The 1,4-naphthoquinone scaffold in the design of cysteine protease inhibitors |
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Authors: | Valente Cláudia Moreira Rui Guedes Rita C Iley Jim Jaffar Mohammed Douglas Kenneth T |
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Affiliation: | 1. CECF, Faculty of Pharmacy, University of Lisbon, Avenida das Forças Armadas, Lisboa 1600-083, Portugal;2. Chemistry Department, The Open University, Milton Keynes, MK7 6AA, UK;3. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK |
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Abstract: | A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These 1,4-naphthoquinone derivatives were found to be irreversible inhibitors for both cysteine proteases, with second-order rate constants, k(2), ranging from 0.67 to 35.4M(-1)s(-1) for papain, and from 0.54 to 8.03M(-1)s(-1) for cathepsin B. Some derivatives display a hyperbolic dependence of the first-order inactivation rate constant, k(obs), with the inhibitor concentration, indicative of a specific interaction process between enzyme and inhibitor. The chemical reactivity of the compounds towards cysteine as a model thiol is dependent on the naphthoquinone LUMO energy, whereas papain inactivation is not. The 1,4-naphthoquinone derivatives are inactive against the serine protease, porcine pancreatic elastase. |
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