Antiplasmodial activity of sulfonylhydrazones: in vitro and in silico approaches

Malaria is still a life-threatening public health issue, and the upsurge of resistant strains requires continuous generation of active molecules. In this work, 35 sulfonylhydrazone derivatives were synthesized and evaluated against Plasmodium falciparum chloroquine-sensitive (3D7) and resistant (W2) strains. The most promising compound, 5b, had an IC50 of 0.22 mu M against W2 and was less cytotoxic and 26-fold more selective than chloroquine. The structure-activity relationship model, statistical analysis and molecular modeling studies suggested that antiplasmodial activity was related to hydrogen bond acceptor count, molecular weight and partition coefficient of octanol/water and displacement of frontier orbitals to the heteroaromatic ring beside the imine bond. This study demonstrates that the synthesized molecules with a simple scaffold allow the hit-to-lead process for new antimalarials to commence.

Automated summary

This study synthesized 35 sulfonylhydrazone derivatives and found one compound, 5b, to be the most promising against resistant strains of Plasmodium falciparum, showing lower cytotoxicity and higher selectivity compared to chloroquine. The structure-activity relationship, statistical analysis, and molecular modeling studies suggested that antiplasmodial activity is related to specific molecular characteristics.