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

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 5; pp. 1274 - 1279
• Main Authors: Weldon, David J., Shah, Falgun, Chittiboyina, Amar G., Sheri, Anjaneyulu, Chada, Raji Reddy, Gut, Jiri, Rosenthal, Philip J., Shivakumar, Develeena, Sherman, Woody, Desai, Prashant, Jung, Jae-Chul, Avery, Mitchell A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.03.2014
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; 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; Life Sciences & Biomedicine; Molecular Docking Simulation; Peptides - chemistry; Peptidomimetics; Pharmacology & Pharmacy; Physical Sciences; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Protein Binding; Protein Structure, Tertiary; Science & Technology; Structure-Activity Relationship; Thermodynamics; Cruzain; HYDROPHOBIC ENCLOSURE; Malaria; Peptidomimetic; DOCKING; GLIDE; Drug resistance; IDENTIFICATION; SOLVENT; CYSTEINE PROTEASE INHIBITORS; BINDING-AFFINITY; Falcipain; RESISTANCE; PROTEINASE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.01.062

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 a-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. (c) 2014 Elsevier Ltd. All rights reserved.