Medicinal Chemistry and Target Identification of Synthetic Clinical and
Advanced Preclinical Antimalarial Candidates (2000 - 2022)

Cheuka, Peter Mubanga; Mambwe, Dickson; Mayoka, Godfrey

doi:10.2174/1568026623666221220140526

Cited by 3 publications

(2 citation statements)

References 126 publications

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“…This compound was also found to rapidly disturb Na + homeostasis in the parasite, which was followed by substantial physical changes in the infected cells . Other small molecules with promising activity against Pf ATP4 include cipargamin (Table ), which has since been evaluated in phase I and phase II clinical trials, with further phase II studies still ongoing. , …”

Section: Novel Antimalarial Drug Targetsmentioning

confidence: 99%

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Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Cheuka,

Njaria,

Mayoka

et al. 2024

J. Med. Chem.

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Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors. ■ SIGNIFICANCEFor the first time, we report some emerging antimalarial targets with special emphasis on mechanistic details of how they function. We believe such details are of value in medicinal chemistry toward facilitating rapid design of inhibitors. While considerable efforts have been made regarding drug target identification, the corresponding medicinal chemistry hit identification and hit-to-lead optimization have been insufficient. We believe this Perspective will contribute to bridging the gap between target discovery and inhibitor design.

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Section: Novel Antimalarial Drug Targetsmentioning

confidence: 99%

“…132 Other small molecules with promising activity against PfATP4 include cipargamin (Table 1), which has since been evaluated in phase I and phase II clinical trials, with further phase II studies still ongoing. 133,134 2.5.4. P. falciparum Niemann−Pick-Type C1-Related Protein (Pf NCR1).…”

Section: P Falciparum Adenosine Triphosphatase (Atpase) 4 (Pfatp4mentioning

confidence: 99%