Synthesis, Antiprotozoal Activity, and Physicochemical Evaluation of Benzamido–Menadione Derivatives

The naphthoquinone skeleton is known for broad biological applications and, in particular, for antiparasitic efficacy. As part of our ongoing search for new antiprotozoal naphthoquinone derivatives, we incorporated computer-aided optimization models utilizing physicochemical parameters into our approach. Herein, we report on the synthesis of 21 new benzamido–menadione and naphthoquinone derivatives via the Kochi–Anderson reaction. The antiprotozoal activity of all the synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. Several ligand efficiency metrics, such as LLE, SILE, and FQ, were calculated, and the results were visualized in scatterplots. Almost all of the synthesized benzamido–menadione derivatives exhibited high activity against NF54 (IC50 < 1 µM), with the strongest activity and excellent selectivity observed in the 2-fluoro-5-trifluoromethylbenzamido derivative 2f (IC50 = 0.021 µM, SI = 10,000). Specific ligand efficiency metrics, such as SILE, LLE or FQ, showed a clear correlation with the corresponding antiplasmodial activities. Toxicity predictions confirmed low acute oral toxicity for most compounds, further supporting their potential as safe drug candidates. Our findings highlight the benzamido–menadione scaffold as a viable option for new antiplasmodial drugs.