Oxadiazol-based mTOR inhibitors with potent antiproliferative activities: synthetic and computational modeling

Abstract

Series of N-aryl-1,3,4-oxadiazole-2-amines and 3-aryl-1,2,4-oxadiazole-5-carboxamides derivatives were synthesized as novel chemotherapeutic agents. Synthesized compounds were evaluated for their anticancer activities against several cancer cell lines. Many analogues of 1,3,4-oxadiazole scaffold showed potent antiproliferative activities against breast cancer cell lines, with higher activities toward the metastatic breast cancer cell line (MDA-MB-231). Active analogues were profiled using in-house pharmacophore database in search for molecular target. Active analogues (2j and 2k) were found to fit the pharmacophoric map of ATP-competitive inhibitors of mTOR. The mTOR inhibitory activities of the most active compounds were confirmed with IC₅₀ values in nanomolar range. The N-aryl-1,3,4-oxadiazole-2-amines linked to a basic head is a novel ATP-competitive inhibitors of mTOR with potential activities for treatment of different types of cancer.

Keywords: Anticancer; Oxadiazole; Pharmacophore; mTOR.