Structural Basis of 2-Phenylamino-4-phenoxyquinoline Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

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.

Exploring Darunavir, Rilpivirine and Etravirine as Potential Therapies for Bladder Cancer: Efficacy and Synergistic Effects

“…This drug has been tested in several cancer cell types, but never in bladder cancer. Of note, a study that used 10 cancer cell lines, from breast, lung, cervical, and liver cancer, among others, showed that this drug is also effective at 48 h in most of them with an IC 50 ranging from 4.3–87.4 µM, showing that the results obtained in this study are lower than most obtained in the literature for the same time point, only having a lower result in acute leukemia cells, demonstrating the extreme promise of RPV in bladder cancer [ 39 ]. In contrast, the IC 50 obtained for 72 h (59.63 µM) was higher than what was obtained in two studies, one for acute myeloid leukemia and colorectal, pancreatic, and ovarian carcinoma [ 40 ], and the other for pancreatic cancer [ 31 ].…”

Computational Screening of Phenylamino-Phenoxy-Quinoline Derivatives against the Main Protease of SARS-CoV-2 Using Molecular Docking and the ONIOM Method

“…To analyze the enzyme–small molecule interaction, ONIOM supports accurate molecular docking and has been widely used to study antiviral activity [ 23 , 24 ]. The two-layered ONIOM calculations were managed using the Gaussian 16 program and optimized by DFT at the B3LYP/6-31G(d,p) level and the semi-empirical PM6 method.…”

“…In the search for novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), phenylamino-phenoxy-quinoline derivatives have been synthesized from a combination of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), and rilpivirine (TMC278) [ 22 , 23 ]. These compounds can be divided into two groups, 4,6-disubstituted quinoline ( 1 – 4 ) and 2,4-disubstituted quinoline ( 5 – 8 ), and have been evaluated for their inhibitory effect on HIV-1 reverse transcriptase.…”

Design, cross-docking and ONIOM studies of potent antiviral HIV-1 nonnucleoside reverse transcriptase inhibitors

“…In addition, the crystal structure 4G1Q of the HIV-1 RT enzyme in a complex with RPV corresponded with the inhibitory activity against HIV-1 RT. A previous report also showed that RPV provided the most potential inhibition of nonnucleoside reverse transcriptase inhibitors (NNRTIs) [19,20]. Consequently, 4G1Q was selected for further study as the most suitable crystal structure for the binding interaction between ligands and HIV-1 RT based on the determination of the binding energy.…”

“…The interaction of (2) in the binding pocket of HIV-1 RT was similar to that of NVP, EFV, and RPV because those ligands performed two conventional hydrogen bonds with LYS101. In addition, compounds (1) and ( 2) have also been examined for HIV-1 RT inhibiting activity and exhibited inhibition rates of 25.46% and 27.85% at 1 µM concentration, respectively [19,20]. Therefore, 4-(2′,6′-dimethyl-4′-cyanophenoxy)-6-(4′′-cyanophenyl)-aminoquinoline (1) and 4-(2′,6′-dimethyl-4′cyanophenoxy)-2-(4′′-cyanophenyl)-aminoquinoline (2) will be utilized to develop new anti-HIV-1RT agents.…”