Role of Trifluoromethyl Substitution in Design of Antimalarial Quinolones: a Comprehensive Review.

Malaria represents a significant health issue, and novel effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. The most popular antimalarial drugs are focused on the 7-chloro-4-aminoquinoline [e.g., chloroquine (CQ), amodiaquine (AQ), isoquine (IQ), and tebuquine (TBQ)], artemisinin, and atovaquone systems. Recently, endochin has been used as a platform to design a variety of novel potent and safe antimalarial agents named endochin-like quinolones (ELQs). Also, antimalarial quinolones have been constructed from other quinolones drugs such as ICI-56780 and floxacrine. Trifluoromethyl substitution has provided a significant increase in the antimalarial response of many of the designed ELQs against Plasmodium-resistant strains and for in vivo models. In particular, attachment of a substituted trifluoromethoxy (or trifluoromethyl in some cases) biaryl side chain at 2-, 3-, 4-, or 6-position of the quinolone core has shown to be crucially important to generate selective and potent novel ELQs. Furthermore, 6-chloro and 7-methoxy moieties on the quinolone core have been identified as essential pharmacophores when the trifluoromethoxy biaryl side chain is placed at 2- or 3-position of the quinolone core. Methyl or ethyl ester attached at 3-position is essential when the trifluoromethoxy aryl side chain is attached at 6- or 7-position of the quinolone core. Some promising ELQs are currently under clinical trials, representing an excellent platform for the design of new potent, selective, effective, and safe antimalarial drugs against emergent resistance malarial models.