HIV-1 protease inhibitors Compound C7(Colorado State University)

A series of 3-(2,2,2-trichloro-1-hydroxyethyl)imidazo[1,2-a]benzimidazole dihydrochlorides, e.g., I·2HCl, were synthesized and various pharmacol. properties studied.It was established that the synthesized compounds exhibited weak antioxidant activity.In addition, some of the synthesized compounds possessed platelet and erythrocyte antiaggregant properties, showed pronounced spasmolytic action, and had low toxicity.Some of them also exhibited anti-radiomimetic, hypotensive, and antiarrhythmic properties.

HIV-1 protease (PR) is initially synthesized as part of the Gag-Pol polyprotein precursor, which undergoes temporospatially regulated autoprocessing to liberate mature PR. The free mature enzyme is the target of currently available protease inhibitors (PIs). To explore alternative therapeutic strategies, we developed a cell-based high-throughput screening (HTS) platform targeting precursor autoprocessing, screened approximately 320,000 small molecules, and identified 27 compounds that partially suppress precursor autoprocessing. A highly sensitive infectivity assay confirmed that several compounds inhibited viral infectivity in a dose-dependent manner, with EC₅₀ values in the low micromolar range. Notably, hit compound C7 exhibited comparable potency against both wild-type and drug-resistant HIV strains, suggesting a novel mechanism of action. An initial structure-activity relationship (SAR) analysis via analog-by-catalog suggested that antiviral activity is influenced by specific chemical groups. This study provides proof of concept for an innovative drug discovery approach targeting HIV-1 PR autoprocessing as a potential strategy to combat drug resistance.