Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.

Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino-Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo-11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro-11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi-aminoquinine in terms of selectivity.

An unexpected diastereoselective C-alkylation of a mefloquine derivative in up to 57% yield was the result of an attempted Williamson etherification of Boc-mefloquine. The domino reaction involved oxazolidinone ring closure, deprotonation, and stereoselective carbon–carbon bond formation. The structure was confirmed with 2D NMR experiments.

Mefloquine (MQ) is an important component for antiparasitic therapy. Herein, the synthesis and antiplasmodial and antischistosomal activities of MQ–metal complexes of the general formula [M(II)(L)(MQ)]PF₆ are described. Variation of the metal center (platinum and palladium) and coligand (phosphine or bipyridine) consistently yielded MQ coordinated as a N,O-bidentate ligand. Biological evaluation against Plasmodium falciparum and Schistosoma mansoni revealed that the metal center augmented the antiparasitic property of MQ by functioning as a thioredoxin/glutathione reductase-targeting moiety, while the coligand modulated chemical reactivity and physicochemical properties. MQ–Pt complexes displayed high in vivo efficacy. The intracellular accumulation of the metal in parasite cells contributed to the abrogation of essential biochemical pathways. Notably, despite being isostructural, Pd complexes differed from their Pt counterparts in their ligand dissociation behavior. The current work establishes a new structural framework for developing metal-based antiparasitic agents capable of selectively targeting essential parasite biochemical pathways while sparing mammalian cells.