According to the UNAIDS reports, more than 38 million people have been infected with HIV to date. With 5000 infections per day, 1.8 million new infections were reported in 2016. The combination of antiretroviral therapy (cART) has been able to control AIDS, but drug resistance and latency allow the HIV-1 virus to remain in cellular reservoirs preventing eradication. Studies have shown that in the case of HIV-1 infection, inhibition of Heat shock protein 90 (HSP90) prevents the reactivation of the virus from latent reservoirs in CD4+ T cells. These findings concluded HSP90 as a promising target to overcome the limitations of the current antiviral drug discovery approach.<br/>Our previously synthesized isoxazole acetamide analog 2l having a 3.5 times better therapeutic index (TI) than AUY922, a second-generation HSP90 inhibitor. Biological studies and molecular modeling confirm the importance of 2l as a potential anti-HIV candidate mediating through HSP90 modulations. Expanding our continued efforts towards drug discovery, we optimized the lead candidate 2l using SAR studies and synthesized novel isoxazole acetamide derivatives which showed similar biological activity against the HIV-1 infection. In this study, activity cliffs arising due to trivial structural change (6g vs 6d as shown in Figure 1) by Structure-activity Landscape index (SALI) analysis. This analysis aided 3-D pharmacophore generation that further will be used in virtual screening for the discovery and development of alternative antiviral leads for HIV.

"Synthesis and lead optimization of isoxazole acetamide derivatives as an anti-HIV agent"

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.