Abstract
New target molecules, namely, 2-phenylamino-4-phenoxyquinoline derivatives, were designed using a molecular hybridization approach, which was accomplished by fusing the pharmacophore structures of three currently available drugs: nevirapine, efavirenz, and rilpivirine. The discovery of disubstituted quinoline indicated that the pyridinylamino substituent at the 2-position of quinoline plays an important role in its inhibitory activity against HIV-1 RT. The highly potent HIV-1 RT inhibitors, namely, 4-(2′,6′-dimethyl-4′-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6b) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6d) exhibited half-maximal inhibitory concentrations (IC50) of 1.93 and 1.22 µM, respectively, which are similar to that of nevirapine (IC50 = 1.05 µM). The molecular docking results for these two compounds showed that both compounds interacted with Lys101, His235, and Pro236 residues through hydrogen bonding and interacted with Tyr188, Trp229, and Tyr318 residues through π–π stacking in HIV-1 RT. Interestingly, 6b was highly cytotoxic against MOLT-3 (acute lymphoblastic leukemia), HeLA (cervical carcinoma), and HL-60 (promyeloblast) cells with IC50 values of 12.7 ± 1.1, 25.7 ± 0.8, and 20.5 ± 2.1 µM, respectively. However, 6b and 6d had very low and no cytotoxicity, respectively, to-ward normal embryonic lung (MRC-5) cells. Therefore, the synthesis and biological evaluation of 2-phenylamino-4-phenoxyquinoline derivatives can serve as an excellent basis for the development of highly effective anti-HIV-1 and anticancer agents in the near future.
Funder
Chulabhorn Research Institute
Thailand Research Fund
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献