Pyrrolidino Analogues of Gefitinib with Improved EGFR Inhibition, Cancer Cell Cytotoxicity, and Pharmacokinetic Properties
The binding mode analysis of Gefitinib revealed that 6-propylmorpholino group
(sidechain) shows no interactions due to its weak electron density. In order to modify the
electron density of Gefitinib’s sidechain, novel pyrrolidino analogs of Gefitinib where
morpholino groups were replaced by substituted pyrrolidino groups were synthesized. Gefitinib
derivatives with high electronegativity atoms or groups in the pyrrolidino moiety always exhibit
high potent activity against EGFR and human cancer cell lines, A431, MDA-MB-231 and
A549. Among these derivatives, 16 displayed the best pharmacokinetic properties that make it
to be a promising candidate for developing drugs to replace Gefitinib.
Keywords: Gefitinib, anticancer, EGFR, pyrrolidino analogue, pharmacokinetic property.
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