Design, Synthesis, And in Silico Studies Of 1,2,4-Triazole Clubbed Thioesters Of P-Thymol as Potent Antimalarial and Antimicrobial Agents

A novel series of thioester-clubbed triazole hybrids (7a-7j) were designed, synthesized, and evaluated for their antimalarial and antimicrobial potential. The synthesized compounds were screened for in vitro antimalarial activity against Plasmodium falciparum, where compounds 7b, 7c, and 7j exhibited promising potency with IC50 values 0.69, 0.62, and 0.68 μg/mL respectively, comparable to standard drugs. Antimicrobial evaluation revealed that several derivatives displayed significant antibacterial and antifungal activities, with compounds 7b and 7d showing excellent activity against E. coli, compound 7c against P. aeruginosa, and compounds 7b, 7f, and 7g against S. aureus. Furthermore, compounds 7c and 7g demonstrated notable antifungal activity against Candida albicans. Molecular docking studies against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme (PDB ID: 1TV5) revealed strong binding affinities, particularly for compound 7c (-9.3 kcal/mol), which formed multiple hydrogen bond interactions with key active site residues such as Lys429, Asn274, and Tyr528. In silico ADME predictions indicated favorable pharmacokinetic properties, with most compounds obeying Lipinski’s rule of five and showing good oral bioavailability. Toxicity prediction suggested moderate safety profiles, although some compounds exhibited mutagenicity concerns. Structure-activity relationship (SAR) analysis highlighted the importance of balanced lipophilicity, optimal polarity, and enhanced hydrogen bonding interactions for improved biological activity. Overall, compound 7c emerged as the most promising lead molecule with potent antimalarial activity, strong binding affinity, and acceptable pharmacokinetic properties, warranting further investigation for the development of new antimalarial agents.