Discovery of new S-adenosylmethionine decarboxylase inhibitors for the treatment of Human African Trypanosomiasis (HAT)
ABSTRACT Modification of the structure of trypanosomal AdoMetDC inhibitor 1 (MDL73811) resulted in the identification of a new inhibitor 7a, which features a methyl substituent at the 8-position. Compound 7a exhibits improved potencies against both the trypanosomal AdoMetDC enzyme and parasites, and better blood brain barrier penetration than 1.
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ABSTRACT: The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi are the causative agents of African trypanosomiasis and Chagas disease, respectively. These are debilitating infections that exert a considerable health burden on some of the poorest people on the planet. Treatment of trypanosome infections is dependent on a small number of drugs that have limited efficacy and can cause severe side effects. Here, we review the properties of these drugs and describe new findings on their modes of action and the mechanisms by which resistance can arise. We further outline how a greater understanding of parasite biology is being exploited in the search for novel chemotherapeutic agents. This effort is being facilitated by new research networks that involve academic and biotechnology/pharmaceutical organisations, supported by public-private partnerships, and are bringing a new dynamism and purpose to the search for trypanocidal agents.Expert Reviews in Molecular Medicine 10/2009; 11:e31. DOI:10.1017/S1462399409001252 · 5.15 Impact Factor
- ChemInform 10/2009; 40(42). DOI:10.1002/chin.200942196
- Annual reports in medicinal chemistry 01/2010; 45:277-294. DOI:10.1016/S0065-7743(10)45017-4 · 1.36 Impact Factor