Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB |
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| Institution: | 1. Medicinal & Biological Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry-University of São Paulo (IQSC-USP), São Carlos, SP, Brazil;2. School of Chemistry, University of Nottingham, Nottingham, UK;3. School of Pharmacy, University of Nottingham, Nottingham, UK;1. Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan;2. Whol Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 7610001, Israel;3. Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel;1. Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15701 Athens, Greece;2. Department of Bioorganic Chemistry, Faculty of Chemistry, Wroc?aw University of Science and Technology, Wybrze?e Wyspiańskiego 27, 50-370 Wroc?aw, Poland;1. Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States;2. Fronthera US Pharmaceuticals, LLC, San Diego, CA, USA;1. Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore;2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore;3. Immunology Program, Life Science Institute, National University of Singapore, 117456, Singapore;4. SHARE, Molecular Mechanisms of Inflammatory Disease Interdisciplinary Research Group, Singapore;5. Drug Discovery and Optimization Platform, Medical Science Cluster, Yong Loo Lin School of Medicine, National University Health System, Singapore |
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| Abstract: | Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi < 5). The inversion of the stereochemistry from S to R was more detrimental to potency when placed at the P2 position than at P3. The p-Br derivatives were more potent than the p-CH3 and p-OCH3 derivatives, probably due to intermolecular interactions with the S3 subsite. |
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| Keywords: | Dipeptidyl nitrile derivatives Enzymatic inhibitors Additive effect SAR Crystallographic structure |
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