Abstract
This paper describes the design, synthesis and evaluation of a series of 2,4-diaminoquinazolines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were designed by a generating virtual library of compounds and docking them into the enzyme active site. Following their synthesis, they were found to be potent and selective inhibitors of leishmanial dihydrofolate reductase. The compounds were also found to have potent activity against Trypanosoma brucei rhodesiense, a causative organism of African trypanosomiasis and also against Trypanosoma cruzi, the causative organism of Chagas disease. There was significantly lower activity against Leishmania donovani, one of the causative organisms of leishmaniasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiprotozoal Agents* / chemical synthesis
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Antiprotozoal Agents* / chemistry
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Antiprotozoal Agents* / pharmacology
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors* / chemical synthesis
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacology
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Leishmania donovani / drug effects
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Leishmania donovani / enzymology
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Models, Molecular
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Molecular Structure
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Parasitic Sensitivity Tests
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Quinazolines* / chemical synthesis
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Quinazolines* / chemistry
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Quinazolines* / pharmacology
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Structure-Activity Relationship
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Tetrahydrofolate Dehydrogenase / drug effects*
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Trypanosoma brucei rhodesiense / drug effects
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Trypanosoma brucei rhodesiense / enzymology
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Trypanosoma cruzi / drug effects
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Trypanosoma cruzi / enzymology
Substances
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Antiprotozoal Agents
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Enzyme Inhibitors
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Quinazolines
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Tetrahydrofolate Dehydrogenase