Ultrasound assisted synthesis of tetrazole based pyrazolines and isoxazolines as potent anticancer agents via inhibition of tubulin polymerization

Abstract

In search of new active molecules against MCF-7, A549 and HepG2, tetrazole based pyrazoline and isoxazoline derivatives under both conventional and ultrasonic irradiation method were designed and efficiently synthesized. Structures of newly synthesized compounds 5a-h and 6a-h were characterized by ¹H NMR, ¹³C NMR, MS and elemental analysis. Several derivatives were found to be excellent cytotoxic against MCF-7, A549 and HepG2 cell lines characterized by lower IC₅₀ values (0.78-3.12 µg/mL). Compounds 5b and 5c demonstrated an antiproliferative effect comparable to that of CA-4. Western blot analysis revealed that, reported compounds accumulate more tubulin in the soluble fraction. Docking studies suggested that, binding of these compounds mimics at the colchicine site of tubulin. In vitro study revealed that the tetrazole based pyrazolines and isoxazolines may possess ideal structural requirements for further development of novel therapeutic agents.

Keywords: Anticancer; Docking; Isoxazoline; Pyrazoline; Tetrazole; Tubulin; Ultrasound.