S. Selvan, N. Gopal, J.K. Gupta, Synthesis and pharmacological evaluation of some indanone-3-acetic acid derivatives, Asian J. Chem. 18 (4) (2006) 2597e2604. [10] W.C. Black, Li Chung-Sung, D. Guay, P. Prasit, P. Roy, Alkanesulfonamido-1indanone derivatives as inhibitors of cyclooxygenase, US patent 5409944, 1995. [11] M.R. Panara, A. Greco, G. Santini, M.G. Sciulli, M.T. Rotondo, R. Padovano, M. Giamberardino, F. Cipollone, F. Cuccurullo, C. Patrono, P. Patrignani, Effect of the novel anti-inflammatory compounds N-[2-(cyclohexyloxy)-4nitrophenyl] methansulfonamide (NS-398) and 5-methansulfonamido-6(2,4-diflurothiophenyl)-1-indanone (L-745,337), on the cyclo-oxygenase activity of human blood prostaglandin endoperoxidesynthases, Br. J. Pharmacol. 116 (1995) 2429e2434. [12] Li Chung-Sung, W.C. Black, C.C. Chan, A.W. Ford-Hutchison, J.Y. Gauthier, R. Gordon, D. Guay, S. Kargman, C. K. Lau, J. Mancini, N. Ouimet, P. Roy, P. Vickers, E. Wong, R.N. Young, R. Zamboni, P. Prasit, Cyclooxygenase-2inhibitors. Synthesis and pharmacological activities of 5methanesulfonamido-1-indanone derivatives, J. Med. Chem. 38 (1995) 4897e4905. [13] M.L. Tang, C. Zhong, Z.Y. Liu, P. Peng, X. Sun, Discovery of novel sesquistilbene indanone analogues as potent anti-inflammatory agents, Eur. J. Med. Chem. 113 (2016) 63e74. [14] P.D. Hammen, G.M. Milne, 2-Aminomethyleneindanone Analgesic Agents, US Patent 4164514, 1979. [15] R. Albrecht, H.J. Kessler, E. Schroder, Antimicrobial Indanones, US Patent 3671520, 1972. [16] L.M. Finkieisztein, E.F. Castro, L.E. Fabian, G.Y. Moltrasio, R.H. Campos, L.V. Cavallaro, A.G. Moglioni, New 1-indanone thiosemicarbazone derivatives active against BVDV, Eur. J. Chem. 43 (2008) 1767e1773. [17] Z. Omran, T. Cailly, E. Lescot, J.S. Santos, J.H. Agondanou, V. Lisowski, F. Fabis, A.M. Godard, S. Stiebing, G. LeFlem, M. Boulouard, F. Dauphin, P. Dallemagne, S. Rault, Synthesis and biological evaluation as AChE inhibitors of new indanones and thiaindanones related to donepezil, Eur. J. Med. Chem. 40 (2005) 1222e1245. [18] R. Sheng, Yu-Xu, H. Chunqi, Z. Jing, L. Xiao, L. Jingya, B. Yang, Q. He, Y. Hu, Design, synthesis and AChE inhibitory activity of indanone and auronederivatives, Eur. J. Med. Chem. 20 (2008) 1e11. [19] R.D. Sindelar, J. Mott, C.F. Barfknecht, S.P. Arneric, J.R. Flynn, J.P. Long, R.K. Bhatnagar, 2-Amino-4,7-dimethoxyindan derivatives: synthesis and assessment of dopaminergic and cardiovascular actions, J. Med. Chem. 25 (7) (1982) 858e864. [20] N. Gomez, D. Santos, R. Vazquez, L. Suescun, A. Mombru, M. Vermeulen, L. Finkielsztein, C. Shayo, A. Moglioni, D. Gambino, C. Davio, Synthesis, structural characterization, and pro-apoptotic activity of 1-indanone thiosemicarbazone platinum(II) and palladium(II) complexes: potential as Antileukemic agents, Chem. Med. Chem. 6 (2011) 1485e1494. [21] J.E. Charris, G.M. Lobo, J. Camacho, R. Ferrer, A. Barazarte, J.N. Domínguez, N. Gamboa, J.R. Rodrigues, J.E. Angel, Synthesis and antimalarial activity of (E) 2-(2-chloro-3-quinolinylmethylidene)-5,7-dimethoxyindanones, Lett. Drug Des. Discov. 4 (2007) 49e54. [22] D.G. Shih, Y.D. Zhou, P.U. Park, V.J. Paul, I. Rajbhandari, C.J.G. Duncan, D. Pasco, A new indanone from the marine cyanobacterium Lyngbyamajuscula that inhibits hypoxia-induced activation of the VEGF promoter in Hep3B cells, J. Nat. Prod. 63 (2000) 1431e1433. [23] J.C.M. Van der Hoeven, W.J. Lagerweij, M.A. Posthumus, A. van Veldhuizen, H.A. Holterman, A. Aquilide, A new mutagenic compound isolated from bracken fern (Pteridiumaquilinum (L.) Kuhn), Carcinogenesis 4 (1983) 1587e1590. [24] Y. Yang, D. Philips, S. Pan, A concise synthesis of paucifloral F and related indanone analogues via palladium-catalyzed a-arylation, J. Org. Chem. 76 (2011) 1902e1905. [25] X.D. Hao, J. Chang, B.Y. Qin, C. Zhong, Z.B. Chu, J. Huang, W.J. Zhou, X. Sun, Synthesis, estrogenic activity, and anti-osteoporosis effects in ovariectomized rats of resveratrol oligomer derivatives, Eur. J. Med. Chem. 102 (2015) 26e38. [26] S.A. Patil, V. Patil, R. Patil, K. Beaman, S.A. Patil, Identification of novel 5,6dimethoxyindan-1-one derivatives as antiviral agents, Med. Chem. (2017), http://dx.doi.org/10.2174/1573406413666170330094822. [27] V. Patil, E. Barragan, S.A. Patil, S.A. Patil, A. Bugarin, Direct synthesis and antimicrobial evaluation of structurally complex chalcones, ChemistrySelect

1 (2016) 1e5. [28] H. Sugimoto, Structure-activity relationships of acetylcholinesterase inhibitors: donepezil hydrochloride for the treatment of Alzheimer's disease, Pure Appl. Chem. 71 (1999) 2031e2037. [29] L.M. Leoni, E. Hamel, D. Genini, H. Shih, C.J. Carrera, H.B. Cottam, D.A.J. Carson, Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-resistant cancer cells, Natl. Cancer Inst. 92 (2000) 217e224. [30] M. Wu, L. Li, A. Feng, B. Su, D. Liang, Y. Liu, Q. Wang, First total synthesis of Papilistatin, Org. Biomol. Chem. 9 (2011) 2539e2542. [31] D.R. Beukes, M.T. Davies-Coleman, M. Kelly-Borges, M.K. Harper, D.J. Faulkner, Dilemmaones AC, unusual indole alkaloids from a mixed collection of South African sponges, J. Nat. Prod. 61 (1998) 699e701. [32] R. Galici, C.K. Jones, K. Hemstapat, Y. Nong, N.G. Echemendia, L.C. Williams, T. de Paulis, P.J. Conn, Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice, J. Pharmacol. Exp. Ther. 318 (1) (2006) 173e185. [33] R. Sheng, Y.X. Chunqi Hu, J. Zhang, X. Lin, J. Li, B. Yang, Q. He, Y. Hu, Design, synthesis and AChE inhibitory activity of indanone and aurone derivatives, Eur. J. Med. Chem. 44 (2009) 7e17. [34] A.M. Zawisza, B. Ganchegui, I. Gonzalez, S. Bouquillon, A. Roglans, F. Henin, J. Muzart, Heck-type reactions of allylic alcohols Part IV: (2-substituted)-1indanones via 5-endo-trig cyclizations, J. Mol. Catal. A Chem. 283 (2008) 140e145. [35] M. Turek, D. Szcze˛ sna, M. Koprowski, P. Bałczewski, Synthesis of 1-indanones with a broad range of biological activity, Beilstein J. Org. Chem. 13 (2017) 451e494. [36] A.K. Sharma, A.V. Subramani, C.B. Gorman, Efficient synthesis of halo indanones via chlorosulfonic acid mediated FriedeleCrafts cyclization of arylpropionic acids and their use in alkylation reactions, Tetrahedron 63 (2007) 389e395. [37] R.S. Senaiar, J.A. Teske, D.D. Young, A. Deiters, Synthesis of indanones via solid-supported [2þ2þ2] cyclotrimerization, J. Org. Chem. 72 (2007) 7801e7804. [38] H. Kajiro, S.-I. Mitamura, A. Mori, T. Hiyama, Enantioselective synthesis of 2hydroxy-1-indanone, a key precursor of enantiomerically pure 1-amino-2indanol, Tetrahedron Asymmetry 9 (1998) 907e910. [39] K. Iwaya, M. Tamura, M. Nakamura, E. Hasegawa, Novel transformation of 2substituted alkyl 1-indanone-2-acetates to 6-substituted 3,4benzotropolones through sequential reduction and oxidation processes using Sm(II) and Ce(IV) salts, Tetrahedron Lett. 44 (2003) 9317e9320. [40] R. Grupta, D.P. Jindal, B. Jit, G. Narang, A. Palusczak, R.W. Hartmann, Synthesis of evaluation of a dimer of 2-(4-pyridylmethyl)-1-indanone as a novel nonsteroidal aromatase inhibitor, Arch. Pharm. 337 (2004) 398e401. [41] C. Bonnefous, J.M. Vernier, J.H. Hutchinson, M.F. Gardner, M. Cramer, J.K. James, B.A. Rowe, L.P. Daggett, H. Schaffhauser, T.M. Kamenecka, Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor, Bioorg. Med. Chem. Lett. 15 (2005) 4354e4358. [42] L.M. Finkielsztein, E.F. Castro, L.E. Fabian, G.Y. Moltrasio, R.H. Campos, L.V. Cavallaro, A.G. Moglioni, New 1-indanone thiosemicarbazone derivatives active against BVDV, Eur. J. Med. Chem. 43 (2008) 767e1773. [43] J.P. Scott, M.S. Ashwood, K.M.J. Brands, S.E. Brewer, C.J. Cowden, U.H. Dolling, K.M. Emerson, A.D. Gibb, A. Goodyear, S.F. Oliver, G.W. Stewart, D.J. Wallace, Development of a phase transfer catalyzed asymmetric synthesis for an estrogen receptor beta selective agonist, Org. Process Res. Dev. 12 (2008) 723e730. [44] J.D. Townsend, A.R. Williams, A.J. Angel, A.E. Finefrock, C.F. Beam, Preparation of benz[b]indenon[1.2-e1pyran-11(6H)-ones and benz[b]indeno[1,2-e]thiopyran-l1(6H)-one from dilithiated 2-indanone and lithiated methyl salicylates or lithiated methyl thiosalicylate, Synth. Commun. 30 (2000) 689e699. [45] M.L. Tang, P. Peng, Z.Y. Liu, J. Zhang, J.M. Yu, X. Sun, Sulfoxide-based enantioselective Nazarov cyclization: divergent syntheses of (þ)-isopaucifloral F, (þ)-quadrangularin A and (þ)-Pallidol, Chem. Eur. J. 22 (2016) 14535e14539. [46] W. Thies, L. Bleiler, Alzheimer's association: alzheimer's disease facts and figures, Alzheimers Dement. 8 (2012) 131e168. [47] W. Thies, L. Bleiler, Alzheimer's disease: facts and figures, Alzheimer Dement. 9 (2013) 208e215. [48] R. Brookmeyer, E. Johnson, K. Ziegler-Graham, H.M. Arrighi, Forecasting the global burden of Alzheimer's disease, Alzheimer's dementia 3 (2007) 186e191. [49] H.W. Querfurth, F.M. LaFerla, N. Engl, J. Med. 362 (2010) 329e344. [50] I. Campbell-Taylor, Contribution of Alzheimer disease to mortality in the United States, Neurology 83 (2014) 1302. [51] J. Marksteiner, R. Schmidt, Treatment strategies in Alzheimer's disease with a focus on early pharmacological interventions, Drugs Aging 21 (2004) 415e426. [52] J. Meunier, J. Ieni, T. Maurice, The anti-amnesic and neuroprotective effects of donepezil against amyloid 25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor, Br. J. Pharmacol. 149 (2006) 998e1012. [53] D.G. Wilkinson, P.T. Francis, E. Schwam, J. Payne-Parrish, Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

[54]

[55] [56]

[57]

[58] [59]

[60]

[61]

[62]

[63]

[64] [65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

between pharmacological effects and clinical efficacy, Drugs Aging 21 (2004) 453e478. H. Sugimoto, Y. Yamanishi, Y. Iimura, Y. Kawakami, Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors, Curr. Med. Chem. 7 (2000) 303e339. E.A. Van der Zee, B. Platt, G. Riedel, Acetylcholine: future research and perspectives, Behav. Brain Res. 221 (2011) 583e586. Y. Kawakami, A. Inoue, T. Kawai, M. Wakita, H. Sugimoto, A.J. Hopfinger, The rationale for E2020 as a potent acetylcholinesterase inhibitor, Bioorg. Med. Chem. 4 (9) (1996) 1429e1446. M.P. Arce, M.I. Rodriguez-Franco, G.C. Gonzalez-Munoz, C. Perez, B. Lopez, M. Villarroya, M.G. Lopez, A.G. Garcia, S. Conde, Neuroprotective and cholinergic properties of multifunctional glutamic acid derivatives for the treatment of Alzheimer's disease, J. Med. Chem. 52 (2009) 7249e7257. P.J. Harrison, Pathogenesis of alzheimers-disease - beyond the cholinergic hypothesis - discussion paper, J. Roy. Soc. Med. 79 (1986) 347e352. G.V. De Ferrari, M.A. Canales, I. Shin, L.M. Weiner, I. Silman, N.C. Inestrosa, A structural motif of acetylcholinesterase that promotes amyloid betapeptide fibril formation, Biochemistry-Us 40 (2001) 10447e10457. D.G. van Greunen, W. Cordier, M. Nell, C. van der Westhuyzen, V. Steenkamp, J.L. Panayides, D.L. Riley, Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil, Eur. J. Med. Chem. 127 (2017) 671e690. €
lık, S. Ilgın, Y. Ozkay, B.N. Sag Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes, Eur. J. Med. Chem. 124 (2016) 1026e1040. P. Costanzo, L. Cariati, D. Desiderio, R. Sgammato, A. Lamberti, R. Arcone, R. Salerno, M. Nardi, M. Masullo, M. Oliverio, Design, synthesis, and evaluation of Donepezil-like compounds as AChE and BACE-1 inhibitors, ACS Med. Chem. Lett. 7 (5) (2016) 470e475. A. Rampa, F. Mancini, A. De Simone, F. Falchi, F. Belluti, R.M. Di Martino, S. Gobbi, V. Andrisano, A. Tarozzi, M. Bartolini, A. Cavalli, A. Bisi, From AChE to BACE1 inhibitors: the role of the amine on the indanone scaffold, Bioorg. Med. Chem. Lett. 25 (14) (2015) 2804e2808. S. Rizzo, A. Cavalli, L. Ceccarini, M. Bartolini, F. Belluti, A. Bisi, V. Andrisano, M. Recanatini, A. Rampa, Chem. Med. Chem. 4 (2009) 670e679. S. Rizzo, M. Bartolini, L. Ceccarini, L. Piazzi, S. Gobbi, A. Cavalli, M. Recanatini, V. Andrisano, A. Rampa, Targeting Alzheimer's disease: novel indanone hybrids bearing a pharmacophoric fragment of AP2238, Bioorg. Med. Chem. 18 (5) (2010) 1749e1760. L. Huang, H. Miao, Y. Sun, F. Meng, X. Li, Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer's disease, Eur. J. Med. Chem. 87 (2014) 429e439. F.C. Meng, F. Mao, W.J. Shan, F. Qin, L. Huang, X.S. Li, Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents, Bioorg. Med. Chem. Lett. 22 (13) (2012) 4462e4466. L. Huang, C. Lu, Y. Sun, F. Mao, Z. Luo, T. Su, H. Jiang, W. Shan, X. Li, Multitarget-directed benzylideneindanone derivatives: anti-b-amyloid (Ab) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease, J. Med. Chem. 55 (19) (2012) 8483e8492. S.N. Bukhari, I. Jantan, V.H. Masand, D.T. Mahajan, M. Sher, M. Naeem-ulHassan, M.W. Amjad, Synthesis of a, b-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid binduced cytotoxicity, Eur. J. Med. Chem. 83 (2014) 355e365.  ski, E. Mikiciuk-Olasik, Synthesis and biological activity of E. Zurek, P. Szyman new donepezil-hydrazinonicotinamide hybrids, Drug Res. (Stuttg) 63 (3) (2013) 137e144.  mez, D. Mun ~ oz-Torrero, P. Camps, X. Formosa, C. Galdeano, T. Go s, M. Bartolini, M. Scarpellini, E. Viayna, A. Badia, M.V. Clos, A. Camins, M. Palla F. Mancini, V. Andrisano, J. Estelrich, M. Lizondo, A. Bidon-Chanal, F.J. Luque, Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced b-amyloid aggregation, J. Med. Chem. 51 (12) (2008) 3588e3598.  mez, D. Mun ~ oz-Torrero, L. Ramírez, P. Camps, X. Formosa, C. Galdeano, T. Go mez, N. Isambert, R. Lavilla, A. Badia, M.V. Clos, M. Bartolini, E. Viayna, E. Go F. Mancini, V. Andrisano, A. Bidon-Chanal, O. Huertas, T. Dafni, F.J. Luque, Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates, Chem. Biol. Interact. 187 (2010) 411e415. ~ oz, E. García-Palomero, M. Del D. Alonso, I. Dorronsoro, L. Rubio, P. Mun Monte, A. Bidon-Chanal, M. Orozco, F.J. Luque, A. Castro, M. Medina, A. Martínez, Donepezil-tacrinehybrid related derivatives as new dual binding site inhibitors of AChE, Bioorg. Med. Chem. 13 (2005) 6588e6597. M.A. Ali, M.S. Yar, M.Z. Hasan, M.J. Ahsan, S. Pandian, Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4substituted phenyl methanone analogues, Bioorg. Med. Chem. Lett. 19 (2009) 5075e5077. J. Zhang, D. Zhu, R. Sheng, H. Wu, Y. Hu, F. Wang, T. Cai, B. Yang, Q. He, BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicalsinduced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide, Eur. J. Pharmacol. 613 (2009) 1e9. R. Sheng, Y. Xu, C. Hu, J. Zhang, X. Lin, J. Li, B. Yang, Q. He, Y. Hu, Design,

[77]

[78]

[79]

[80] [81]

[82] [83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

197

synthesis and AChE inhibitory activity of indanone and aurone derivatives, Eur. J. Med. Chem. 44 (2009) 7e17. R. Sheng, X. Lin, J. Li, Y. Jiang, Z. Shang, Y. Hu, Design, synthesis, and evaluation of 2-phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors, Bioorg. Med. Chem. Lett. 15 (2005) 3834e3837. J.P. Qiao, C.S. Gan, C.W. Wang, J.F. Ge, D.D. Nan, J. Pan, J.N. Zhou, Novel indanone derivatives as potential imaging probes for ss-amyloid plaques in the brain, Chem. Bio. Chem. 13 (2012) 1652e1662. D.D. Nan, C.S. Gan, C.W. Wang, J.P. Qiao, X.M. Wang, J.N. Zhou, 6-Methoxyindanone derivatives as potential probes for b-amyloid plaques in Alzheimer's disease, Eur. J. Med. Chem. 124 (2016) 117e128. M. Dobbelstein, U. Moll, Targeting tumor-supportive cellular machineries in anti-cancer drug development, Nat. Rev. Drug. Disc. 13 (2014) 179e196. W. Shan, Y. Pan, H. Fang, M. Guo, Z. Nie, Y. Huang, S. Yao, An aptamerbasedquartz crystal microbalance biosensor for sensitive and selective detection ofleukemia cells using silver-enhanced gold nanoparticle label, Talanta 126 (2014) 130e135. L. Hajba, A. Guttman, Circulating tumor-cell detection and capture usingmicrofluidic devices, TrAC, Trends. Anal. Chem. 59 (2014) 9e16. F.R. Li, Q. Li, H.X. Zhou, H. Qi, C.Y. Deng, Detection of circulating tumor cells inbreast cancer with a refined immunomagnetic nanoparticle enriched assayand nested-RT-PCR, Nanomed. Nanotechnol. 9 (2013) 1106e1113. M. Salahuddin, A. Shaharyar, A. Mazumder, M.J. Ahsan, Synthesis, characterization and anti-cancer evaluation of 2-(naphthalen-1-ylmethyl/naphthalen2-yloxymethyl)-1-[5-(substituted phenyl)-[1,3,4]oxadiazol-2ylmethyl]-1H-benzimidazole, Arab. J. Chem. 7 (2014) 418e424. D. Szcze˛ snaa, M. Koprowskia, E.R. Sokołowskab, B. Marciniakb, P. Bałczewski, Selective HornereWittig/Nazarov vs. Knoevenagel/Nazarov reactions in the synthesis of biologically active 3-aryl-substituted 1-indanones, Synlett 28 (01) (2017) 113e116. A. Singh, K. Fatima, A. Srivastava, S. Khwaja, D. Priya, A. Singh, G. Mahajan, S. Alam, A.K. Saxena, D.M. Mondhe, S. Luqman, D. Chanda, F. Khan, A.S. Negi, Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilize, Chem. Biol. Drug. Des. 88 (5) (2016) 625e634. A.P. Prakasham, A.K. Saxena, S. Luqman, D. Chanda, T. Kaur, A. Gupta, D.K. Yadav, C.S. Chanotiya, K. Shanker, F. Khan, A.S. Negi, Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization, Bioorg. Med. Chem. 20 (2012) 3049e3057. A. Singh, K. Fatima, A. Singh, A. Behl, M.J. Mintoo, M. Hasanain, R. Ashraf, S. Luqman, K. Shanker, D.M. Mondhe, J. Sarkar, D. Chanda, A.S. Negi, Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule, Eur. J. Pharm. Sci. 76 (2015) 57e67. D. Chanda, S. Bhushan, S.K. Guru, K. Shanker, Z.A. Wani, B.A. Rah, S. Luqman, D.M. Mondhe, A. Pal, A.S. Negi, Anticancer activity, toxicity and pharmacokinetic profile of an indanone derivative, Eur. J. Pharm. Sci. 47 (2012) 988e995. H.O. Saxena, U. Faridi, S. Srivastava, J.K. Kumar, M.P. Darokar, S. Luqman, C.S. Chanotiya, V. Krishna, A.S. Negi, S.P.S. Khanuja, Gallic acid-based indanone derivatives as anticancer agents, Bioorg. Med. Chem. Lett. 18 (2008) 3914e3918. J. Hu, J. Yan, J. Chen, Y. Pang, L. Huang, X. Li, Synthesis, biological evaluation and mechanisms study of a class of benzylideneindanone derivatives as novel anticancer agents, Med. Chem. Commun. 6 (2015) 1318e1327. C. Charrier, J. Roche, J. Gesson, P. Bertrand, Antiproliferative activities of a library of hybrids between indanones and HDAC inhibitor SAHA and MS-275 analogues, Bioorg. Med. Chem. Lett. 17 (2007) 6142e6146. H. Shih, L. Deng, C.J. Carrera, S. Adachi, H.B. Cottam, D.A. Carson, Rational design, synthesis and structure-activity relationships of antitumor (E)-2benzylidene-1-tetralones and (E)-2-benzylidene-1-indanones, Bioorg. Med. Chem. Lett. 10 (5) (2000) 487e490. L.M. Leoni, E. Hamel, D. Genini, H. Shih, C.J. Carrera, H.B. Cottam, D.A. Carson, Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-resistant cancer cells, J. Natl. Cancer. Inst. 92 (3) (2000) 217e224. V.M. Patel, N.D. Bhatt, P.V. Bhatt, H.D. Joshi, Novel derivatives of 5,6dimethoxy-1-indanone coupled with substituted pyridine as potential antimicrobial agents, Arab. J. Chem. (2014). http://dx.doi.org/10.1016/j. arabjc.2014.07.014. B.N. Brousse, R. Massa, A.G. Moglioni, M. Martins Alho, N.D. Accorso, G. Gutkind, G.Y. Moltrasio, Antibacterial and antifungal activity of some thiosemicarbazones and 1,3,4 thiadiazolines, J. Chil. Chem. Soc. 49 (2004) 45e49. R.J. Glisoni, D.A. Chiappetta, L.M. Finkielsztein, A.G. Moglioni, A. Sosnik, Selfaggregation behaviour of novel thiosemicarbazone drug candidates with potential antiviral activity, New J. Chem. 34 (2010) 2047e2058. ~ a, A.G. Moglioni, A. Sosnik, R.J. Glisoni, M.L. Cuestas, V.L. Mathet, J.R. Oubin Antiviral activity against the hepatitis C virus (HCV) of 1-indanone thiosemicarbazones and their inclusion complexes with hydroxypropyl-bcyclodextrin, Eur. J. Pharm. Sci. 47 (2012) 596e603. R.J. Glisoni, E.F. Castro, L.V. Cavallaro, A.G. Moglioni, A. Sosnik, Complexation of a 1-indanone thiosemicarbazone with hydroxypropyl-cyclodextrin enhances its activity against a Hepatitis C virus surrogate model, J. Nanosci. Nanotechnol. 15 (2015) 4224e4228. B.N. Brousse, A.G. Moglioni, M. Martins Alho, A.A. lvarez-Larena,

198

S.A. Patil et al. / European Journal of Medicinal Chemistry 138 (2017) 182e198

G.Y. Moltrasio, N.B. D'Accorso, ARKIVOC x (2002) 14e23. [101] P.D. Rouge, B.N. Brousse, A.G. Moglioni, G.A. Cozzi, A. Alvarez-Larena, N. D'Accorso, G.Y. Moltrasio, ARKIVOC xii (2005) 8e21. [102] B.N. Brousse, R. Massa, A.G. Moglioni, M. Martins Alho, N. D'Accorso, G. Gutkind, G.Y. Moltrasio, J. Chil, Chem. Soc. 49 (2004) 45e49.

[103] E.F. Castro, L.E. Fabian, M.E. Caputto, D. Gagey, L.M. Finkielsztein, G.Y. Moltrasio, A.G. Moglioni, R.H. Campos, L.V. Cavallaro, Inhibition of bovine viral diarrhea virus RNA synthesis by thiosemicarbazone derived from 5,6-dimethoxy-1-indanone, J. Virol. 85 (2011) 5436e5445.