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.

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.