Synthesis, Characterization and Glyoxalase Inhibitory Activity of 4,6-Diheteroarylpyrimidine-2-amine Derivatives: In Vitro and In Silico Studies

Alidmat, Mohammad Murwih; Alhawarri, Maram B.; Al-Refai, Mahmoud; Mansi, Iman A.; Al-Balas, Qosay; Ibrahim, Mohammad M.

doi:10.21608/ejchem.2024.289371.9720

Synthesis, Characterization and Glyoxalase Inhibitory Activity of 4,6-Diheteroarylpyrimidine-2-amine Derivatives: In Vitro and In Silico Studies

Document Type : Original Article

Authors

¹ Department of Chemistry, Faculty of Science, Al al-Bayt University, P.O.BOX 130040, Al-Mafraq 25113, Jordan

² Department of Pharmacy, Faculty of Pharmacy, Jadara University, P.O.Box 733, Irbid 21110, Jordan.

³ Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical sciences, The Hashemite University, Zarqa, Jordan.

⁴ Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.

10.21608/ejchem.2024.289371.9720

Abstract

New series of 4,6-diheteroarylpyrimidine-2ـamines (4a-e) and (5a-c) were prepared by cyclization of particular chalcones (2) or (3) with guanidine nitrate in the presence of potassium hydroxide. Chalcones (2) and (3) were prepared by base-catalyzed Claisen-Schmidt condensation of heteroaryl aldehydes (1) with 2-acetyl-5-chlorothiophene and 3-acetyl-2,5-dichlorothiophene, respectively. All the newly synthesized compounds were characterized by spectroscopic and spectrometric techniques such as IR, 1H NMR, 13C NMR and mass spectrometry. This study evaluated in vitro glyoxalase I (GLO-I) inhibitory activity, coupled with molecular docking analysis. Spectroscopic methods confirmed the structures, and structure-activity relationship was established, revealing the importance of chloro substitutions and a furan ring for enhanced inhibition. In vitro glyoxalase inhibitory activity showed that 5b has excellent inhibitory activity against the glyoxalase I enzyme, with an IC50 of 15 µM. Molecular docking using AutoDock 4.2 highlighted key interactions within the active site of the human glyoxalase I enzyme, underscoring the absence of direct Zn interactions in the synthesized compounds compared to the cocrystallized ligand and revealing the need for structural optimization to introduce metal-binding functionalities. This research paves the way for the rational design of more potent glyoxalase I inhibitors, contributing significantly to the field of enzyme inhibition and therapeutic agent development.

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