Letters in Drug Design & Discovery - Volume 9, Issue 7, 2012

In this study we present synthesis and biological evaluation of derivatives of 4-fluorobenzoic acid and 2,3- dihydro-1H-cyclopenta[b]quinoline towards inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Synthesis of acquired molecules involved the reaction of condensation between the activated 4-fluorobenzoic acid and amino derivatives of 2,3-dihydro-1H-cyclopenta[b]quinoline. Biological testing towards the inhibition of cholinesterases was conducted according to the Ellman’s spectrophotometric method. Compounds 4b and 4e were found to be less active in comparison with tacrine. However, compounds 4d, 4g and 4h showed similar activity to tacrine. Compounds 4a, 4c and 4f were more active towards inhibition of AChE than tacrine. Every synthesized compound displayed higher selectivity towards AChE and lower selectivity towards BChE in comparison with tacrine apart from compound 4b. Compound 4b was characterized by similar selectivity towards AChE and higher selectivity towards BChE than tacrine.

A series of 2-thiohydantoins were prepared as somatostatin subtype 4 (sst4) ligands. Reaction of a Nsubstituted- L-tryptophan methyl ester with an isothiocyanate in the presence of triethylamine readily afforded the target compounds. The 2-thiohydantoins were evaluated for binding affinities in cell lines expressing somatostatin receptor subtypes 2A (sst2A) and 4 (sst4). Compared to the thiourea NNC-26-9100 (3), all 2-thiohydantoins demonstrated lower binding affinities at sst4. Incorporation of the thiourea moiety into the more rigid 2-thiohydantoin nucleus leads to a loss of conformational freedom and may prevent optimal interaction with sst4.

Ingested L-serine reduces the locomotor activity of socially isolated rats, but its effects on brain function and its underlying mechanisms of action have not yet been fully clarified. D-Serine is synthesized from L-serine by serine racemase and intraperitoneal injection of this D-amino acid attenuates depressive-like behavior in rats. We therefore hypothesized that oral intake of L-serine would stimulate the metabolism of L-serine to D-serine, and subsequently not only L-serine but also the newly formed D-serine would simultaneously affect brain functions and/or behaviors. In the present study, as the first step to test this hypothesis, L- and D-serine levels of the plasma and brain (cerebral cortex and hippocampus) were investigated at 0.5, 2, 6 and 10 h after oral administration of L-serine (6 mmol/kg) to fasted rats. In the plasma, the levels of both L-serine and D-serine were significantly increased at 0.5 h compared to control rats and thereafter their levels gradually decreased over time and had returned to the control values by 10 h. In both the cerebral cortex and the hippocampus, the increase in the level of L-serine paralleled the increase in the plasma L-serine level, whereas the levels of D-serine increased slowly for over 10 h, resulting in a small increase in D-serine. The combined data indicate that oral intake of L-serine might influence brain functions and/or behaviors not only through activity of L-serine itself but also due to activity of its metabolite D-serine.

Human Topoisomerase IIα (htopoIIα) is an approved and validated target for designing anticancer agents. Among the various methods to block the functions of htopoIIα, targeting ATP site for its competitive inhibition has been relatively less investigated. Therefore, to identify some novel htopoIIα inhibitors to target the ATP-binding site, we designed and synthesized a small library of 5-aryl-1,3,4-thiadiazole coupled phthalimide derivatives structurally related to thalidomide. Initially, 2-amino-5-aryl-1,3,4-thiadiazole derivatives (TDZ 1-8) were synthesized by ferric chloride catalysed oxidative cyclization of thiosemicarbazone derivatives (THZ 1-8) which were obtained by the reaction of substituted aryl aldehydes with thiosemicarbazide. TDZ 1-8 on reaction with 4-bromophthalic anhydride in presence of 4Å molecular sieves and glacial acetic acid gave 5-bromo-2-(5-aryl-1,3,4-thiadiazol-2-yl)isoindoline-1,3-dione derivatives (PTD 1-8). All the synthesized compounds were characterized by IR, 1H-NMR and LCMS. The final compounds, PTD 1- 8 were docked at the ATP-binding site of chain B of htopoIIα. The compounds with best in silico results were further screened by dye exclusion test for short term cytotoxicity study on Dalton’s lymphoma Ascites (DLA) cells using Trypan blue dye. One of the synthesized compound PTD-2 exhibited prominent in silico and in vitro anticancer activity.

This study evaluated the antioxidant activity of five resveratrol analogs using the DPPH method. The molecules activity was related with their chemical structure. Besides descriptive statistics, the analysis of variance (ANOVA) followed by Tukey’s post hoc test were performed (p<0.05). The antioxidant activity of analogs A and B was statistically similar with each other and from the reference standard resveratrol, possibly due to the presence of 4-hydroxy grouping. The aromatic hydroxyl reduces reactive free radicals and produces phenoxyl radical, stabilized by resonance. Although the analog C has shown IC50 value statistically different from the resveratrol (p<0.001), its antioxidant activity was considered satisfactory. The other analogs (D and E), which have a 4-acid grouping in place of 4-hydroxy grouping, showed lower antioxidant activity than resveratrol (p<0.001). Further studies to address possible advantages of analogs in relation to resveratrol should be conducted in order to make them feasible for therapeutic use.

Sixteen C-2-substituted quinolines were tested in both human cancer cell lines (MCF-7, H-460 and SF-268) and normal cell lines (Vero and THP-1). Preliminary results indicate that 2-α-furyl- and 2-γ-pyridinyl quinoline derivatives 1, 13 and 14 are active against three human cancer cell lines and, at the same time, were devoid of cytotoxic effect on normal cells. Biological activity and SAR results were compared with different molecular descriptors determined in silico using online available software, in an attempt to show a relationship with the possible mode of action of these quinoline derivatives.

A new series of 1,2,4-triazole derivatives 3a-i of (E)-4-(4-substitutedbenzylideneamino)-3-((5-phenyl-1,3,4- oxadiazol-2-yl)methyl)-1H-1,2,4-triazole-5(4H)-thione (2) were synthesized, deriving from 4-amino-3-((5-phenyl-1,3,4- oxadiazol-2-yl)methyl-1H-1,2,4-triazole-5(4H)-thione (1). The compounds were elucidated by IR, 1H NMR, 13C NMR, MS and elemental analyses. These compounds were screened for their antimicrobial activity. Among the synthesized compounds (E)-4-(4-chlorobenzylideneamino)-3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-2-(morpholinmethyl)-1H-1,2,4- triazole-5(4H)-thione, 3c was found to exhibit most potent In vitro antimicrobial activity with minimum inhibitory concentrations (MIC) of 1.56, 3.125, 1.56, 25, 25 and 25 μg/ml against E. coli, S. typhimurium, L. monocytogenes, S. aureus, P. aeruginosa and S. pyogenes respectively. Compound (E)-4-(benzylideneamino)-3-((5-phenyl-1,3,4-oxadiazol- 2-yl)methyl)-2-(morpholinmethyl)-1H-1,2,4-triazole-5(4H)-thione 3a was found to exhibit most potent In vitro antifungal activity with MICs 0.78 and 0.097 μg/ml against C. albicans and F. solani.

There is a need to develop new antischistosomal compounds when the only available therapeutic agents praziquantel large-scale used in the world. A series of novel aminoalcohol derivatives bearing 4-phenylphenol moiety were designed and synthesized. The structures of all the newly synthesized compounds were identified by elemental analysis, 1H-NMR, 13C-NMR and LC-MS. Their biological activities were evaluated against Schistosoma japonicum in mice by an oral route. Among these compounds, in vivo, at concentrations 400mg/kg of mouse, compound 1-(biphenyl-4’- yloxy)-3-(1’-(3’,4’-difluorophenyl)ethylamino)propan-2-ol (3j) produced the highest activity with 93.0% deparasitization. These compounds may find usefulness in the discovery and development of new antischistosomal drugs.

Leishmaniasis is a poverty related disease caused by protozoan parasites belonging to the genus Leishmania. No effective vaccine is presently available to treat this disease. The present study identifies specific epitopes in highly antigenic peptides of Leishmania infantum. Interestingly we found amastin like surface proteins as relevant markers for vaccine development for design of epitopes. A major glycoprotein GP63 leishmanolysin which directly binds to human natural killer cells (NK cells) was also selected as highly antigenic and considered for the analysis. Overall two different amastin like surface proteins were found as relevant for designing 9-mer epitopes for vaccine development against L. infantum and the best identified antigenic segments interacted with at least 8 alleles of each MHC classes. These epitopes are potential candidates to induce both T cell and B cell mediated immune responses.

Lipinski’s rule of five is well received throughout the world and widely used as one of the basic filters to screen ligands for their druggability. In this direction, we have studied 148 biologically active natural products which are available as drugs. Physicochemical parameters such as molecular weight, logP, hydrogen bond donors, hydrogen bond acceptors, number of aromatic rings, molar refractivity and Gibbs free energy were calculated. Statistical results reveal that, they do fall under the Lipinski’s rule of 5 (RO5). The illustration about need for the study, methods followed and results obtained are reported here.

A new series of 2,3-disubstituted thiazolidin-4-ones were synthesized from the appropriate amines, substituted aldehyde, and mercaptoacetic acid in the presence of DCC in anhydrous THF by microwave irradiation. The title compounds were investigated for their anticonvulsant activity. Among the test compounds, compound 2-(4- bromophenyl)-2-methylthiazolidin-4-one-3-isonicotinamide (8) emerged as most active compound of the series and it is moderately more potent than the reference standard diazepam.