Screening for in vitro antimycobacterial activity and three-dimensional quantitative structure-activity relationship (3D-QSAR) study of 4-(arylamino)coumarin derivatives.

The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4-(arylamino)coumarins with various aromatic amines at the C(4) - position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37) Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25 µg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom-fit and field-fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field-fit alignment were the best with statistically good correlation coefficients (r²) and cross-validated q². The values of r²(pred) for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure-activity relationship of the compounds could be gained.

Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines.

In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H (37)Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3-93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r (2)) of 0.98 and 0.95 with cross-validated r (2)(q (2)) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive r(2)(r(r)(pred)) is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.

Tumour-specific cytotoxicity and MDR-reversal activity of dihydropyridines.

The ability of 41 1,4-diphenyl-1,4-dihydropyridine derivatives to inhibit the transport activity of P-glycoprotein were studied by flow cytometry in a multidrug-resistant human colon cancer cell line (COLO320) and in human mdr1 gene-transfected mouse lymphoma cells (L 5178 Y). The cytotoxicities of these compounds were also examined against human normal and cancer cell lines. The majority of the tested compounds proved to be effective inhibitors of rhodamine 123 outward transport, but their cytotoxicities were not negligible. Some dihydropyridine derivatives displayed cytotoxic activity against four human oral tumour cell lines and against three normal human oral cell lines. There was no clear-cut relationship between the multidrug-resistance activity or cytotoxicity and the chemical structures of the compounds. New ring substituents could prevent the oxidation of the ring of the aromatic compound.