Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3K alpha inhibitors with potent antitumor activity

摘要

Using a rational design strategy for isoform-selective inhibition of PI3K alpha, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3K alpha inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms beta, gamma, delta and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties. (C) 2020 Elsevier Masson SAS. All rights reserved.