Abstract
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.
Highlights
Malaria is an infectious disease, which is responsible for more than 600,000 deaths annually, mainly in tropical areas [1]
Unlike the natural products [8,9] or the de novo synthesized analogs [11,12,13,14], there is no comprehensive review on the late-stage modification of other quinoline drugs
It transpired that the presence of the benzyl group at the N-13 atom in mefloquine increased the activity of MQ-20 against Mycobacterium tuberculosis H37 Rv in respect to (+)-erythro-mefloquine hydrochloride with MIC: 6.7 μM in MABA and 7.3 μM in LORA
Summary
Malaria is an infectious disease, which is responsible for more than 600,000 deaths annually, mainly in tropical areas [1]. The other is to use an already available natural product or an industrially available active pharmaceutical ingredient (API) and perform further transformations Such method referred to as semi-synthesis, late-stage modification, or top-down approach, has the advantage of usually being short. Unlike the natural products [8,9] or the de novo synthesized analogs [11,12,13,14], there is no comprehensive review on the late-stage modification of other quinoline drugs. (−)-threo and (−)-erythro-mefloquine are up to two times less active against malaria parasites. Researchers have strived to enhance the biological activity of mefloquine and circumvent the development of resistance to the drug by modifying mefloquine scaffold, sometimes using late-stage modification rather than synthesizing new analogs de novo. No reactions at other sites including the quinoline ring have been reported in the literature
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