Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase
نویسندگان
چکیده
منابع مشابه
Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase.
There is an urgent need for the development of new drugs to treat Chagas' disease, which is caused by the protozoan parasite Trypanosoma cruzi. The enzyme dihydrofolate reductase (DHFR) has been a very successful drug target in a number of diseases and we decided to investigate it as a potential drug target for Chagas' disease. A homology model of the enzyme was used to search the Cambridge Str...
متن کاملDesign, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1
Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. ...
متن کاملDihydrofolate reductase from pyrimethamine-resistant Plasmodium berghei.
An investigation of the Hz-folate reductases from pyrimethamine-sensitive (Pb/WLTM) and -resistant (Pb/ WLTM/50-63) strains of Plasmodium berghei has revealed that the specific activity of the enzyme from the resistant strain is IO-fold higher than that of the sensitive strain. Since turnover numbers (based on amethopterin binding) are equivalent, the increase in specific activity must be due t...
متن کاملStructure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate
The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of ...
متن کاملThe roles of pteridine reductase 1 and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major.
Trypanosomatid protozoans depend upon exogenous sources of pteridines (pterins or folates) for growth. A broad spectrum pteridine reductase (PTR1) was recently identified in Leishmania major, whose sequence places it in the short chain alcohol dehydrogenase protein family although its enzymatic activities resemble dihydrofolate reductases. The properties of PTR1 suggested a role in essential pt...
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ژورنال
عنوان ژورنال: Pharmaceuticals
سال: 2021
ISSN: 1424-8247
DOI: 10.3390/ph14070636