Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors.

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Deprez-Poulain R, Flipo M, Piveteau C, Leroux F, Dassonneville S, Florent I, Maes L, Cos P, Deprez B

Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors.

J Med Chem. 2012 Dec 27;55(24):10909-17. doi: 10.1021/jm301506h. Epub 2012 Dec 5.

PubMed ID

23176597 [ View in PubMed

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Abstract

Malaria is a severe infectious disease that causes between 655,000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure-activity relationships of a selective family of hydroxamate PfAM1 inhibitors based on the malonic template. In particular, we performed a "fluoro-scanning" around hit 1 that enlightened the key positions of the halogen for activity. The docking of the best inhibitor 2 is consistent with in vitro results. The stability of 2 was evaluated in microsomes, in plasma, and toward glutathione. The in vivo distribution study performed with the nanomolar hydroxamate inhibitor 2 (BDM14471) revealed that it reaches its site of action. However, it fails to kill the parasite at concentrations relevant to the enzymatic inhibitory potency, suggesting that killing the parasite remains a challenge for potent and druglike catalytic-site binding PfAM1 inhibitors. In all, this study provides important insights for the design of inhibitors of PfAM1 and the validity of this target.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 2	IC 50 (nM)	29	N/A	N/A	Details