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Bioorg Med Chem Lett. 2014 Mar 1;24(5):1274-9. doi: 10.1016/j.bmcl.2014.01.062. Epub 2014 Jan 31.

Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum.

Author information

1
School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States; School of Pharmacy, Department of Pharmaceutical Sciences, Loma Linda University, Loma Linda, CA 92350, United States.
2
School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States.
3
School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States; National Center for Natural Products Research, University of Mississippi, University, MS 38677, United States.
4
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143, United States.
5
Schrodinger, Inc., 120 West 45th Street, 17th Floor, New York, NY 10036, United States.
6
School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States; National Center for Natural Products Research, University of Mississippi, University, MS 38677, United States. Electronic address: mavery@olemiss.edu.

Abstract

A new series of peptidomimetic pseudo-prolyl-homophenylalanylketones were designed, synthesized and evaluated for inhibition of the Plasmodium falciparum cysteine proteases falcipain-2 (FP-2) and falcipain-3 (FP-3). In addition, the parasite killing activity of these compounds in human blood-cultured P. falciparum was examined. Of twenty-two (22) compounds synthesized, one peptidomimetic comprising a homophenylalanine-based α-hydroxyketone linked Cbz-protected hydroxyproline (39) showed the most potency (IC50 80 nM against FP-2 and 60 nM against FP-3). In silico analysis of these peptidomimetic analogs offered important protein-ligand structural insights including the role, by WaterMap, of water molecules in the active sites of these protease isoforms. The pseudo-dipeptide 39 and related compounds may serve as a promising direction forward in the design of competitive inhibitors of falcipains for the effective treatment of malaria.

KEYWORDS:

Cruzain; Drug resistance; Falcipain; Malaria; Peptidomimetic

PMID:
24507921
DOI:
10.1016/j.bmcl.2014.01.062
[Indexed for MEDLINE]

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