Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Abstract

A new series of 1 H -pyrrole ( 6a–c , 8a–c ), pyrrolo[3,2- d ]pyrimidines ( 9a–c ) and pyrrolo[3,2- e ][1, 4]diazepines ( 11a–c ) were designed and synthesised. These compounds were designed to have the essential pharmacophoric features of EGFR Inhibitors, they have shown anticancer activities against HCT116, MCF-7 and Hep3B cancer cells with IC 50 values ranging from 0.009 to 2.195 µM. IC 50 value of doxorubicin is 0.008 µM, compounds 9a and 9c showed IC 50 values of 0.011 and 0.009 µM respectively against HCT-116 cells. Compound 8b exerted broad-spectrum activity against all tested cell lines with an IC 50 value less than 0.05 µM. Compound 8b was evaluated against a panel of kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 and GSK3 alpha kinases with 10–23% compared to imatinib (1–10%). It has also arrested the cell cycle of MCF-7 cells at the S phase. Its antiproliferative activity was further augmented by molecular docking into the active sites of EGFR and CDK2 cyclin A1.

Design, synthesis, anticancer evaluation, and in silico ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

“…The toxicity parameters of the synthesized compounds were calculated using Discovery studio 4.0 as described 46–49 in ESI †…”

Design, synthesis, and biological evaluation of novel bioactive thalidomide analogs as anticancer immunomodulatory agents

“…The toxicity parameters of the synthesized compounds were calculated using Discovery studio 4.0 as described 62–65 in ESI †…”

Discovery of Some Heterocyclic Molecules as Bone Morphogenetic Protein 2 (BMP-2)-Inducible Kinase Inhibitors: Virtual Screening, ADME Properties, and Molecular Docking Simulations

“…The output from MOE was further analyzed and visualized using Discovery Studio 4.0 software [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”