Synthesis, characterization, biological evaluation and molecular docking of a new quinazolinone-based derivative as a potent dual inhibitor for VEGFR-2 and EGFR tyrosine kinases.

An efficient process for the preparation of a new ethyl 2-((3-(4-fluorophenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio) acetate (5) was described. The prepared derivative was synthesized using the S-arylation method. Several analytical techniques, such as NMR, Raman and infrared spectroscopy, were used to characterize this compound. The compound was screened for cytotoxic activity against three human cancer cell lines: human cervical cancer (HeLa), human lung adenocarcinoma (A549) and triple negative breast cancer (MDA-MB-231) cells using an MTT assay. It exhibited potent cytotoxic activity against the tested cell lines with IC50 values in the low micromolar range when compared to a standard drug, docetaxel. It also displayed potent inhibitory activity towards VEGFR-2 and EGFR tyrosine kinases, reflecting its potential to act as an effective anti-cancer agent.Communicated by Ramaswamy H. Sarma.

Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors.

We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 µM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM.