β-Carboline and chloroquine hybrids as potent antiplasmodial agents: Design, synthesis and biological evaluation.

Abstract

A series of thirteen novel β-carboline and chloroquine (CQ) hybrids was designed and synthesized. The compounds were evaluated for in vitro antiplasmodial activity against Plasmodium falciparum strains 3D7 (CQ-sensitive) and Dd2 (multidrug-resistant). All compounds exhibited potent activity, with IC ₅₀ values in the nanomolar to low micromolar range, while retaining potency against the resistant strain (1.0 to 365.5 nmol L^-1 for 3D7 and from 2.2 to 2415.3 nmol L^-1 for Dd2 strain). Several compounds were more active against Dd2, then against 3D7 strain with resistance index (RI) lower than 1. Moreover, nearly all compounds showed lower RI values compared to CQ which additionally underscores their outstanding activity. At the highest tested concentration (250 μmol L^-1), no cytotoxicity was observed in HepG2 cells, resulting in favourable selectivity indices expressed as lower limits. Overall, the obtained results confirm strong antiplasmodial activity of the β-carboline and chloroquine hybrids as promising antiplasmodial candidates, particularly due to their activity against resistant strains and improved selectivity.