3 years ago

N-hydroxy-substituted 2-aryl acetamide analogs: A novel class of HIV-1 integrase inhibitors

N-hydroxy-substituted 2-aryl acetamide analogs: A novel class of HIV-1 integrase inhibitors
Ajay Kesharwani, Aakanksha Agarwal, Satish K. Gupta, Utsab Debnath, Prachi Kumar, Seturam B. Katti
An in silico method has been used to discover N-hydroxy-substituted 2-aryl acetamide analogs as a new class of HIV-1 integrase inhibitors. Based on the molecular requirements of the binding pocket of catalytic active site, two molecules (compounds 2 and 4b) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound 4b as an active fragment which was further used to synthesize new leads as HIV-1 integrase inhibitors. Finally, six promising compounds (compounds 5b, 5c, 5e, 6–2c, 6–3b, and 6–5b) were identified by integrase inhibition assay (>50% inhibition). Based on in vitro anti-HIV-1 activity in a reporter gene-based cell assay system, compounds 5d, 6s, and 6k were found as novel HIV-1 integrase inhibitors due to its better selectivity index. Additionally, docking study revealed the importance of H-bond as well as hydrophobic interactions with Asn155, Lys156, and Lys159 which were required for their anti-HIV-1 activity. Based on an in silico approach, novel classes of N-hydroxy-substituted 2-aryl acetamide analogues were identified as anti-HIV-1 integrase inhibitors. To do that, de novo-designed molecules were chemically and biologically evaluated to find out a hit (compound 4b). The structure of compound 4b was further optimized for better binding affinity toward the integrase binding pocket. Finally, biological evaluation followed by docking studies revealed compounds 6–2c and 6–5b as new leads of HIV-1 integrase inhibitors.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12974

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