Synthesis of C-2 and C-3 substituted quinolines and their evaluation as anti-HIV-1 agents

• Published in: Bioorganic chemistry 2018-10, Vol.80, p.591-601
• Main Authors: Shah, Purvi, Naik, Dharav, Jariwala, Nisha, Bhadane, Deepali, Kumar, Sanjay, Kulkarni, Smita, Bhutani, Kamlesh Kumar, Singh, Inder Pal
• Format: Article
• Language: English
• Subjects: 1,3,4-Oxadiazole; Anti-HIV-1; Entry inhibition; Fusion inhibition; Quinoline; α,β-Unsaturated amide
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.07.016

[Display omitted] •Thirty-one substituted quinolines were synthesized exploring C-2 and C-3 positions.•Synthesized compounds included imines, amides and 1,3,4-oxadiazoles of quinoline.•All the compounds were evaluated for anti-HIV-1 potential.•31 showed activity against HIV-1VB59 (IC50 3.35 μM) and HIV-1UG070 (IC50 2.57 μM).•31 showed entry inhibition (IC50 1.40 μM) and cell fusion inhibition (IC50 0.96 μM). A plenty of natural products and synthetic derivatives containing quinoline moiety have been reported to possess various pharmacological activities. Quinolines such as 2-styrylquinolines and 8-hydroxyquinolines are extensively studied for their anti-HIV-1 activity and found to act mainly through HIV-1 integrase enzyme inhibition. In continuation of our efforts to search for newer anti-HIV-1 molecules, thirty-one quinoline derivatives with different linkers to ancillary phenyl ring were synthesized and evaluated for in vitro anti-HIV-1 activity using TZM-bl assays. Compound 31 showed higher activity in TZM-bl cell line against HIV-1VB59 and HIV-1UG070 cell associated virus (IC50 3.35 ± 0.87 and 2.57 ± 0.71 μM) as compared to other derivatives. Compound 31 was further tested against cell free virus HIV-1VB59 and HIV-1UG070 (IC50 1.27 ± 0.31 and 2.88 ± 1.79 μM, TI 42.20 and 18.61, respectively). This lead molecule also showed good activity in viral entry inhibition assay and cell fusion assay defining its mode of action. The activity of compound 31 was confirmed by testing against HIV-1VB51 in activated peripheral blood mononuclear cells (PBMCs). Binding interactions of 31 were compared with known entry inhibitors.