Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)-[1,2,4]triazolo[1,5-c]quinazolines

The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds' structures were established by ¹H, ¹³C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N'-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI₅₀ level (MG_MID, GI₅₀ is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI₅₀=0.34), CNS (SF-295, GI₅₀=0.95), ovarian (OVCAR-3, GI₅₀=0.33), prostate (PC-3, GI₅₀=0.56), and breast cancer (MCF7, GI₅₀=0.52), leukemia (K-562, GI₅₀=0.41; SR, GI₅₀=0.29), and melanoma (MDA-MB-435, GI₅₀=0.31; SK-MEL-5, GI₅₀=0.74; UACC-62, GI₅₀=0.32). SAR-analysis is also discussed.

Kovalenko S. I.; Antypenko L. M.; Bilyi A. K.; Kholodnyak S. V.; Karpenko O. V.; Antypenko O. M.; Mykhaylova N. S.; Los T. I.; Kolomoets O. S.
Scientia pharmaceutica 2013, 81 (2), 359-391
DOI: 10.3797/scipharm.1211-08