N‐hydroxy‐substituted 2‐aryl acetamide analogs: A novel class of HIV‐1 integrase inhibitors. (26th April 2017)

• Record Type: Journal Article
• Authors: Debnath, Utsab; Kumar, Prachi; Agarwal, Aakanksha; Kesharwani, Ajay; Gupta, Satish K.; Katti, Seturam B.
• Is Part Of: Chemical biology & drug design. Volume 90:Number 4(2017)
• Page Start: 527
• Page End: 534
• Publication Date: 2017-04-26
• Subjects: AIDS -- HIV‐1 integrase -- molecular modeling -- ZINC database; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12974
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : 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 (compounds2 and4b ) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound4b as an active fragment which was further used to synthesize new leads as HIV‐1 integrase inhibitors. Finally, six promising compounds (compounds5b, 5c, 5e, 6–2c, 6–3b, and6–5b ) were identified by integrase inhibition assay (>50% inhibition). Based on in vitro anti‐HIV‐1 activity in a reporter gene‐based cell assay system, compounds5d, 6s, and6k 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. Abstract : 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 (compound4b ). The structure of compound4b was further optimized for better binding affinity toward the integrase binding pocket. Finally, biological evaluation followed by docking studies revealed compounds6–2c and6–5b as new leads of HIV‐1 integrase inhibitors.