DESIGN, SYNTHESIS, MOLECULAR DOCKING AND ANTI-PROLIFERATIVE EVALUATION OF NOVEL PYRAZOLO[4,3-E][1,2,4]TRIAZOLO[4,3-C]PYRIMIDINE DERIVATIVES AS POTENTIAL DNA INTERCALATORS AND TOPOISOMERASE II INHIBITORS

Abstract

A series of novel hybrid pyrazolotriazolopyramidine derivatives was designed and synthesized in synthetically useful yields. All the new synthesized compounds were biologically evaluated in vitro for their cytotoxic activities against a panel of three cancer cell lines namely, HepG-2, MCF-7, and HCT-116. The results of cytotoxic evaluation indicated that compounds 12, and 11 exhibited the most prominent cytotoxic effect against all tested cell lines with IC50 values ranging from 12.41 to 22.18 µM comparable to that of doxorubicin as a control drug (IC50 values of 8.17 and 9.27 µM). Moreover, the most potent compound was further evaluated for its topoisomerase II inhibitory activities and DNA intercalating affinities as potential mechanisms for its anti-proliferative activities. In particular, compound 12 exhibited higher intercalative activity with IC50 value of 30 µM than doxorubicin (31 µM). Interestingly, compound 12 displayed a significant topoisomerase II inhibitory activity with IC50 value of 0.055 µM. Furthermore, molecular docking study was also performed in order to understand the binding mode in the active site and explain the anti-cancer results with prospective target.