A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

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.

Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis

“…One of the most important heterocyclic compounds in the field of medicinal and organic chemistry is quinoline, which occurs in the backbone of molecules with great biological importance of natural ( Musiol et al, 2017 ; Nainwal et al, 2019 ) or synthetic origin ( Narwal et al, 2017 ; Sharma et al, 2017 ; Shang et al, 2018 ), such as quinine, camptothecin or skimminanine ( Musiol et al, 2017 ; Nainwal et al, 2019 ). These bioactive quinoline-based compounds were the precursors of several derivatives that are now used clinically and contribute greatly to the control of serious diseases worldwide ( Narwal et al, 2017 ; Sharma et al, 2017 ; Shang et al, 2018 ; Kucharski et al, 2022 ). In addition, several other compounds with quinoline nuclei fused or unfused to other heterocyclic compounds have been synthesized recently, exhibiting a wide range of biological properties in vitro and in vivo , such as antimalarials ( Leven et al, 2019 ), antifungals ( Shruthi et al, 2019 ), anticancer agents ( Hamdy et al, 2019 ), anticonvulsants ( Kumar and Abdullah, 2019 ), antihypertensives ( Vellalacheruvu et al, 2017 ), anti-inflammatories ( Deaton et al, 2019 ), antidepressants ( Galambos et al, 2017 ), and antivirals ( Kos et al, 2019 ).…”

Squaramide Tethered Clindamycin, Chloroquine, and Mortiamide Hybrids: Design, Synthesis, and Antimalarial Activity

“…For one thing, chemical modification of existing drugs was shown to be effective for the preparation of compounds with antimalarial activities. 7 Among other approaches and related to countering drug resistance, a molecular hybridization (covalent biotherapy) 8−10 strategy was widely studied in recent years. 11−15 This approach involves the covalent linking of biologically active compounds to form a unique molecule with better therapeutic potential.…”

“…We selected the terminal position of chloroquine for the installation of the linker since biologically active chloroquine analogues were prepared by functionalization at this position. 7 Accordingly, a modified Mitsunobu protocol furnished the azide 8 41 and reduction of the latter moiety using a catalytic amount of Pd/C gave the corresponding amine 9. Chloroquine-monosquaramide ester 10 was prepared in 72% yield using the same conditions as above.…”

“…Consequently, other approaches have emerged over the years to fight drug resistance. For one thing, chemical modification of existing drugs was shown to be effective for the preparation of compounds with antimalarial activities …”

“…A similar strategy was executed starting from hydroxychloroquine sulfate 2 . We selected the terminal position of chloroquine for the installation of the linker since biologically active chloroquine analogues were prepared by functionalization at this position . Accordingly, a modified Mitsunobu protocol furnished the azide 8 and reduction of the latter moiety using a catalytic amount of Pd/C gave the corresponding amine 9 .…”