Design, synthesis, in silico pharmacokinetics prediction and biological evaluation of 1,4-dihydroindeno[1,2-c]pyrazole chalcone as EGFR /Akt pathway inhibitors

In an attempt to develop potent and selective anticancer agents, a series of 15 conjugates of 1,4-dihydroindeno[1,2-c]pyrazole chalcone (12a-o) were designed, synthesized and evaluated for their antiproliferative activity against MCF7, A549, MDA-MB-231, HCT116 and SKBR3 human cancer cell lines. Among them, 12h, 12l and 12m showed IC50 values: 3.82, 5.33 and 4.21 μM, respectively, on A549 cell with respect to the positive control, Erlotinib (IC50 value: 10.26 μM). Detailed biological assays showed accumulation of mitotic cells in G2/M phase. In addition, Western blot analysis and immunofluorescence study revealed inhibition of EGFR and Akt pathways. In silico computational studies were also carried out to predict the binding modes and pharmacokinetic parameters of these conjugates. [Display omitted] •A series of fifteen 1,4-dihydro indeno[1,2-c]pyrazole chalcone conjugates (12a-12o) were synthesized and screened for their anti-proliferative activity.•Compounds 12h, 12l and 12m showed significant cytotoxicity with IC50 values ranging from 3.82–5.89 μM and also induced cell cycle arrestat G2/M phase.•Western blot analysis and immunofluoresence study showed EGFR and Akt pathway inhibition which was proved by molecular docking studies.•In sillico studies like Lipinski rule and Swiss ADME showed zero violation of Lipinski rule and pharmacokinetics drug like property.•Compounds 12h, 12l and 12m can be considered as interesting lead molecules for further development of more potent anticancer agents.