Development and Synthesis of Bioactive (3‐Arylediene‐1‐phenyl‐1 H ‐pyrazol‐4‐yl)acryloyl‐4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐ones With Anti‐Malarial and Anti‐Inflammatory Activities

ABSTRACT Chalcones are versatile scaffolds with broad pharmacological relevance, particularly as anti‐inflammatory and anti‐malarial agents. In the current investigation, a series of (3‐arylediene‐1‐phenyl‐1 H ‐pyrazol‐4‐yl)acryloyl‐4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one analogs/1,3‐diarylprop‐2‐en‐1‐ones were successfully synthesized, leveraging dehydroacetic acid (DHA) as the precursor molecule. The choice of DHA is strategic as it is a bioactive and highly versatile scaffold bearing a 4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one moiety, which enhances structural diversity and provides multiple reactive sites for functionalization. Its inherent anti‐microbial, anti‐inflammatory, and anti‐malarial potential offers an added advantage over conventional precursors, thereby increasing the likelihood of generating pharmacologically active chalcone hybrids. The synthetic protocol employed in this study involved the implementation of a Claisen condensation reaction, wherein DHA was reacted with formyl pyrazole to afford the corresponding chalcones, with yields ranging from moderate to good. The synthesized compounds were subjected to a rigorous characterization protocol, involving a battery of analytical techniques, including 1 H‐NMR, 13 C‐NMR, FT‐IR, and HRMS analyses. Biological evaluation focused on anti‐malarial and anti‐inflammatory activities, while molecular docking (PyRx 0.8) was performed to explore binding interactions with cyclooxygenase‐2 (COX‐2; PDB ID: 3LN1) and enoyl‐acyl‐carrier‐protein reductase (EACPR; PDB ID: 1NHG). Notably, compound 3c emerged as the most potent one within the synthesized series, exhibiting remarkable anti‐inflammatory and anti‐malarial potency, as evidenced by its IC 50 values of 7.05 ± 0.17 µM and 0.95 ± 0.06 µM, respectively. Docking studies revealed strong binding affinities and favorable molecular interactions, supporting the observed bioactivities. This study highlights chalcone–pyrazole hybrids as promising therapeutic scaffolds. In particular, compound 3c emerges as a compelling lead candidate for further optimization and preclinical investigation as a dual‐action agent against malaria and inflammation.