Abstract
Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12 nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, approximately 233-fold improved potency over trimethoprim and approximately 7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biguanides / chemical synthesis*
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Biguanides / pharmacology
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Computer Simulation
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Drug Design
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / pharmacology
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Liver / microbiology
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Microbial Sensitivity Tests
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Mycobacterium avium / drug effects
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Mycobacterium avium / enzymology
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Opportunistic Infections / drug therapy*
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Opportunistic Infections / microbiology
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Pneumocystis carinii / drug effects
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Pneumocystis carinii / enzymology
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Protein Binding
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Rats
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Structure-Activity Relationship
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Tetrahydrofolate Dehydrogenase / drug effects*
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Toxoplasma / drug effects
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Toxoplasma / enzymology
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Triazines / chemical synthesis*
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Triazines / pharmacology
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Trimethoprim / pharmacology
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Trimetrexate / pharmacology
Substances
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Biguanides
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Folic Acid Antagonists
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Triazines
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Trimethoprim
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Tetrahydrofolate Dehydrogenase
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Trimetrexate