A series of thirty compounds of quinazolinone-Schiff's base hybrids were rationally designed, synthesized, and evaluated for their in vitro Phosphodiesterase 4B inhibition, anti-lung and anti-colon cancer activities. Compounds 9, 16, 23, 29, 30, 31, 32 and 33, each possessing a tri-hydroxy moiety, showed the highest inhibitory activity (56.05-89.07%) at 10 µM concentration if compared to rolipram. Compounds 16 and 23 showed good anti-lung cancer activity with IC50 1.55 and 1.30 µM, respectively. Moreover, compound 16 showed high anti-colon cancer activity with IC50 0.6 µM. Compound 33 showed good affinity and molecular binding modes towards the key amino acid Gln 443 and Phe 446 for inhibition of the target enzyme. Finally, active compounds showed good ADME calculations.
Genus Tabebuia is famous for its traditional uses and valuable phytoconstituents. Our previous investigation of Tabebuia species noted the promising anticancer activity of T. guayacan Hemsl. leaves extract, however, the mechanism underlying the observed anticancer activity is still unexplored. The current research was designed to explore the phytochemical content as well as to address the phytoconstituent(s) responsible for the recorded anticancer activity. Accordingly, sixteen compounds were isolated, and their structures were elucidated using different spectroscopic techniques. The drug-likeness of the isolated compounds, as well as their binding affinity with four anticancer drug target receptors: CDK-2/6, topoisomerase-1, and VEGFR-2, were evaluated. Additionally, the most promising compounds were in vitro evaluated for inhibitory activities against CDK-2/6 and VEGFR-2 enzymes using kinase assays method. Corosolic acid (3) and luteolin-7-O-β-glucoside (16) were the most active inhibitors against CDK-2 (−13.44 kcal/mol) and topoisomerase 1 (−13.83 kcal/mol), respectively. Meanwhile, quercetin 3-O-β-xyloside (10) scored the highest binding free energies against both CDK-6 (−16.23 kcal/mol) as well as against VEGFR-2 protein targets (−10.39 kcal/mol). Molecular dynamic simulation indicated that quercetin 3-O-β-xyloside (10) exhibited the least fluctuations and deviations from the starting binding pose with RMSD (2.6 Å). Interestingly, in vitro testing results confirmed the potent activity of 10 (IC50 = 0.154 µg/mL) compared to IC50 = 0.159 µg/mL of the reference drug ribociclib. These findings suggest the three noted compounds (3, 10, and 16) for further in vivo anticancer studies.
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