Ruthenium-Catalyzed Enantioselective Hydrogenation of Quinoxalinones and Quinazolinones

An efficient Ru-catalyzed enantioselective hydrogenation of quinoxalinone and quinazolinone derivatives has been successfully developed, providing a straightforward and facile access to chiral dihydroquinoxalinones and dihydroquinazolinones with excellent results (89-98% yields,...

Design, synthesis of novel quinazolinone-based oxobutanonitrile derivatives as antiproliferative agents targeting human breast cancer

Background: Breast cancer (BC) is among the leading causes of death among women worldwide. Medical interest has focused on quinazolinone derivatives approved and utilized in antitumor medications. Objective: Novel quinazolinone-based oxobutanonitrile derivatives were designed, synthesized, and screened for in vitro anti-BC activity. Methods: The antiproliferative activities were determined using MTT assay against MCF-7 and MDA-MB-231 cell lines. EGFR, ARO, and caspase-9 enzymes were selected to explore the mechanism of action of the most potent compounds. Results: Tested compounds showed better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed with the most active compounds. The thienyl derivative 5 induced the greatest activation in caspase-9 level in treated MCF-7 breast cancer samples. The o-tolylhydrazone 3b, exhibiting promising ARO inhibition and weak EGFR inhibition, produced a noticeable high overexpression of caspase-9 and showed pre-G1 apoptosis and cell cycle arrest at G2/M phase for MCF-7 cells and at S-phase for MDA-MB-231 cells. Docking results revealed that 3b, elicited binding affinities to ARO comparable to those of letrozole. Conclusion: The obtained results support the therapeutic importance of some of these compounds as anti-BC agents in light of the simple methodology used for their synthesis. Their design offered a way for the optimization and development of apoptotic quinazolinone-based ARO and EGFR inhibitors.

Synthesis of Alicyclic 2-Methylenethiazolo[2,3-b]quinazolinone Derivatives via Base-Promoted Cascade Reactions

The synthesis of alicyclic 2-methylenethiazolo[2,3-b]quinazo­l­inones is performed via base-promoted cascade reactions, starting from either alicyclic β-amino propargylamides using carbon disulfide, or from alicyclic ethyl 2-isothiocyanatocarboxylates by addition of propargylamine. In both cases the cascade reaction proceeds by way of a favoured 5-exo-dig process during the second ring closure, as confirmed by full NMR spectroscopic assignments. Moreover, a high-yielding retro­-Diels–Alder (RDA) reaction is performed on the norbornene derivatives leading to 2-methylene-2H-thiazolo[3,2-a]pyrimidin-5(3H)-ones. The obtained compounds exert modest antiproliferative activities against a panel of human gynaecological cancer cell lines.

Molecular Dynamic Simulations and Binding Free Energy Evaluations of Thiazolo-[2,3-b] Quinazolinone Derivatives With wtEGFR-TKD and "TMLR" Mutant EGFR-TKD

Cancer causes innumerable deaths every year globally. Breast cancer and non-small cell lung carcinoma (NSCLC) are the most prevalent worldwide. The epidermal growth factor receptor tyrosine kinases play a pivotal role in manifestations of cellular signals in carcinoma cells and thus are endorsed as therapeutic targets in cancer management. EGFR-TKD is a good option for the treatment of cancer, but the resistance shown by first-generation TKIs leads to hyperphosphorylation, overexpression, and mutations of EGFR-TKD. The new molecular scaffolds of thiazolo-[2,3-b] quinazolinones were evaluated against EGFR-TKD via molecular docking simulations and thereby linked with molecular dynamic simulations to identify the ligand stability with EGFR-TKD’s. The binding energy of thiazolo-[2,3-b] quinazolinones is approximately similar to that of reference molecules found against both wild type wtEGFR-TKD and EGFR-TKD mutant "TMLR" (T790M/L858R) in this study. According to ADMET analysis, thiazolo-[2,3-b] quinazolinone derivatives (5ab, 5aq, and 5bq) are safe. The stability was investigated at an atomistic level by molecular dynamic simulations, and the strength of the bindings was calculated by the molecular mechanics Poisson-Boltzmann surface areas continuum solvation MM-PBSA method. The RMSD, radius of gyration, and SASA trajectories were studied in detail. The ΔGbind generated by heterocyclic 5aq thiazolo-[2,3-b] quinazolinone was found to be -63.723 ± 0.419 kJ/mol against the EGFR-TKD mutant "TMLR" and it was -51.551 ± 0.409 kJ/mol against wtEGFR-TKD. This study concludes that the top ranked complexes 5ab, 5aq, and 5bq with both wild and mutated types of EGFR-TKD corroborate that thiazolo-[2,3-b] quinazolinone derivatives, like the FDA-approved drug erlotinib, may be potent inhibitors of EGFR-TKD for patients with NSCLC.