Abstract
Thirteen structural analogs of two initial intermediates of the L-α-aminoadipate pathway of L-lysine biosynthesis in fungi have been designed and synthesized, including fluoro- and epoxy-derivatives of homoaconitate and homoisocitrate. Some of the obtained compounds exhibited at milimolar range moderate enzyme inhibitory properties against homoaconitase and/or homoisocitrate dehydrogenase of Candida albicans. The structural basis for homoisocitrate dehydrogenase inhibition was revealed by molecular modeling of the enzyme-inhibitor complex. On the other hand, the trimethyl ester forms of some of the novel compounds exhibited antifungal effects. The highest antifungal activity was found for trimethyl trans-homoaconitate, which inhibited growth of some human pathogenic yeasts with minimal inhibitory concentration (MIC) values of 16-32 mg/mL.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aconitic Acid* / analogs & derivatives
-
Aconitic Acid* / chemical synthesis
-
Aconitic Acid* / chemistry
-
Aconitic Acid* / pharmacology
-
Alcohol Oxidoreductases / antagonists & inhibitors
-
Antifungal Agents* / chemical synthesis
-
Antifungal Agents* / chemistry
-
Antifungal Agents* / pharmacology
-
Candida albicans / drug effects
-
Candida albicans / enzymology
-
Enzyme Inhibitors* / chemical synthesis
-
Enzyme Inhibitors* / chemistry
-
Enzyme Inhibitors* / pharmacology
-
Humans
-
Hydro-Lyases / antagonists & inhibitors
-
Lysine / biosynthesis
-
Models, Molecular
-
Tricarboxylic Acids* / chemical synthesis
-
Tricarboxylic Acids* / chemistry
-
Tricarboxylic Acids* / pharmacology
Substances
-
Antifungal Agents
-
Enzyme Inhibitors
-
Tricarboxylic Acids
-
homoisocitric acid
-
Aconitic Acid
-
Alcohol Oxidoreductases
-
homoisocitrate dehydrogenase
-
Hydro-Lyases
-
homoaconitate hydratase
-
Lysine