Inhibition of bovine dihydrofolate reductase and enhancement of methotrexate sensitivity by N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone.
N4-(2-Acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC) belongs to a series of molecules known to have broad antimicrobial inhibitory activity. These molecules contain the 2-acetoxyethoxy moiety which could conceivably take up a conformation analogous to that of the ribosyl group. Moreover, the thiosemicarbazone moiety, when in the presence of a suitable enzymatic site, could mimic the triazine group, which is found in a number of antifolate drugs. AATSC, which has both bacterial inhibitory activity and water solubility, was accordingly evaluated for its antifolate activity against the bovine liver dihydrofolate reductase. AATSC is shown to be a fully uncompetitive inhibitor of that enzyme. Furthermore, AATSC enhances the activity of methotrexate. Such a potentiation could be useful for therapeutic purposes.
Lebrun
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Department of Organic Chemistry (CNRS URA 464), University of Haute Normandie, Mont Saint-Aignan, France.
Tu
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van Rapenbusch
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Banijamali
A R
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Foye
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WO
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002417:Cattle; D004357:Drug Synergism; D005493:Folic Acid Antagonists; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000494:pharmacology*
D000890:Anti-Infective Agents; D005493:Folic Acid Antagonists; D011725:Pyridines; D013882:Thiosemicarbazones; C063829:N(4)-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone; D008727:Methotrexate