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 μg/mL.
Highlights
Microbial resistance to antibiotics and synthetic drugs is an emerging challenge for clinicians and the pharmaceutical industry
It was expected that the ester forms of potential enzyme inhibitors should better penetrate the fungal cell membrane than their salt counterparts and after internalization could be cleaved by intracellular esterases
In order to elucidate a molecular basis for this inhibition, we have studied a pattern of interactions of 7c docked into the modeled C. albicans homoisocitrate dehydrogenase (HIcDH) active site
Summary
Microbial resistance to antibiotics and synthetic drugs is an emerging challenge for clinicians and the pharmaceutical industry. Among different strategies of searching for new potential drugs, identification of novel, unexploited molecular targets and their inhibitors seems one of the most promising approaches. These days many researchers are concentrated on fungal enzymes that catalyze essential biochemical reactions, specific to pathogen cells, and absent from the host cells. Bioactive compounds that selectively block metabolic pathways in human pathogenic fungi could be potential antifungals with low mammalian toxicity. L-Lysine is an essential amino acid for humans, while bacteria, plants and fungi have developed pathways of lysine biosynthesis. In this paper we present results of our studies on the design, synthesis and evaluation of biological properties of some novel structural analogs of homoaconitate and homoisocitrate, intermediates of the AAP pathway
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