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

TL;DR

Researchers designed new pyrrolopyrimidine compounds that act as dual inhibitors of COX-2 and ACE2, showing promise as anti-inflammatory drugs.

Contribution

The study introduces novel pyrrolopyrimidine derivatives with dual COX-2/ACE2 inhibitory activity, offering a new approach for inflammation control.

Findings

Compounds 5a and 5b demonstrated potent dual inhibitory activity against COX-2 and ACE2.

Molecular docking and dynamics simulations supported the inhibitory potential of the compounds.

The compounds show broader anti-inflammatory efficacy and relevance to viral entry pathways.

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.

Chemical structures of Indomethacin and a novel pyrrolopyrimidine compound. Indomethacin features a benzo-pyrrole fused ring, indole bearing C=O, and a para-substituted phenyl ring. The novel compound shows a pyrrolopyrimidine fused ring, a free C=O, a pyrazole ring, and a para-substituted phenyl ring, described as active NSAIDs against SARS-CoV-2 main protease.

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