Multiple spectroscopic and computational studies on binding interaction of 2-phenylamino-4-phenoxyquinoline derivatives with bovine serum albumin.

Binding characteristics of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 4-(2',6'-dimethyl-4'-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (1) and 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (2), to bovine serum albumin (BSA) under simulative physiological conditions were investigated by multiple spectroscopic and computational methods. The experimental results demonstrated that (1) and (2) bound to BSA at site III (subdomain IB), and quenched BSA fluorescence through a static quenching process. The binding interaction of (1) or (2) to BSA forms stable complexes with the binding constants (Kb) at the level of 104 L/mol and the number of binding site was determined to be 1 for both systems, indicating that new synthesized compounds occupied one site in BSA with moderate binding affinities. Based on the analysis of the thermodynamic parameters, it can be indicated that the main binding forces for interaction between BSA and both compounds were hydrogen bonding and van der Waals force. Synchronous fluorescence results revealed that the interaction of two compounds with BSA led to modifications in the microenvironment surrounding tryptophan residue of BSA. Circular dichroism spectra demonstrated alterations in the secondary structure of BSA induced by (1) and (2). Moreover, the experimental data of molecular docking and molecular dynamics (MD) simulations supported the results obtained from multiple spectroscopic techniques, confirming the binding interactions between both compounds and BSA.

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

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.

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

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.

Binding interaction of potent HIV-1 NNRTIs, amino-oxy-diarylquinoline with the transport protein using spectroscopic and molecular docking.

In the present investigation, the intermolecular interaction of 4-(4'-cyanophenoxy)-2-(4''-cyanophenyl)-aminoquinoline (1), a potent non-nucleoside HIV-1 reverse transcriptase inhibitors, with the transport proteins, namely bovine serum albumin (BSA) and human serum albumin (HSA), has been investigated under physiological conditions employing UV-Vis, fluorescence spectrophotometry, competitive binding experiments and molecular docking methods. The results indicated that binding of (1) to the transport proteins caused fluorescence quenching though a static quenching mechanism. The number of binding site (n) and the apparent binding constant (Kb) between (1) and the transport proteins were determined to be about 1 and 104-105 L·mol-1 (at three different temperatures; 298, 308, 318 K), respectively. The interaction of (1) upon binding to the transport proteins was spontaneous. The enthalpic change (ΔH°) and the entropic change (ΔS°) were calculated to be -56.50 kJ·mol-1, -72.31 J·mol-1 K-1 for (1)/BSA, respectively and computed to be -49.35 kJ·mol-1, -58.64 J·mol-1 K-1, respectively for (1)/HSA, respectively. The results implied that the process of interaction force of (1) with the transport protein were Vander Waals force and/or hydrogen bonding interactions. The site maker competitive experiments revealed that the binding site of (1) with the transport proteins were mainly located within site I (sub-domain IIA) in both proteins. Additionally, the molecular docking experiment supported the above results which confirmed the binding interaction between (1) and the transport proteins. This study will come up with basic data for explicating the binding mechanisms of (1) with the transport protein and can be great significance in the opening to clarify the transport process of (1) in vivo.

Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors.

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.