Design, Synthesis and Antiplasmodial Evaluation of Sulfoximine-triazole Hybrids as Potential Antimalarial Prototypes.

BACKGROUND: Malaria, caused by the deadly Plasmodium falciparum strain, claims the lives of millions of people annually. The emergence of drug-resistant strains of P. falciparum to the artemisinin-based combination therapy (ACT), the last line of defense against malaria, is worrisome and urges for the development of new chemo-types with a new mode of action. In the search of new antimalarial agents, hybrids of triazoles and other known antimalarial drugs have been reported to possess better activity than either of the parent compounds administered individually. Despite their better activity, no hybrid antimalarial drugs have been developed so far. OBJECTIVE: In the hope of developing new antimalarial prototypes, we propose the design, synthesis and antimalarial evaluation of novel sulfoximine-triazole hybrids owing to their interesting biological and physiological properties. METHODS: The sulfoximine part of the hybrid will be synthesized via imidation of the corresponding sulfoxide. Propargylation of the NH moiety of the sulfoximine followed by copper-catalyzed click chemistry with benzyl azide was envisaged to provide the target sulfoximine-triazole hybrids. RESULTS: Five novel sulfoximine-triazole hybrids possessing various substituents on the sulfoximine moiety have been successfully synthesized and evaluated for their antiplasmodial and cytotoxicity activities. The results revealed that the co-presence of the sulfoximine and triazole moieties along with a lipophilic alkyl substituent on the sulfur atom impart significant activity. CONCLUSION: Sulfoximine-triazole hybrids could be used as a prototype for the synthesis of new derivatives with better antiplasmodial activities.

Design, synthesis, and antiplasmodial evaluation of a series of novel sulfoximine analogues of carbohydrate-based thiochromans.

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond.