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

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

Eur J Med Chem. 2019 Feb 01;163:636-648

Authors: Khan I, Garikapati KR, Setti A, Shaik AB, Kanth Makani VK, Shareef MA, Rajpurohit H, Vangara N, Pal-Bhadra M, Kamal A, Kumar CG

Abstract
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.

PMID: 30562699 [PubMed - indexed for MEDLINE]

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