Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity.

A series of 4-styrylcoumarin have been synthesized by Knoevenagel condensation between substituted 4-methylcoumarin-3-carbonitrile and different heterocyclic or aromatic aldehydes. 4-Methylcoumarin-3-carbonitrile has been synthesized by the base catalyzed reaction between substituted 2-hydroxyacetophenone and ethyl cyanoacetate. The structures of the newly synthesized compounds were confirmed by (1)H NMR, IR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-α and IL-6) and anti-tubercular activity. Compounds 6a, 6h and 6j exhibited promising activity against IL-6 with 72-87% inhibition and compound 6v showed potent activity against TNF-α with 73% inhibition at 10 µM concentration. Whereas compounds 6n, 6o, 6r and 6u showed very good anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at <6.25 µM.

Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides.

Multi-drug resistance to commonly used antitubercular drugs has propelled the development of new structural classes of antitubercular agents. This paper reports the synthesis, evaluation and 3D-QSAR analysis of a set of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides as antitubercular agents. Substituted acetoacetanilides were reacted with various aromatic aldehydes and urea which yielded the tetrahydropyrimidine derivatives with a phenyl carbamoyl group at C5 position, and with various substitutions on the 4-phenyl and the N-phenyl aromatic rings. All compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The QSAR models were generated on a training set of 23 molecules. The molecules were aligned using the atom-fit and field-fit techniques. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r2) of 0.98 and 0.95 with cross-validated r2(q2) of 0.68 and 0.58, respectively. The 3D-QSAR models were externally validated against a test set of 7 molecules for which the predictive r2 (r(pred)2) is recorded as 0.41 and 0.32 for the CoMFA and CoMSIA models, respectively. The CoMFA and CoMSIA contours helped to design some new molecules with improved 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.