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

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-1H-pyrazol-4-yl)acryloyl-4-hydroxy-6-methyl-2H-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-2H-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 ¹H-NMR, ¹³C-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 IC₅₀ 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.