Synthesis of N-(2-(tert-Butylamino)-2-oxoethyl)-2,2-dichloro-N-aryl(alkyl)acetamides as Anticancer Agents: Molecular Modeling and Biological Evaluations

Abstract

Dichloroacetate (DCA) is considered as a highly bioavailable and small anticancer agent which reduces tumor growth through inhibition of pyruvate dehydrogenase kinases. Various DCA derivatives were designed, synthesized and eluated by FT-IR, 1HNMR, 13CNMR and Mass spectrum. Biological evaluations of the synthesized compounds were evaluated against three human cancer cell lines, A549 (lung), MCF-7 (breast), and MDA-MB-231 (breast), as well as a non-tumorigenic breast cell line (MCF-10A). Among synthesized compounds, N-(2-(tert-butylamino)-1-(4-nitrophenyl)-2-oxoethyl)-2,2-dichloro-N-(2-fluorophenyl)acetamide (A5) had a promising cytotoxic effect with IC50 values of 11.94, 15.57, and 16.54 μM against MCF-7, MDA-MB-231, and A549 cells, respectively. It can also induce apoptosis in MCF-7 cell line. Molecular docking and molecular dynamic simulation studies were also carried out show binding sites and energies to the PDKs isoenzymes. All of the compounds demonstrated appropriate selectivity between cancerous and non-cancerous cell lines. These results provide valuable insight for the additional development of novel dichloroacetate-containing compounds.