Synthesis of polyhalo 2-aryl-4-aminoquinazolines and 3-amino-indazoles as anti-cancer agents

Abstract

A series of polyhalo 2-aryl-4-aminoquinazolines 3a–3n were prepared by reacting polyhalo isophthalonitriles 1a–1c with amidine hydrochlorides under basic conditions with good yields (70–93%). Also, through the reaction of polyhalo isophthalonitriles 1a–1c with hydrazines to give novel polyhalo 3-aminoindazoles 5 and 7 with moderate yield (70–87%). The anticancer activities of compounds 3, 5 and 7 were evaluated in vitro against human cell lines SKOV-3, HeLa, U2-OS, A549, and MCF-7. Some compounds showed excellent growth inhibitory activities and 3a was found to be the most potent derivative, with an IC₅₀ value lower than 3.86 μg mL⁻¹ against the five tumor cell lines. The mechanism of action of representative compound 5b was investigated in the HCT116 colorectal cancer cell line. It was shown that 5b reduced cell viability of cancer cells in a time and concentration dependent manner. Cells treated with 5b accumulate in the G2/M phase of the cell cycle and finally go into apoptosis.