Novel anti-cancer agents: design, synthesis, biological activity, molecular docking, and MD simulations of 2, 3, 4, 5-tetrahydro-1 H -pyrido-[4,3-b]indole derivatives

In the previous research, our group designed and synthesized 2,3,4,5-tetrahydro-1 H -pyrido-[4,3-b] indoles, which showed high anti-tumor activity. In this study, a series of novel 2,3,4,5-tetrahydro-1 H -pyrido-[4,3-b] indole derivatives were designed by introducing an alkyl or aralkyl and a sulfonyl group, which are considered as the pharmacophores of some antitumor drugs based on the combination principles, and synthesized. The antiproliferative activity of all the target compounds were evaluated against Hela, A549, HepG2, and MCF-7 cell lines using the MTT assay in vitro. The results were represented by IC 50 values. All compounds showed moderate to excellent antiproliferative activity with IC 50 values between 0 μM and 100 μM against cancer cells. The proliferations of Hela, A549, HepG2, and MCF-7 cell lines were inhibited in a dose-dependent manner, and the cytolytic activity was markedly inhibited at the same time. The IC 50 values of intermediate 3 inhibited against Hela, A549, HepG2, and MCF-7 cell lines were 52.75, 50.30, 60.31, and 54.39 μM, respectively, which were higher than the new compounds that we expected. The compounds 4a – 4d bearing sulfonyl, substituted by electron donating group, showed moderate to significant antiproliferative activity, in which compound 4c was the best with the IC 50 values of 13.71, 9.42, 15.06, and 14.77 μM, and these results suggested that the introduction of sulfonyl could increase the antiproliferative activity of 2,3,4,5-tetrahydro-1 H -pyrido-[4,3-b]indole. Compounds 4e – 4g bearing alkyl, phenyl, and arylated alkyl produced good antiproliferative activity and the IC 50 value of 4 g was lower than 30 μM. The target compounds were more potent against A549 compared to the other three cell lines. Molecular docking studies revealed the binding orientations of all the synthesized compounds in the active site of c-Met. Moreover, molecular dynamics simulations have been performed to evaluate the binding stabilities between the synthesized compounds and their receptors.