Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors
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2019
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Georg Thieme Verlag
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Journal Title
Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors
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Abstract
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 �-� 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 _M concentration. Interestingly, 8a was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC 50 of 4.63�0.62 _g/mL, which was similar with that in EFV and TMC278 (IC 50 7.76�0.37 and 1.57�0.20 _g/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. � 2019 Georg Thieme Verlag. All rights reserved.
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Drug Research