Abstract:Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block humanto-mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4… Show more
Toward
repositioning the antitubercular clinical candidate
SQ109
as an antimalarial, analogs were investigated for structure–activity
relationships for activity against asexual blood stages of the human
malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes.
We show that equipotent activity (IC50) in the 100–300
nM range could be attained for both asexual and sexual stages, with
the activity of most compounds retained against a multidrug-resistant
strain. The multistage activity profile relies on high lipophilicity
ascribed to the adamantane headgroup, and antiplasmodial activity
is critically dependent on the diamine linker. Frontrunner compounds
showed conserved activity against genetically diverse southern African
clinical isolates. We additionally validated that this series could
block transmission to mosquitoes, marking these compounds as novel
chemotypes with multistage antiplasmodial activity.
Toward
repositioning the antitubercular clinical candidate
SQ109
as an antimalarial, analogs were investigated for structure–activity
relationships for activity against asexual blood stages of the human
malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes.
We show that equipotent activity (IC50) in the 100–300
nM range could be attained for both asexual and sexual stages, with
the activity of most compounds retained against a multidrug-resistant
strain. The multistage activity profile relies on high lipophilicity
ascribed to the adamantane headgroup, and antiplasmodial activity
is critically dependent on the diamine linker. Frontrunner compounds
showed conserved activity against genetically diverse southern African
clinical isolates. We additionally validated that this series could
block transmission to mosquitoes, marking these compounds as novel
chemotypes with multistage antiplasmodial activity.
Malaria drug research and development efforts have resurged in the last decade following the decelerating rate of mortality and malaria cases in endemic regions. The inefficiency of malaria interventions is largely driven by the spreading resistance of the Plasmodium falciparum parasite to current drug regimens and that of the malaria vector, the Anopheles mosquito, to insecticides. In response to the new eradication agenda, drugs that act by breaking the malaria transmission cycle (transmission-blocking drugs), which has been recognized as an important and additional target for intervention, are being developed. These drugs take advantage of the susceptibility of Plasmodium during population bottlenecks before transmission (gametocytes) and in the mosquito vector (gametes, zygotes, ookinetes, oocysts, sporozoites). To date, compounds targeting stage V gametocytes predominate in the chemical library of transmission-blocking drugs, and some of them have entered clinical trials. The targeting of Plasmodium mosquito stages has recently renewed interest in the development of innovative malaria control tools, which hold promise for the application of compounds effective at these stages. In this review, we highlight the major achievements and provide an update on the research of transmission-blocking drugs, with a particular focus on their chemical scaffolds, antiplasmodial activity, and transmission-blocking potential.
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