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

David J Weldon; Falgun Shah; Amar G Chittiboyina; Anjaneyulu Sheri; Raji Reddy Chada; Jiri Gut; Philip J Rosenthal; Develeena Shivakumar; Woody Sherman; Prashant Desai; Jae-Chul Jung; Mitchell A Avery

doi:10.1016/j.bmcl.2014.01.062

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

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

Authors

Affiliations

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.

PMID: 24507921
DOI: 10.1016/j.bmcl.2014.01.062

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.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Binding Sites
Cysteine Endopeptidases / chemistry
Cysteine Endopeptidases / metabolism
Cysteine Proteinase Inhibitors / chemical synthesis*
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Dipeptides / chemical synthesis*
Dipeptides / chemistry
Dipeptides / pharmacology*
Drug Resistance
Humans
Hydrogen Bonding
Ketones / chemical synthesis
Ketones / chemistry
Ketones / pharmacology
Molecular Docking Simulation
Peptides / chemistry*
Peptidomimetics
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Protein Binding
Protein Structure, Tertiary
Structure-Activity Relationship
Thermodynamics

Substances

Antimalarials
Cysteine Proteinase Inhibitors
Dipeptides
Ketones
Peptides
Peptidomimetics
Cysteine Endopeptidases
falcipain 2
falcipain 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding