Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Abstract

Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large-scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.

Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach

“…This demonstrates a successful improvement pipeline of targeted drug discovery. As we have observed in our previous studies 23,40, 43 , once the 3CLpro is sufficiently expressed even after inhibition of virus, the multiplication cycle continues due to the presence of a small fraction of uninhibited enzyme. Therefore, compound activities are better observed in viral entry assays when initial blocking of freshly expressed 3CLpro occurs and succeeds in blocking the viral cycle more effectively.…”

Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages

“…26,27 The paucity of novel antimalarial drugs against other stages of malaria infection demands more efforts to screen for compounds that may be active against Plasmodium at single or multiple stages of the infection cycle. 28 Based on recent evidence, compounds such as atovaquone, pyronaridine, quinolones, imidazolopiperazines, pyrazines, azetidines, and xenomycins have all exhibited the capacity to inhibit several life stages of the malaria parasite, 18,29−38 prompting us to further look for chemical moieties with similar effects.…”

Novel Antiplasmodial Compounds Leveraged with Multistage Potency against the Parasite Plasmodium falciparum: In Vitro and In Vivo Evaluations and Pharmacokinetic Studies

“…Although ACTs remain the first line of treatment for life-threatening Pf infections, the emergence of ACT-resistant strains from South East Asia (SEA), Eastern India, central Africa, and their inevitable spread to other regions creates serious challenges against malaria eradication initiatives. − It thus creates an urgent need to discover more efficacious antimalarials. Moreover, the malaria elimination program recommended that new antimalarial drugs must include novel chemical entities that possess acute multistage cidal activity including drug-resistant strains, good pharmacokinetics (PK), and minimal or no-toxicity. − Only two approved drugs, namely, atovaquone (ATQ) and pyronaridine were demonstrated with multistage antimalarial activity. − Finding new effective multistage antimalarial therapeutics with novel modes of action remains an exigent task aligning with the WHO malaria eradication program. − …”