SYNTHESIS AND BIOLOGICAL EVALUATION OF THE DERIVATIVES OF 1,3,5-TRIAZIN-2,4-DIONES AND THEIR FUSED ANALOGUES.

Abstract

A series of 1,3,5-triazin-2,4-diones and its fused analogues viz. 1,2,4-triazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a][1,3,5]triazine was synthesized and evaluated for their anti-thymidine phosphorylase (Anti-TP) activity. The preliminary biological evaluation revealed that among the different derivatives, compounds having keto group (C=O) and thioketo group (C=S) at particular position viz. 5-thioxo-5,6-dihydro-4H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one and 2-thioxo-2,3 dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one their thiomethyl derivatives showed varying degrees of TP inhibitory activity comparable to positive control, 7-deazaxanthine (IC50 value = 42.63 µM). The enzyme inhibition kinetics study provided evidence that compounds behaved as mixed type inhibitor of the enzyme in presence of variable substrates concentration. A 3D-QSAR study based on CoMFA method conducted for pharmacophore elucidation was satisfactory according to its statistical validation results and contour map analysis. Moreover, the evaluation of the effects of the selected compounds on the expression of downstream markers of angiogenesis demonstrated the ability to attenuate the MMP-9 and VEGF expression level in breast cancer cell line.