Design, Synthesis and Biological Evaluation of New 4-(4-(Methylsulfonyl) Phenyl)-6-Phenylpyrimidin-2-Amine Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors.

Abstract

Introduction: Cyclooxygenase, an enzyme that occurs in at least two distinct variants (COX-1 and COX-2), is the target of classical inhibitors, which lack selectivity and inhibit both types of COX. However, a recent approach focuses explicitly on inhibiting COX-2, commonly found in inflamed tissue, resulting in fewer adverse effects than COX-1 inhibitors.

Methods: A series of 4-(4-(methylsulfonyl)phenyl)-6-phenylpyrimidin-2-amine derivatives were synthesized through a two-step process. First, 4-substituted acetophenones underwent base-catalyzed Claisen-Schmidt condensation with 4-(methylsulfonyl)benzaldehyde to yield chalcones, which were then cyclized with guanidine hydrochloride under basic reflux conditions. Molecular docking was performed using AutoDock Vina software. The inhibitory activities of COX-1 and COX-2 were evaluated using enzymatic assays. Antiplatelet aggregation was measured via a turbidimetric method, and antiproliferative activity was assessed using the MTT assay.

Results: The in vitro experiments on COX inhibition revealed that a substantial number of the synthesized compounds presented a strong suppressive effect against COX-2. The assessment of antiplatelet aggregation activity indicated that most of the derivatives effectively inhibited ADP-induced platelet aggregation. Compound 4i exhibited the most potent antiproliferative activity, comparable to cisplatin. The docking studies and molecular modeling results demonstrated that the designed compounds, except for 4b, exhibited a binding behavior comparable to that of celecoxib. In addition, the insertion of the SO2Me moiety within the secondary binding site of COX-2 was observed.

Discussion: These findings suggest that the structural modifications introduced in the synthesized derivatives contribute significantly to their selective COX-2 inhibition and antiplatelet properties. The correlation between docking results and biological assays supports the rationale behind the design of the compound.

Conclusion: The 4-(4-(methylsulfonyl)phenyl)-6-phenylpyrimidin-2-amine exhibits unique properties as a COX-2 inhibitor, displaying effective inhibition of COX-2 while showing minimal interaction with the COX-1 enzyme. Furthermore, our study revealed that most of these compounds exhibited inhibitory effects on ADP-induced platelet aggregation.