Synthesis, anticancer evaluation and in silico studies of novel N-substituted arylidenethiazolidine-2,4-dione derivatives as adenosine monophosphate-activated protein kinase activators

Abstract

Design and development of AMP‐activated protein kinase (AMPK) activator emerged as a potential therapeutic approach for various types of cancers. In this context, thiazolidine 2,4‐dione was invariably found as an important skeleton for the development of new lead compounds. The present study described the synthesis and antitumor evaluation of new hybrids of N‐substituted arylidenethiazolidine‐2,4‐diones as AMPK activators. The in vitro results revealed that several of newly prepared compounds exhibited significant anticancer activity against human prostate cancer (PC3) and breast cancer (MDMB‐231) cell growths with IC50 in the range of 2–10 μM. Particularly, molecular hybridization of thiazolidine 2,4‐dione with N‐2‐(4‐(trifluoromethyl)phenyl)ethanol and azaindole (compound 16) was the most effective among the series against both PC3 and MDMB‐231 cell lines with IC50 4.28 and 2.5 μM, respectively. Western blot analysis of these thiazolidine 2,4‐dione hybrids showed increased (p)‐AMPK level in the PC‐3 cells indicating direct activation of AMPK. The docking studies at the interface of activator binding site of the AMPK reinforced the in vitro results of potent compounds 13, 16, and 25 having low docking scores −9.0, −9.5, and −9.1 Kcal/mol, respectively.