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Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines.
Khan, M O; Austin, S E; Chan, C; Yin, H; Marks, D; Vaghjiani, S N; Kendrick, H; Yardley, V; Croft, S L; Douglas, K T.
Afiliação
  • Khan MO; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
J Med Chem ; 43(16): 3148-56, 2000 Aug 10.
Article em En | MEDLINE | ID: mdl-10956223
Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a, 10a-dihydrophenothiazin-10-yl)propyl]dimethylammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as >/=5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K(i) values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl](3, 4-dichlorobenzyl)dimethylammonium derivative (K(i) 0.12 microM), was approximately 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at <1 microM. Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED(50) < 1 microM). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED(50) < 1 microM) growth of the amastigote stage of T. cruzi.
Assuntos
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Base de dados: MEDLINE Assunto principal: Fenotiazinas / Inibidores Enzimáticos / Compostos de Amônio Quaternário / NADH NADPH Oxirredutases / Antiparasitários Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2000 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Fenotiazinas / Inibidores Enzimáticos / Compostos de Amônio Quaternário / NADH NADPH Oxirredutases / Antiparasitários Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2000 Tipo de documento: Article