Design and anti-HIV activity of arylsulphonamides as non-nucleoside reverse transcriptase inhibitors

作者：Singh Anuradha; Yadav Madhu; Srivastava Ritika; Singh Nidhi; Kaur Rajinder; Gupta Satish K; Singh Ramendra K^*

来源：Medicinal Chemistry Research, 2016, 25(12): 2842-2859.

DOI：10.1007/s00044-016-1707-7

• Arylsulphonamide
• HIV
• NNRTIs
• TZM-bl cells
• Luciferase reporter assay

Design and anti-HIV activity of a series of arylsulphonamide derivatives as possible non-nucleoside reverse transcriptase inhibitors have been discussed. Compounds designed on the basis of Lipinski's rule of five and having H-bond donor and acceptor sites were synthesized and screened in vitro to assess their human immunodeficiency virus type 1 reverse transcriptase inhibitory activity using TZM-bl cells. In silico studies using Discovery Studio 3.0 software showed that these molecules formed H-bonds and exhibited pi-pi, pi-+ interactions, with amino acids in the non-nucleoside inhibitor binding pocket, and formed more stable complexes (total interaction energy in the range of (-) 47.85-(-) 77.01 kcal/mol) with human immunodeficiency virus type 1 reverse transcriptase in comparison to nevirapine and etravirine, (-) 45.79 and (-) 61.43 kcal/mol, respectively, and thus, lower EC50 values were predicted. The molecule, 4-(4-chloro-benzenesulphonyl amino)-N-(1H-indazole-5-yl)-benzamide showed significant inhibition of human immunodeficiency virus type 1 growth under in vitro conditions with EC50 value in the range of 4.89 x 10(-5) mu m. However, its selectivity index value was 2.45 only, which was much lower than nevirapine and etravirine. The reverse transcriptase analysis, based on luciferase reporter assay, of this compound proved its nature as non-nucleoside reverse transcriptase inhibitors. Though the molecules showed low inhibitory action against human immunodeficiency virus type 1 under in vitro conditions, the idea to develop non-nucleoside reverse transcriptase inhibitors was vindicated.

• 出版日期2016-12