Preparation of Some Novel Imidazopyridine Derivatives of Indole As Anticancer Agents: One-Pot Multicomponent Synthesis, Biological Evaluation and Docking Studies Publisher



Bakherad Z^{1, 5} ; Safavi M² ; Sepehri S³ ; Fassihi A¹ ; Sadeghialiabadi H¹ ; Bakherad M⁴ ; Rastegar H⁵ ; Larijani B⁶ ; Saghaie L¹ ; Mahdavi M⁶ Show Affiliations
Source: Research on Chemical Intermediates Published:2019

Abstract

A series of novel imidazopyridine derivatives of indole has been synthesized. All the synthesized derivatives were evaluated for their antiproliferative activity against A-549, T-47D, Hep-G2 and MCF-7 human cancer cell lines. The results demonstrated that some of these derivatives exhibited moderate to excellent cytotoxic activities. Compounds 7a having a cyclohexyl ring substituted to the second amine of imidazopyridyl moiety and phenyl ring of the C-2 indole ring and 7f with a para-methylphenyl ring at the same position exhibited the highest activity against the A-594 cell line with IC50 of 11.48 μM and 10.66 μM, respectively. The results indicate that compounds 7a and 7f are more cytotoxic towards cancer cell lines compared with etoposide in vitro. In addition, compounds, 7d and 7j showed the most potent activity against Hep-G2, equal to etoposide as the standard drug. Also, most of the compounds were inactive against the T-47D and MCF-7 cell lines. The morphological analysis by the acridine orange/ethidium bromide double-staining test and flow cytometry analysis indicated that compounds 7a and 7f induced apoptosis in A-549 cells. Furthermore, in silico and in vitro results of the synthesized compounds showed good correlation with each other. Molecular docking results of the compounds of the 7a–k series with the cyclohexyl ring substituted to the second amine of the imidazopyridyl moiety compared with the 7l–t members with the t-butyl group at the same position confirmed the effect of the higher lipophilicity on hydrophobic interactions with the studied enzymes. Moreover, all the compounds showed higher affinity to tubulin than topoisomerase IIα enzyme. © 2019, Springer Nature B.V.