Design, Synthesis, In Vivo Antimalarial Activity, and In Silico Studies of Sulfonamide‐Alkanamido Thiazole‐5‐Carboxylate Derivatives

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A series of nine substituted derivatives of 4-methyl-2-(3-methyl-2-(4-methylphenylsulfonamido)-butanamido)thiazole-5-carboxylate were synthesized, characterized, and evaluated for antimalarial activity. The synthesis involved a two-step process using methyl acetoacetate and various substituted benzenesulfonamoyl alkanamides. Structural confirmation was achieved using NMR and mass spectroscopy. The in vivo antimalarial efficacy was tested against Plasmodium berghei in Swiss albino mice, with artemisinin as the reference drug. Compounds 4e and 4h exhibited the highest inhibition rates of 81.68% and 85.34%, respectively, closely matching artemisinin (90%). Structure-activity relationship (SAR) analysis identified the sulfonamide group, alkyl chain length, and molecular flexibility as critical determinants of activity. Docking studies revealed strong binding affinities for 4e and 4h, supported by stable hydrogen bonds and hydrophobic interactions with the enzyme's active site, corroborated by molecular dynamics simulations. ADMET analysis revealed favorable pharmacokinetic and safety profiles, including high GI absorption, acceptable solubility, and low mutagenic risk. These findings highlight compounds 4e and 4h as promising leads for antimalarial drug development.