Letters in Drug Design & Discovery - Volume 8, Issue 9, 2011

A focused library of more than 90 N-benzenesulfonyl derivatives of heterocycles was generated by a practical and efficient solution-phase parallel synthesis. The methodology used led to pure compounds in a shorter time compared with the classical synthesis. The reaction conditions were carefully studied to achieve a one-pot method that allows the use of automated equipment. A simple chromatography-free workup procedure was developed making this method not only efficient but also fast and simple. The overall yield for the synthesis of this library was over 90% with an average purity of 97%. Five of the tested compounds have shown a moderate inhibitory activity (up to MIC = 32 μg/mL) against Escherichia coli (ATCC 25922).

A series of isonicotinic acid hydrazide derivatives (1-14) was synthesized and tested for their in vitro antimycobacterial activity against Mycobacterium tuberculosis and the compounds with bromo, N2-2,4-hexadienoyl, N2-lauryl and N2-octadecanoyl groups were found to be the most effective, especially isonicotinic acid-N'-octadecanoyl hydrazide (12) was more active than the standard drug isoniazid. The results of antiviral activity testing showed that none of the tested compounds were active at subtoxic concentrations. The synthesized compounds were also screened for their antimicrobial potential against S. aureus, B. subtilis, E. coli, C. albicans and A. niger and the results indicated that compounds 4, 11, 12 and 14 were found to be active with Benzoic acid N'-(4-hydroxy-3,5-dimethoxy-benzylidene)-N-(pyridine-4- carbonyl)-hydrazide (14) having highest antimicrobial potential. The QSAR studies indicated the importance of topological parameters 3χ and κ1 in governing the antimicrobial activity of synthesized derivatives.

In this study, we aimed at the synthesis of new N,N-disubstituted dithiocarbamoic acid, 2-[(9-ethyl-9Hcarbazol- 3-yl)amino]-2-oxoethyl esters and their antimicrobial evaluations. The chemical structures of the compounds were elucidated by IR, 1H NMR, 13C NMR, MS spectral data and elemental analysis. The antibacterial and antifungal activities of the synthesised derivatives were tested against Gram (+), Gram (-) bacteria and yeasts such as Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Bacillus cereus, Methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans (two strains), Candida glabrata, Candida tropicalis, Candida parapsilosis and Saccharomyces cerevisiae using a microbroth dilution technique. The results showed that the compounds displayed different degrees of antimicrobial activities; however, when compared almost all of the compounds displayed better antifungal activities (minimum inhibitory concentrations, 312.5->1250 μg mL-1).

A series of andrographolide (Andro) derivatives (3-14) were designed, synthesized and screened for their antibacterial activities against both gram-positive and gram-negative bacteria in vitro. The most promising compounds 14a-c exhibited at least eight-fold stronger antibacterial activities compared to Andro. Especially, Compound 14a, which showed 32-fold stronger antibacterial activity than Andro, has a potency to be a new lead.

Some benzothiazole derivatives bearing piperazine and dithiocarbamate moieties were synthesized in order to investigate their anticancer activity. The structures of the obtained compounds were confirmed by spectral data and elemental analysis. Synthesized compounds were evaluated for their anticancer activity at the National Cancer Institute against a panel of approximately 60 different human tumor cell lines derived from nine neoplastic cancer types. Compound 3f was found to be significantly active against all cancer types in single concentration assay and selected for second step which includes five concentration assays. In the second step, it exhibited very significant activity on melanoma (LOX IMVI) cell line.

The present anticancer research demands more potent anticancer agents with fewer side effects than the existing ones. A series of novel substituted thiazole and benzothiazole containing nitrogen mustards (5-8; 15-17; 22-23) were synthesized and the structures of the compounds were analyzed by IR, NMR and mass spectras. Their in-vitro cytotoxicity against human lung carcinoma (A549) was investigated by MTT Assay. The compounds 16, 8 showed promising activity against A549 human lung carcinoma cell lines with % CPI 52 (More than Cisplatin) and 45.9 respectively. The DNA binding properties of the compounds were also evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration. The compounds 22 and 5 showed the highest binding affinity with binding constant (Ki) 48.34 and 41.8 respectively.

Novel fluorine-containing pyrazolines (2a-2g) and pyrazoles (5a-5e) were synthesized and evaluated for their cytotoxicity in vitro in a panel of four human cancer cell lines using Sulforhodamine B (SRB) assay. Though the compounds showed varying degrees of cytotoxicity in different cell lines, it was noteworthy that the 4H pyrazoles (5a-5e) were distinguished by their potent and selective action against MCF7 breast cancer cell line.

Several physicochemical and topological descriptors used for estimating anti-cancer activity of benzothiazole derivatives indicated that the use of physicochemical parameters alone yield most appropriate model for modeling the activity.

To search for potential anti-cancer analogs, 16 aromatic esters of 4'-demethyl-4-deoxypodophyllotoxin (6a-p) were synthesized and tested their cytotoxicity on six cancer cell lines. The results indicated that all derivatives showed potent cytotoxic activity against A-549 cell line with IC50 values of 0.00009-0.037 μg/mL.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is being evaluated clinically for cancer therapy, selectively induces apoptosis in tumor cell lines without causing toxicity to normal cells. However, its therapeutic potential is limited by occurring resistance in a majority of lung carcinoma, breast and prostate cells. Various chemotherapeutic drugs have been found to enhance TRAIL-induced apoptosis. The objective of this study was to examine whether non-small cell lung cancer (NSCLC) cell line A-549, one of the most drug-resistant tumor cells in human, can be sensitized by doxorubicin (DOX) to TRAIL-mediated apoptosis. We show that DOX and recombinant human TRAIL (TRAIL) have a synergistic cytotoxic effect against A-549 cells in vitro. However, no obvious antitumor effects were observed in A-549 tumor bearing nude mice treated by TRAIL alone, DOX alone or both agents, suggesting that further works should be carried to improve the efficacy of combined treatment of DOX and TRAIL.

A set of one hundred and twenty two coumarin derivatives with TNF-α inhibitory activity was subjected to the two dimensional quantitative structure activity relationships (2D-QSAR) studies using MDS 3.0 drug designing module with Multiple Linear Regression (MLR), Principle Component Regression (PCR) and Partial Least Square Regression (PLS) analysis being carried out. Among these three methods, PCR-model has come out with significant result as compared to other models. The best PCR QSAR model (r2 = 0.8721, Fisher test value F = 40.67, Pred_r2 = 0.654) has acceptable statistical quality and predictive potential as indicated by the value of cross validated squared correlation coefficient (q2= 0.7123). From the build model it seems to be clear that SaaCHE-index, T_2_O_1, T_N_O_6 contributes positively while as SssCH2E-index descriptor negatively contributes to the biological activity. Thus this validated model brings important structural insight to aid the design of novel coumarins TNF- α inhibitor as anti-cancer agents.

Comparative molecular field analysis (CoMFA) was carried out on Carbonic anhydrase inhibitor hCA IX- tumor-associated (Hypoxia). Database contains a series of aromatic benzene sulfonamides incorporating 1, 3, 5-triazine moieties derivative. This study correlates the inhibitory activities of structurally related 1, 3, 5-triazine moiety derivatives derived to Tripos standard in CoMFA. The data base alignment conformation yielded good predictive CoMFA model (r2cv = 0.82, F-value = 460.320, r2pred = 0.787 with five components). The contour maps obtained from 3D - QSAR studies were appraised for the activity trends of the molecules analyzed. The result indicates that the steric and electrostatic features play a significant role in the carbonic anhydrase inhibition activity and potency of these compounds. The data generated from the present study can be used as putative pharmacophore in the design of novel, potent and selective hCA IX inhibitors.

A series of 1-arylpyrazole and their N- and S- glycosides has been synthesized. The key step is the synthesis of 3- (furan-2-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde 1 via Vilsmeier -Haack reaction on the hydrazone of 2-acetylfuran. Compound 1 was transformed to N,N-dialkyl acrylamide (and/or acetamide) derivatives 3a, 3b and 6 through reaction with malonic acid and application of Willgerodt-Kindler reaction followed by reaction with dialkylamine. Moreover, the aglycons 5-[3-(furan-2-yl)-1-phenyl-1H-pyrazol-4-yl]-1,3,4-oxadiazole-2(3H)-thione 10 and 6-(furan-2-yl)-4-[3-(furan-2- yl) -1-phenyl-1H-pyrazol-4-yl]-2-oxo -1,2-dihydro-pyridine-3-carbonitrile 14b were prepared and coupled with 2',3',4',6'- tetra-O-acetyl-α-D-gluco pyranosyl bromide under basic conditions to yield S-and N-glycoside derivatives 12 and 15, respectively. All the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral studies. Antiviral activity was shown for most of the synthesized compounds. Compounds 4 and 14b exhibited a promising antiviral activity against vesicular stomatitis virus (VSV).

4, 5, 6, 7-Tetrahydropravastatin and its sodium salt as the hydrogenated derivatives of pravastatin were evaluated as HMG-CoA reductase inhibitor in vitro and in vivo, and they exhibited similar antihyperlipidaemic activity to pravastatin. The results could be regarded as a particular case to the reported SARs of statins up to now.

Results of the modelling of thiosemicarbazone-based inhibitors of ES suggest that these compounds interact with the calcium ion whilst undergoing hydrogen bonding interaction with the active site - the extent of H-bonding determining the overall inhibitory activity. Novel inhibitors were designed, synthesised and evaluated and found to possess potent inhibitory activity.