Discovery of 2-isoxazol-3-yl-acetamide analogues as heat shock protein 90 (HSP90) inhibitors with significant anti-HIV activity

• Published in: European journal of medicinal chemistry 2019-12, Vol.183, p.111699-111699, Article 111699
• Main Authors: Trivedi, Jay, Parveen, Afsana, Rozy, Farhana, Mitra, Alapani, Bal, Chandralata, Mitra, Debashis, Sharon, Ashoke
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Androstenols - chemical synthesis; Androstenols - chemistry; Androstenols - pharmacology; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; anti-HIV compound; Dose-Response Relationship, Drug; Drug Discovery; HIV-1 - drug effects; HIV-1 - metabolism; HSP90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Isoxazole; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111699

The recent burst of explorations on heat shock protein 90 (HSP90) in virus research supports its emergence as a promising target to overcome the drawbacks of current antiviral therapeutic regimen. In continuation of our efforts towards the discovery of novel anti-retroviral molecules, we designed, synthesized fifteen novels 2-isoxazol-3-yl-acetamide based compounds (2a-o) followed by analysis of their anti-HIV activity and cytotoxicity studies. 2a-b, 2e, 2j, and 2l-m were found to be active with inhibitory potentials >80% at their highest non-cytotoxic concentration (HNC). Further characterization of anti-HIV activity of these molecules suggests that 2l has ∼3.5 fold better therapeutic index than AUY922, the second generation HSP90 inhibitor. The anti-HIV activity of 2l is a cell type, virus isolate and viral load independent phenomena. Interestingly, 2l does not significantly modulate viral enzymes like Reverse Transcriptase (RT), Integrase (IN) and Protease (PR) as compared to their known inhibitors in a cell free in vitro assay system at its HNC. Further, 2l mediated inhibition of HSP90 attenuates HIV-1 LTR driven gene expression. Taken together, structural rationale, modeling studies and characterization of biological activities suggest that this novel scaffold can attenuate HIV-1 replication significantly within the host and thus opens a new horizon to develop novel anti-HIV therapeutic candidates. [Display omitted] •15 novel 2-isoxazol-3-yl-acetamide analogues were synthesized through novel intramolecular ring contraction.•6, out of 15 derivatives inhibited HIV-1 replication significantly at nontoxic concentration.•Compound 2l demonstrated high therapeutic index with highly conserved anti-HIV activity.•2l binds to the N-terminal ATP binding pocket of HSP90 and inhibits HIV-1 transcription in HSP90 dependent manner.