N-hydroxy-substituted 2-aryl acetamide analogs: A novel class of HIV-1 integrase inhibitors.
Utsab DebnathPrachi KumarAakanksha AgarwalAjay KesharwaniSatish K GuptaSeturam B KattiPublished in: Chemical biology & drug design (2017)
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.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- hepatitis c virus
- hiv aids
- men who have sex with men
- molecular docking
- south africa
- stem cells
- molecular dynamics
- gene expression
- high throughput
- single cell
- dna methylation
- transcription factor
- copy number
- genome wide
- ionic liquid
- single molecule