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1.
J Med Chem ; 49(20): 6094-103, 2006 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-17004723

RESUMO

In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.


Assuntos
Antimaláricos/síntese química , Azasteroides/síntese química , Esteróis/síntese química , Tripanossomicidas/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Azasteroides/química , Azasteroides/farmacologia , Leishmania donovani/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Estereoisomerismo , Esteróis/química , Esteróis/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
2.
Bioorg Med Chem ; 13(18): 5435-53, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16046134

RESUMO

There is an urgent need for new drugs to treat leishmaniasis and Chagas disease. One important drug target in these organisms is sterol biosynthesis. In these organisms the main endogenous sterols are ergosta- and stigmata-like compounds in contrast to the situation in mammals, which have cholesterol as the sole sterol. In this paper we discuss the design, synthesis and evaluation of potential transition state analogues of the enzyme Delta24(25)-methyltransferase (24-SMT). This enzyme is essential for the biosynthesis of ergosterol, but not required for the biosynthesis of cholesterol. A series of compounds were successfully synthesised in which mimics of the S-adenosyl methionine co-factor were attached to the sterol nucleus. Compounds were evaluated against recombinant Leishmania major 24-SMT and the parasites L. donovani and Trypanosoma cruzi in vitro, causative organisms of leishmaniasis and Chagas disease, respectively. Some of the compounds showed inhibition of the recombinant Leishmania major 24-SMT and induced growth inhibition of the parasites. Some compounds also showed anti-parasitic activity against L. donovani and T. cruzi, but no inhibition of the enzyme. In addition, some of the compounds had anti-proliferative activity against the bloodstream forms of Trypanosoma brucei rhodesiense, which causes African trypanosomiasis.


Assuntos
Leishmania/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Esteróis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma/efeitos dos fármacos , Animais , Proliferação de Células , Humanos , Leishmania/enzimologia , Lipídeos/química , Metiltransferases/química , Camundongos , Mimetismo Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Esteróis/síntese química , Relação Estrutura-Atividade , Tripanossomicidas/química
3.
J Med Chem ; 46(22): 4714-27, 2003 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-14561091

RESUMO

This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3beta,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3beta-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.


Assuntos
Compostos Aza/síntese química , Inibidores Enzimáticos/síntese química , Leishmania/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Pregnanodiol/síntese química , Esteróis/síntese química , Tripanossomicidas/síntese química , Trypanosoma/efeitos dos fármacos , Animais , Compostos Aza/química , Compostos Aza/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Leishmania/enzimologia , Leishmania/ultraestrutura , Metiltransferases/química , Pregnanodiol/análogos & derivados , Pregnanodiol/química , Pregnanodiol/farmacologia , Proteínas Recombinantes/química , Especificidade da Espécie , Esteróis/química , Esteróis/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma/enzimologia , Trypanosoma/ultraestrutura
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