Thymol Derivatives as Antimalarial Agents: Synthesis, Activity Against Plasmodium falciparum, ADMET Profiling, and Molecular Docking Insights

<b>Background:</b> Thymol, a natural phenol with antimicrobial and antioxidant activities, and its derivatives offer promising scaffolds for antimalarial drug development, potentially helping overcome resistance. <b>Materials and Methods:</b> In this study, thymol derivatives were synthesized and assessed as antiplasmodial agents against both resistant and sensitive strains of <i>P. falciparum</i>, as well as <i>Plasmodium knowlesi</i>. The ligand molecules were assessed with <i>Plasmodium falciparum</i> chloroquine resistance transporter (PfCRT)'s potential using in silico molecular docking and ADMET analysis. The parent compound, thymol, was chemically modified through esterification and conjugation with hydroxybenzoic acid and cinnamic acid derivatives to generate analogs with varied substitution patterns. <b>Results:</b> The findings showed that among seven successfully synthesized thymol derivatives, compounds <b>4</b> and <b>6</b> exhibited notable potency against <i>Plasmodium falciparum</i> 3D7 (EC₅₀ = 6.01 ± 1.7 µM and 6.8 ± 1.1 µM, respectively) with high SI values (16.5 and 14.6, respectively), indicating improved selectivity relative to thymol. The cytotoxicity evaluation against HCF mammalian cells revealed that most thymol derivatives were non-toxic, with CC₅₀ values greater than 99 µM, except for compound 3 (CC₅₀ = 71.4 ± 4.5 µM) and compound 1 (CC₅₀ = 58.4 ± 2.3 µM), which exhibited moderate cytotoxic effects. The molecular docking results showed that compounds <b>3</b> (-8.4 kcal/mol), <b>4</b> (-8.3 kcal/mol), and <b>6</b> (-8.3 kcal/mol) exhibited strong binding affinities toward the PfCRT protein. <b>Conclusions:</b> Therefore, thymol derivative compounds <b>4</b> and <b>6</b> exhibited stronger antiplasmodial activity in vitro against <i>P. falciparum</i> and <i>P. knowlesi</i> with safety profiles against mammalian cells, targeting PfCRT, highlighting their potential as lead antimalarial candidates.