Divergent Modes of Enzyme Inhibition in a Homologous Structure−Activity Series

• Published in: Journal of medicinal chemistry Vol. 52; no. 16; pp. 5005 - 5008
• Main Authors: Ferreira, Rafaela S, Bryant, Clifford, Ang, Kenny K. H, McKerrow, James H, Shoichet, Brian K, Renslo, Adam R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.08.2009; Amer Chemical Soc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Colloids; Cysteine Endopeptidases - chemistry; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Databases, Factual; Glycolates - chemical synthesis; Glycolates - chemistry; Glycolates - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Science & Technology; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; HIGH-THROUGHPUT; TRYPANOSOMA-CRUZI; PROMISCUOUS INHIBITORS; DETERGENT; INFECTION; IDENTIFICATION; CYSTEINE PROTEASE CRUZAIN; Kinetoplastida; Protozoa; Five membered ring; Enzyme; Nitrogen heterocycle; Cysteine endopeptidases; Enzyme inhibitor; Aniline derivatives; In vitro; Trypanosoma cruzi; Peptidases; Antiprotozoal agent; Thiophene derivatives; Sulfur heterocycle; Structure activity relation; Pyrazole derivatives; Hydrolases; Parasiticide; Mechanism of action; Aromatic amine; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9009229

A docking screen identified reversible, noncovalent inhibitors (e.g., 1) of the parasite cysteine protease cruzain. Chemical optimization of 1 led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending on the assay conditions employed.