Letters in Drug Design & Discovery - Volume 13, Issue 9, 2016

A quantitative structure-activity relationship analysis has been applied to a series of 97 imidazopyridine analogous Spleen tyrosine kinase (Syk) inhibitors, the enzyme responsible for the signal transduction of classic immunoreceptors. The deregulation of Syk is associated with several pathologies, among which uncontrolled tumor cell growth stands out. The most advanced Syk inhibitor, fostamatinib, has proven efficient in multiple therapeutic indications, but its clinical evolution is still in process. In this context it is necessary to search for new potent inhibitors andin this work we have developed and validated 4D-QSAR models in order to obtain pharmacophoricfeatures that can enhance the potency of the imidazopyridine compounds. The conformations obtained by molecular dynamic simulation were overlapped in a virtual three dimensional box comprised of 1 Å cells, according to the six trial alignments. The models were generated by a combined genetic algorithm (GA) and partial least squares (PLS) regression technique. The best models generated show good adjusted cross-validate value (q2adjusted) and correlation coefficient value (R2). Analyzing the descriptors it can be observethat the nonpolar substituents are detrimental for activity of these compounds, suggesting hydrophilic regions in the Syk active site.

Cancer is the second largest cause of deaths across the globe. The current treatments available for cancer include surgical removal of the infected tissue, radiotherapy, chemotherapy and combinatorial therapeutic approach. Most of the commercially available anti-cancer drugs and their unique modes of action are decoded by the cancer cells, making them less effective. Hence, there is an increasing demand for newer class of drugs with better pharmacological properties and fewer side effects. Camptothecin (CPT), the quinoline alkaloid isolated from Camptotheca acuminata is a wellknown Topoisomerase I inhibitor. It has a proven anti-cancer activity against various cell lines. However, its poor pharmacological properties like low solubility and a narrow therapeutic index calls for better therapeutic alternatives. In this study, eight novel analogues of camptothecin were rationally designed based on the structure-activity relationship of the substituent groups. The designed analogues were further analyzed in-silico for their drug-likeness, quantitative structure-activity relationship (QSAR) and ADME-T properties. All the novel analogues were docked with topoisomerase I using Autodock 4.2 and the docking results were validated with the help of an online docking server, Patchdock. In this study, we have found that the therapeutic profile of some of the designed analogues was comparable to that of Topotecan, the FDA approved drug and better than the parent molecule Camptothecin.

Benign prostatic hyperplasia is non-malignant enlargement of prostate gland which results in severe lower urinary tract symptoms and affects the quality of life of patients. 5α-Reductase inhibitors play a crucial role in the management of benign prostatic diseases with low toxicity and have been a major thrust area for its application in prostate cancers with limited success. In continuation of our program to develop novel 5α-reductase inhibitors, we report herein the synthesis and biological evaluation of 5a-oxo-5-aza-B-homo-3,5-seco-4-nor-cholestan-3-oic acid and 25(R)-5a-oxo-5-aza- B-homo-3,5-seco-4-nor-spirostan-3-oic acid derivatives. In vitro evaluation using human embryonic kidney cell line (HEK) based assay revealed compound MK-234 as most potent inhibitor with an IC50 value of 0.474 ±0.041 μM followed by MK-233 with an IC50 value 4.84 ± 0.088 μM as compared to clinically used drug finasteride (IC50 = 30.3 nM). Compound MK-235 and MK-236 also exhibited moderate inhibition with an IC50 value of 9.24 ± 0.796 and 13.148 ± 0.379 μM, respectively. Additionally, in silico ADME predictive studies were also carried out to assess the ‘druggability properties’ of the synthesised compounds.

Interleukin-1 receptor-associated kinase 4 (IRAK-4) plays a pivotal role in signaling cascades associated with the immune and inflammatory diseases. Regulation of IRAK-4 is an attractive approach to treating related diseases. Herein, ligand-based pharmacophore model and atom-based 3D-QSAR studies have been carried out on 92 known ATP competitive inhibitors to IRAK-4. Fourpoint pharmacophore hypotheses with one hydrogen acceptor (A), one hydrogen donor (D), and two aromatic rings (R) were developed by PHASE module of Schrödinger suit. The best pharmacophore hypothesis was selected on the basis of good PLS statistics (R2 train = 0.9806, Q2 test = 0.7182, Pearson-R = 0.8767, SD = 0.2248, RMSE=0.3152, F= 637.2). Furthermore, a series of virtual screening were performed and the Prime/MM-GBSA method based on the docking complex was used to predict the binding-free energy. Finally, 12 hits were identified as potent and novel IRAK-4 inhibitors. We mainly analyzed the binding modes and binding energies of the candidate compounds with the scaffolds of anthraquinones and 9-fluorenones. The result of virtual screening was further validated using molecular dynamics (MD) simulation analysis. A 10 ns MD simulation analysis revealed high stability and effective binding of ZINC09047206, ZINC12885209 within the active site of IRAK-4. It turned out that the anthraquinones hit ZINC09047206 and ZINC09477176 have more effective IRAK-4 inhibitory potential than those of other obtained hits.

Selected synthesized biologically active fluorinated diethyl-2-(benzylthio)-2,3-dihydro- 1H-imidazole-4,5-dicarboxylate derivatives exhibited promising anti-platelet aggregation activity against thrombin. With a view to understanding their structural features, some common electronic structural characteristics, including polarizability (α), ΔELUMO-HOMO, chemical hardness (η) and softness (S) were calculated using density functional theory (DFT) with B3LYP functional and 6-31+G* basis set. The high polarizabilities (α=139.554 A3, 138.459 A3) with low ΔELUMO-HOMO (3.761 eV,3.662 eV), low chemical hardness (η= 1.880 eV, 1.831 eV) and high chemical values of softness (S=0.265 eV, 0.273 eV) are observed for the two most active imidazole-based anti-platelet derivatives with reasonably good IC50 values (0.40 mg mL-1, 0.44 mg mL-1). Moreover, molecular docking analysis of these anti-platelet compounds in the active binding site of the thrombin receptor identified the potential interaction between these inhibitors with the active residues of thrombin. Inspection of the docked structures implies that the antiplatelet inhibition of the most active compounds is mainly due to the possibilities of hydrogen bonding interaction and intramolecular close contacts of some active residues of the thrombin receptor (Gly219, Glu192, Gly216, Trp60, Tyr60A, Trp215, Leu99, His57, Cys191, Lys60, Glu217) with anti-platelet leads. These results suggest that the active imidazole derivatives could be promising chemical scaffolds to target the thrombin receptor.

Starting from 2-hydroxybenzyl alcohol, a series of 2-arylbenzofurans have been synthesized and evaluated as acetylcholinesterase inhibitors at 23 αM by using modified colorimetric Ellman’s method. The reaction sequence was completed in four steps. All of the fourteen synthesized products were obtained in excellent yields without the need to tedious work-up step. In the last step, different derivatives were obtained by the substitution of bromine with five and six-membered cyclic and acyclic amines. Among the synthesized compounds, the best activity was observed in 1-(4- (Benzofuran-2-yl) benzyl)piperidine 5c with 74% activity compared to donepezil as a reference drug.

In an effort to develop potent antimicrobial agents, new thiazolyl hydrazone derivatives were synthesized and investigated for their inhibitory effects on pathogenic bacteria and yeasts. MTT assay was carried out to determine the cytotoxic effects of the compounds on NIH/3T3 mouse embryonic fibroblast cell line. Among these compounds, 2-[2-[1-(4-(piperidin-1-yl)phenyl)ethylidene] hydrazinyl]-4-(4-fluorophenyl)thiazole (7) exhibited notable antimicrobial activity against Enterococcus faecalis (ATCC 51922), Pseudomonas aeruginosa, Escherichia coli (ATCC 35218), Candida krusei, Candida glabrata and Candida parapsilosis. Due to its promising antimicrobial activity, the mutagenic potential of compound 7 was also evaluated by means of Ames test. According to MTT and AMES assays, this compound was identified as non-toxic and non-mutagenic.

Novel Leflunomide analogues were synthesized and evaluated in vivo against thioacetamide (TAA) induced liver fibrosis in rats. All the animals which were treated with the new analogues showed improved or comparable survival rates to those treated with Leflunomide. Animals which were treated with compounds 8d, 8e, 9 and 11 have shown improved liver parameters than Leflunomide treated animals. Histopathology of the liver has shown that compound 8a is the most active compound, which decreases fibrosis to a minimal level and compounds 8c, 8e and 11 are active compounds with fibrosis score 2-3 which is better than that of Leflunomide.

The reaction of 1-heteroaryl-3-(tetrazolo[1,5-a]quinolin-4-yl)prop-2-en-1-ones with hydrazine hydrate in either ethanol or acetic acid furnished pyrazoline and N-acetylpyrazoline, respectively. N-phenylpyrazolines and pyrazoline-N-carbothioamides were synthesized, in good yields, from reaction of chalcons with phenylhydrazine and thiosemicarbazide, respectively. On the other hand, a series of 2-pyrazolin-1-ylthiazoles have been synthesized via cyclization of pyrazoline-Ncarbothioamides with different α-haloketones such as phenacyl bromides, 3-bromoacetylcoumarin, hydrazonoyl chlorides, and α-chloroacetic acid. The structures of the newly synthesized compounds have been confirmed by spectral analyses also the in vitro antimicrobial activities were studied.

Following our search for antimalarial compounds, novel series of piperazinylalcohol pyrrolo[ 1,2-a]quinoxaline derivatives 1-2 were synthesized from 2-nitroaniline or 2-amino-3- nitrophenol and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 ranging from 0.3 to 21.1 μM. In attempting to investigate the large broad-spectrum antiprotozoal activities of these pyrrolo[1,2-a]quinoxaline derivatives, their properties toward the promastigote form of Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are here discussed.

The potency and aqueous solubility significantly affect the clinical use of Combretastatin A-4 and phenstatin analogs. A lot of Combretastatin A-4 analogs have good potency but they have been rejected in clinical trials due to low solubility. In this research work, cheminformatic approaches i.e., structure activity correlation by rational approach and computational approach (pharmacophore and atom based 3D QSAR), molecular docking, energetic based pharmacophore mapping studies have been used to identify significance of amino group substitution at Combretastatin A-4 and phenstatin analogs. Substitution of amino group in Combretastatin A-4 and phenstatin analogs at R2 or/and R2' or/and R3' exhibited excellent cytotoxic activity with enhanced aqueous solubility. The amino group increased the polarity of the corresponding structure without compromising its bioactivity. It is possible in the future to design structural analogs of Combretastatin A-4 and phenstatin with amino group exhibiting excellent cytotoxic activity with enhanced aqueous solubility.

Background: P-glycoprotein (P-gp) is the most important member of adenosine triphosphate (ATP) binding cassette (ABC) family and plays a critical role in facilitating the efflux mechanism to extrude various drug molecules. It is mostly present in pancreas, kidney, ovary, liver and breast. Piperine is a well known inhibitor of P-gp mediated efflux mechanism that makes it an efficient enhancer for promoting the bioavailability of a number of compounds against various diseases. Objective: The aim of present work is to predict potency of some piperine analogues as inhibitors of P-gp mediated efflux process and enhancer of drugs bioavailability in human and bacterial P-gps using in silico approach. Methods: Many computational approaches like protein modeling, molecular docking simulation and pharmacophore studies have been used in order to explore the prediction of protein ligand interaction and their inhibition. Result: In the present work, the surrounding residues of ATP binding site together with the binding affinity of piperine analogues have been observed for human and bacterial P-gps. This leads to the characterization of few piperine analogues as having higher potency than ATP for inhibiting the efflux process and enhancing bioavailability of drugs. Conclusion: This study is likely to help in designing more potent novel candidates which might be useful as efflux inhibitors and bioavailability enhancers for many pharmaceutically important drug molecules.

We previously reported the discovery of diphenylimidazoles as potent sodium channel blockers, potentially useful in the treatment of epilepsy. In this work we further explore the structural requirements necessary for the potency of these derivatives with the aim to understand which structural modifications of the original scaffold could be tolerated in order to retain activity. We have synthesized new compounds working on the 2-position of the imidazole ring. First we have introduced a carbonyl spacer, that was subsequently reduced to alcohol. Both carbonyl and alcohol derivatives have been tested for their ability to block NaV1.6 sodium channel subtype in vitro and for their antiepileptic activity in rodent acute seizures models.

A series of diethyl (3-((5-aryl-1H-1,2,4-triazol-3-yl)thio)propyl)phos-phonates (7a–t) has been synthesized in excellent yields by coupling diethyl (3-bromopropyl)phosphonate and 5-aryl-1H-1,2,4-triazol-3-thiones employing an efficient, green and nonconventional heterogeneous SO3Hcarbon catalyst derived from glycerol. In addition, a facile and green approach for the esterification of carboxylic acids by utilizing glycerol-based solid acid catalyst has been reported. Structures of the synthesized compounds were characterized by IR, NMR and HRMS studies. These triazole derivatives were screened for their in vitro cytotoxicity using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide) assay against a panel of five different human cancer cell lines (HeLa: Cervix, A549: Lung, A375: Skin, MDA-MB-231: Breast and T98G: Brain). The antimicrobial activities of the synthesized compounds were investigated against four bacterial strains: Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and three fungal strains: Aspergillus niger, Aspergillus terreus, Aspergillus fumigatus. Preliminary results indicate that the compound 7f displayed maximum anticancer activity and the compounds 7d, 7e, 7f, 7m and 7q exhibited moderate antibacterial activity. The compounds 7g, 7h, 7o and 7p showed good antifungal activity with high inhibition zone diameter compared to the standard drug.

In an effort to develop a lead antimalarial compounds, a series of novel 2-aryl/heteroarylethyl-6-chloroquinoline-4-carboxylate derivatives (2a-j) were obtained by using quinoline-4-carboxylic acid derivatives which were produced by a simple one-pot synthesis of Pfitzinger reaction of isatin with Arylketones as intermediates which were finally esterified with ethanol in the presence of concentrated sulfuric acid to get the expected ethyl-6-chloro-2-(furan-2-yl)quinoline-4-carboxylates (2a-j) with good to excellent yields. All the crude products were purified by column chromatography using silica gel (60-120 mesh, petroleum ether: ethyl acetate, 9:1 v/v), to furnish analytically pure 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4-carboxylates (2a-j). Additionally, the structures of the products were confirmed by spectral analysis such as 1H NMR, 13C NMR and LCMS analysis. As Molecular docking results illustrates, the most potent ligands among the synthesized compounds are 2j and 2h. The ligand Ethyl-2-(anthracen-9-yl)-6-chloroquinoline-4-carboxylate (2j) derivative interacts with FTase receptor at the binding sites located within the active site amino acids such as ARG291, LYS294 with binding energy -10.11 kcal/mol, docking energy -11.78 kcal/mol and inhibition constant Ki= 3.88e-008 μM respectively. The another ligand 2h was also shown strong binding interaction with active site HIS248, ARG291and ARG291 with binding energy of -9.81 kcal/mol docking energy -11.27 kcal/mol and inhibition constant Ki=6.5e-008 mM respectively. In the same way ligands 2a, 2b, 2d and 2i forms four hydrogen bonding interaction with amino acids having binding energy -6.72, -6.54, -6.87 and-8.02 kcal/mol respectively, indicates more potent inhibitors of farnesyltransferase receptor. With this it was concluded that the compounds 2a-j were found to be a potent and selective FTase antagonist inhibitors.