Antifungal Activity of Homoaconitate and Homoisocitrate Analogs.docVIP

Molecules 2012, 17, 14022-14036; doi:10.3390/molecules171214022 OPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Antifungal Activity of Homoaconitate and Homoisocitrate Analogs Maria J. Milewska 1,*, Marta Prokop 1, Iwona Gabriel 2, Marek Wojciechowski 2 and S?awomir Milewski 2 1 Department of Organic Chemistry, Gdańsk University of Technology, 11/12 Narutowicza Str., 80-233 Gdańsk, Poland 2 Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, 11/12 Narutowicza Str., 80-233 Gdańsk, Poland * Author to whom correspondence should be addressed; E-Mail: mjm@chem.pg.gda.pl; Tel.: +48-58-347-11-34; Fax: +48-58-347-11-44. Received: 15 October 2012; in revised form: 14 November 2012 / Accepted: 15 November 2012 / Published: 27 November 2012 Abstract: Thirteen structural analogs of two initial intermediates of the L-?-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 ?g/mL. Keywords: homoisocitrate; homoaconitate; synthesis; inhibitors; molecular modeling; antifungal activity 1. Introduction Microbial resistance to antibiotics and synthetic drugs is an emerging challenge for clinicians and the pharmaceutical industry. The multidrug-resistan