title: Antifungal activity of homoaconitate and homoisocitrate analogs.
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.
authors.affiliation: Department of Organic Chemistry, Gdańsk University of Technology, 11/12 Narutowicza Str., 80-233 Gdańsk, Poland. mjm@chem.pg.gda.pl
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Milewska
authors.forename: Marta
authors.initials: M
authors.lastname: Prokop
authors.forename: Iwona
authors.initials: I
authors.lastname: Gabriel
authors.forename: Marek
authors.initials: M
authors.lastname: Wojciechowski
authors.forename: Sławomir
authors.initials: S
authors.lastname: Milewski
mesh_terms: D000156:Aconitic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors; D008239:Lysine / Q000096:biosynthesis; D008958:Models, Molecular; D014233:Tricarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D014233:Tricarboxylic Acids; C517550:homoisocitric acid; D000156:Aconitic Acid; D000429:Alcohol Oxidoreductases; C021368:homoisocitrate dehydrogenase; D006836:Hydro-Lyases; C107855:homoaconitate hydratase; D008239:Lysine