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

Arthit Makarasen; Mayuso Kuno; Suwicha Patnin; Nanthawan Reukngam; Panita Khlaychan; Sirinya Deeyohe; Pakamas Intachote; Busakorn Saimanee; Suchada Sengsai; Pornthip Boonsri; Apinya Chaivisuthangkura; Wandee Sirithana; Supanna Techasakul

doi:10.1055/a-0968-1150

Drug Research, Table of Contents

Drug Res (Stuttg) 2019; 69(12): 671-682
DOI: 10.1055/a-0968-1150

Original Article

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

Arthit Makarasen

¹Department of Chemistry, Laboratory of Organic Synthesis, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Mayuso Kuno

³Department of Chemistry, Faculty of Science, Srinakharinwirot University, Wattana, Bangkok, Thailand

,

Suwicha Patnin

³Department of Chemistry, Faculty of Science, Srinakharinwirot University, Wattana, Bangkok, Thailand

,

Nanthawan Reukngam

¹Department of Chemistry, Laboratory of Organic Synthesis, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Panita Khlaychan

¹Department of Chemistry, Laboratory of Organic Synthesis, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Sirinya Deeyohe

¹Department of Chemistry, Laboratory of Organic Synthesis, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Pakamas Intachote

²Biological Activity Test and Screening Unit, Central Facilities, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Busakorn Saimanee

²Biological Activity Test and Screening Unit, Central Facilities, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Suchada Sengsai

²Biological Activity Test and Screening Unit, Central Facilities, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

,

Pornthip Boonsri

³Department of Chemistry, Faculty of Science, Srinakharinwirot University, Wattana, Bangkok, Thailand

,

Apinya Chaivisuthangkura

³Department of Chemistry, Faculty of Science, Srinakharinwirot University, Wattana, Bangkok, Thailand

,

Wandee Sirithana

⁴Department of Chemical Technology, Faculty of Science and Technology, Suan Dusit University, Bangplat, Bangkok

,

Supanna Techasakul

¹Department of Chemistry, Laboratory of Organic Synthesis, Chulabhorn Research Institute, Laksi, Bangkok, Thailand

› Author Affiliations

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 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.

Keywords

synthesis - quinoline - molecular docking - hybrid - anti HIV-1 activity

Full Text

References

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Supplementary Material

Supplementary Material