Effects of inversion or substitution of the sulfonamide group at 5-position of 8-hydroxyquinoline derivatives against Cryptococcus neoformans and C. gattii

Abstract

Cryptococcosis is an important infectious disease, mainly because the increasing prevalence in recent decades and resistance treatment. Development of new drugs for the treatment of this disease is imperative. Recent studies from our research group revealed significant antimicrobial activity of 5-substituted 8-hydroxyquinoline derivatives as 8-hydroxy-5-quinolinesulfonic acid and 8-hydroxyquinoline-5-(N-4-chlorophenyl) sulfonamide. Therefore, in order to study the structure activity relationships (SAR) of these compounds, sulfonamide derivatives of 8-hydroxyquinoline were synthesized varying the substitution on the 5-sulfonamide and also inverting the sulfonamide group. Derivatives of 8-hydroxyquinoline-5-sulfonyl chloride and 5-aminoquinolin-8-ol were obtained for in vitro screening against Cryptococcus neoformans and C. gattii using broth microdilution method. Compound 3a was the most active derivative of this series, demonstrating activity over 2-fold better than fluconazole against C. neoformans. Derivatives 3b and 3c were equally actives, but not as potent as 3a. The position inversion of the sulfonamide resulted in reduced activity of derivatives 6a and 6b, emphasizing the importance of the sulfonyl group position in the molecule. Finally, the 3-series derivatives can be promising antifungal candidates to treat cryptococcosis.