Click synthesis, anticancer and molecular docking evaluation of some hexahydro-6H-indolo[2,3-b]quinoxalines incorporated triazole moiety

Abstract

In the pathway of anticancer drug development, we designed and synthesized a novel series of 6-((1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4,4a,11a-hexahydro-6H-indolo[2,3-b]quinoxalines 13-20 through a simple multi-step protocol starting from Isatin. Initially, 6H-indolo[2,3-b]quinoxaline (3) was prepared by the condensation of isatin (1) with o-cyclohexyldiamine (2) then the obtained product was reacted with propargyl bromide resulting in the formation of N-propargyl derivatives 4. The latter compound was subjected to cycloaddition with a series of substituted aromatic azides 5-12 in the presence of copper (I) as catalyst to give the target molecules 13-20. The structure of the newly clicked 1,2,3-triazole-1,2,3,4,4a,11a-hexahydro-6H-indolo[2,3-b]quinoxalines 13-20 was confirmed on the basis of their elemental analysis and spectral data. Moreover, these compounds are screened against selected human cancerous cell lines: hepatocellular carcinoma (Hep-G2), breast cancer (MCF-7) and colon cancer (HCT116) relative to healthy noncancerous control skin fibroblast cells (BJ-1) to evaluate their cytotoxic effect. All the compounds showed superior cytotoxic activities against HepG2 while, compounds 15 and 18 exhibited significant in vitro activity against MCF-7 and HCT116, respectively. In addition, compound 15 was found to fit in the ATP binding pocket during docking experiments combined with molecular dynamic simulation. Lastly, we conducted a Petra/Osiris/Molinspiration (POM) study on the recently synthesized compound. The most promising candidates were identified by evaluating primary in silico parameters, which showed considerable differences among individual synthesized compounds. These features can promote future drug candidate designing to produce better derivatives in the search for the anticancer agents, particularly those with favorable ADME parameters, low toxicity, anticipated bioactivity, and bright futures.