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Browsing by Author "Hursthouse, MB"

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  • Amidomethylation of amodiaquine
    Publication . Lopes, F; Capela, R; Goncaves, JO; Horton, PN; Hursthouse, MB; Iley, J; Casimiro, CM; Bom, J; Moreira, R
    Novel N-Mannich base-type derivatives of the antimalarial drug amodiaquine were synthesised by reaction with tertiary N-chloromethylamides. With the exception of the derivative of ethyl hippurate, all the so-formed (1-amidomethyl-1H-quinolin-4-ylidene)arylamines displayed high chemical and enzymatic stability. These compounds displayed antimalarial activity against the multi-drug resistant Plasmodium falciparum strain Dd2 (IC50 values 15-31 nM) and demonstrated no significant loss in activity compared to amodiaquine (IC50 30nM). (C) 2004 Elsevier Ltd. All rights reserved.
    2004Journal article Metadata only Show more
  • Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted beta-lactams as novel inhibitors of human leukocyte elastase
    Publication . Moreira, R; Santana, AB; Iley, J; Neres, J; Douglas, KT; Horton, PN; Hursthouse, MB
    Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5 ' S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.
    2005Journal article Metadata only Show more