Effective synthesis of novel dihydrobenzisoxazoles bearing the 2-aminothiazole moiety and evaluation of the antiproliferative activity of their acylated derivatives.

Effective method of synthesis of 8-aryl-4,5-dihydrothiazolo[4',5':3,4]benzo[1,2-c]isoxazol-2-amines was developed. The method includes α-keto bromination of 3-aryl-6,7-dihydrobenzo[c]isoxazol-4(5H)-ones followed by condensation of obtained bromo derivatives with thiourea in acetonitrile with 92-98% yield. Using virtual screening, a series of acylated derivatives of obtained compounds was selected as potential HSP90 inhibitors. These compounds were prepared and evaluated as antiproliferative agents against three cancer cell lines (A431, 22Rv1, MCF-7). Compounds 8b, 8c and 8q exhibiting high antiproliferative potency against MCF-7 breast cancer cells with the IC50 value range from 2.3 to 9.5 µM were chosen for in-depth evaluation. Remarkable effects of selected compounds have been found on HSP90 client proteins, including steroid hormone receptors and anti-apoptotic factor BCL2. The obtained compounds are of interest for anticancer drug development.