Synthesis of Novel N-Alkyl-3-mesityl-5-methyl-4,5-dihydro-isoxazole-5-carboxamide Molecules: In Vitro Antimicrobial, Antimalarial Evaluation, and In Silico Prediction Studies

Objective: This study reports the synthesis and characterization of a series of novel N-alkyl-substituted 3-mesityl-5-methyl-4,5-dihydroisoxazole-5-carboxamide derivatives (VIa–VI6j). Methods: The compounds were structurally confirmed by ¹H NMR and LC-MS analyses. Their in vitro antimicrobial activities were evaluated against two Gram-positive bacteria (Streptococcus pyogenes and Staphylococcus aureus), two Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and three fungal strains (Candida albicans, Aspergillus niger, and Aspergillus clavatus). Additionally, the antimalarial activity was assessed against Plasmodium falciparum. Results and Discussion: Several compounds, including (VIa), (VIb), (VId), (VIe), and (VIg), exhibited superior potency compared to standard reference drugs. Others, such as (VIc), (VIf), (VIi), and (VIj), demonstrated moderate to comparable activity (~50% relative potency). Molecular docking studies provided insights into the potential binding interactions of these isoxazoline carboxamide derivatives, supporting their observed biological activity. Furthermore, density functional theory (DFT) calculations and ADMET predictions reinforced the pharmacological potential of these molecules. Conclusions: among the evaluated compounds, compound (VId) exhibited the most pronounced biological activity, characterized by significant antibacterial and potent antimalarial effects. Compounds (VIa), (VIb), (VIh), and (VIi) also demonstrated notable antibacterial properties. Although the overall antimicrobial efficacy of the synthesized compounds was inferior to that of the standard reference agents, the observed activities—particularly those of compound (VId)—indicate their potential as lead structures for further optimization and development in antimicrobial and antimalarial drug discovery.