Sulfadoxine derivatization through multicomponent reactions to obtain new antiplasmodial compounds.

Malaria continues to have a devastating impact on disease-endemic countries. Despite significant advances have been achieved, the discovery and development of new drugs capable to avoid resistances remains a challenge. In the same way, the difficulty and complexity of drug discovery processes only aggravates this situation. Nowadays, new strategies have appeared to minimize the impact that resistance evolution entails, such as the improvement of pre-existing drugs through chemical adaptation. In this work, we describe the structural modification of the antimalarial drug sulfadoxine, to which the parasite has developed resistance. Since sulfadoxine displays in its structure an aniline residue capable of undergoing Povarov and Ugi multicomponent reactions, we have used these to obtain new derivatives. Specifically, in the Povarov reaction, sulfadoxine led to phenylquinoline-6-sulfonamide derivatives 5 when phenylstyrene was used as dienophile, or indeno[2,1-c]quinoline-2-sulfonamide derivatives 8a, 9 and 10 when indene was used instead. On the contrary, when sulfadoxine was used as the residue amine in the Ugi reaction, derivatives 13a and 13b were obtained. Some of the synthesized derivatives, namely 8a, 13a and 13b displayed a significantly higher in vitro antiplasmodial activity than the original sulfadoxine compound, and synergistic assays of these analogues in combination with pyrimethamine showed improved efficacy compared to sulfadoxine-pyrimethamine.