Pyrrolopyrimidine Derivatives as Dual COX-2/ACE2 Inhibitors: Design, Synthesis, and Anti-Inflammatory Evaluation

Hala Afifi^1*Samar S. Fatahala²Rania H. Abd El-Hameed²Dr.Shahenda Mahgoub³Radwan Said El-Haggar⁴Omnia Aly⁵Amal F. Gharib⁶Amira I. Sayed^2,7Heba Taha³

• ¹Research Directorate, City University Ajman, Ajman, United Arab Emirates
• ²Pharmaceutical Organic Chemistry Department, Helwan University Faculty of Pharmacy, Helwan, Egypt
• ³Department of Biochemistry and Molecular biology, Helwan University Faculty of Pharmacy, Helwan, Egypt
• ⁴Department of Pharmaceutical Chemistry, Helwan University Faculty of Pharmacy, Helwan, Egypt
• ⁵Medical Biochemistry Department, National Research Centre,Cairo, Egypt, Cairo, Egypt
• ⁶Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
• ⁷Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Egypt

Abstract: In this study, we report the design and synthesis of a new series of pyrrolopyrimidine derivatives de-veloped as dual‑target nonsteroidal anti‑inflammatory agents (NSAIDs). The compounds were evalu‑ ated for anti‑inflammatory properties, cyclooxygenase‑1/2 (COX‑1/COX‑2) inhibitory activity, and angi‑ otensin‑converting enzyme 2 (ACE2)–blocking activity in lipopolysaccharide (LPS)‑stimulated RAW 264.7 cells. Among the synthesized molecules, compounds 5a and 5b showed potent dual inhibitory activity, which was further supported by molecular docking and molecular dynamics simulations. These findings highlight the potential of selective COX‑2 inhibitors with concurrent ACE2 blockade as a prom‑ ising 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.