Computational and Theoretical Characterization of Novel NSAID Candidates Based on Cyclooxygenase and Lipoxygenase Inhibition

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of compounds whose primary function is to reduce inflammation induced by harmful stimuli, mainly through the inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. These enzymes exhibit structural and functional differences associated with their amino acid composition, particularly aromatic residues such as phenylalanine and tyrosine, which play an important role in structural stability and in modulating catalytic activity. These structural features represent a relevant starting point for the rational design of new anti-inflammatory drugs through specific molecular modifications.

In this context, in the present work, the compounds 1-(N-alanine)-4-(p-methoxyphenyl)-butan-1,4-dione and 1-(N-alanine)-4-(p-hydroxyphenyl)-butan-1,4-dione were synthesized, optimized, modeled, and characterized. Their characterization was performed using global reactivity descriptors derived from molecular orbitals (HOMO and LUMO), including chemical potential, chemical hardness, electronegativity, and global electrophilicity index, among other theoretical parameters.

Subsequently, the results were compared with reference drugs such as celecoxib and zileuton in order to evaluate their potential biological activity, toxicity and safety profile. The obtained energy gap values (ΔEgap = 4.903 and 4.444 eV) suggest that both compounds exhibit favorable electronic reactivity, indicating potential interaction with targets such as COX-2 and 5-lipoxygenase. Overall, these findings position the studied molecules as promising candidates for the development of new anti-inflammatory agents.