Molecules 2012, 17(12), 14022-14036; doi:10.3390/molecules171214022
Article

Antifungal Activity of Homoaconitate and Homoisocitrate Analogs

Maria J. Milewska 1,* email, Marta Prokop 1 , Iwona Gabriel 2 , Marek Wojciechowski 2  and Sławomir 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.
Received: 15 October 2012; in revised form: 14 November 2012 / Accepted: 15 November 2012 / Published: 27 November 2012
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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Abstract: Thirteen structural analogs of two initial intermediates of the L-a-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.
Keywords: homoisocitrate; homoaconitate; synthesis; inhibitors; molecular modeling; antifungal activity

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MDPI and ACS Style

Milewska, M.J.; Prokop, M.; Gabriel, I.; Wojciechowski, M.; Milewski, S. Antifungal Activity of Homoaconitate and Homoisocitrate Analogs. Molecules 2012, 17, 14022-14036.

AMA Style

Milewska MJ, Prokop M, Gabriel I, Wojciechowski M, Milewski S. Antifungal Activity of Homoaconitate and Homoisocitrate Analogs. Molecules. 2012; 17(12):14022-14036.

Chicago/Turabian Style

Milewska, Maria J.; Prokop, Marta; Gabriel, Iwona; Wojciechowski, Marek; Milewski, Sławomir. 2012. "Antifungal Activity of Homoaconitate and Homoisocitrate Analogs." Molecules 17, no. 12: 14022-14036.

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