Year: 2026
Type: article
Abstract: The global HIV/AIDS epidemic continues to demand durable antiretroviral therapies. HIV-1 protease (HIV-PR) remains a central target, and although darunavir (DRV) exhibits exceptional resilience, resistance evolution necessitates continued innovation. Building on DRV's success, structural modifications at key positions have yielded promising derivatives. In this work, we report the design and synthesis of over 20 DRV derivatives incorporating pyrazole and amino acid motifs at the P2' position. These substituents were introduced to strengthen interactions within the protease active site and expand opportunities for resistance coverage. Sulfur(VI) fluoride exchange (SuFEx) chemistry was employed as a robust late-stage diversification strategy, enabling efficient coupling and rapid library generation. This approach highlights the potential to access structurally diverse HIV-1 protease inhibitors, laying the groundwork for the development of next-generation therapeutics.
Source: Synthesis
DOI: 10.1055/a-2930-3820
Authors: Bipin Khanal, Pavel Yamanushkin, Brian Gold
Institution: New Mexico State University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7172319760