Evaluation of aminohydantoins as a novel class of antimalarial agents.

doi:10.1021/ml400412x

Paper

Evaluation of aminohydantoins as a novel class of antimalarial agents.

Published Jan 9, 2014 · M. Meyers, M. Tortorella, Jing Xu

ACS medicinal chemistry letters

Q1 SJR score

32

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2

Influential Citations

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Abstract

Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure-activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.

Study Snapshot

Aminohydantoins show potential as a novel class of antimalarial agents by inhibiting Plasmodium aspartic proteases, with compound 8p (CWHM-117) showing promising oral bioavailability and in vivo antimalarial activity in mice.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Evaluation of aminohydantoins as a novel class of antimalarial agents.

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Citations

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Hydantoin derivative 2c shows promising antiplasmodial activity, three-fold better than chloroquine, making it a promising candidate for further exploration as a malaria drug.

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Plasmepsin X plays a crucial role in activating the malaria parasite's SUB1 protease, enabling its membrane breakdown and egress from host red blood cells.

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UCB7362, a once-daily 50 mg dose for 7 days, shows potential as a potent, effective, and safe PMX inhibitor for treating malaria.

Babesia divergens egress from host cells is orchestrated by essential and druggable kinases and proteases

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