Pyrrolopyrimidine derivatives as dual COX-2/ACE2 inhibitors: design, synthesis, and anti-inflammatory evaluation

Abstract

In this study, we report the design and synthesis of a new series of pyrrolopyrimidine derivatives developed as dual-target nonsteroidal anti-inflammatory agents (NSAIDs). The compounds were evaluated for anti-inflammatory properties, cyclooxygenase-1/2 (COX-1/COX-2) inhibitory activity, and angiotensin-converting enzyme 2 (ACE2)–blocking activity in lipopolysaccharide (lipopolysaccharide)-stimulated RAW264.7 cells. Among the synthesized molecules, compounds 5a and 5b showed potent dual inhibitory activity, which was supported by molecular docking and molecular dynamics simulations. These findings highlight the potential of selective COX-2 inhibitors with concurrent ACE2 blockade as a promising therapeutic approach for controlling inflammation and modulating pathways relevant to viral entry and other inflammation-associated disorders. While ACE2 inhibition has received particular attention in the context of recent viral infections, the broader anti-inflammatory efficacy of these derivatives supports their potential as multi-target drug candidates.