Inhibitors of ergosterol synthesis

The biosynthesis of sterols is extremely complicated and a good textbook in biochemistry should be consulted (e.g., Nelson and Cox, 2000). Let us recapitulate the process  

Three molecules of acetyl-CoA condense to form mevalonate. 

Mevalonate is converted to isoprene units (isoprene pyrophosphate having five carbons). 

Six isoprene pyrophosphate molecules are converted to squalene (having 30 carbon atoms). 

Squalene is converted to squalene epoxide and then to lanosterol. 

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Amphotericin B preferentially damages ergosterol-containing membranes fluconazole and several congeners are inhibitors of ergosterol synthesis. 

Godard, A., Lamom-. P. Ribereau, P, and Queguiner, G.. Synthesis of new substituted quinolizidines as potential inhibitors of ergosterol biosynthesis. Tetrahedron. 51, 3247, 1995. 

In research for new fungicides and antimycotics, one has to look for a concept for pathogen-specific inhibitors. This means that inhibition of sterol synthesis should not take place at any common step the aim is to only inhibit pathogen-specific steps in biosynthesis. The reason for this is to minimize the risk of human toxicity. If one compares the biosynthesis of mammalian cholesterol to that of ergosterol, the main sterol of pathogenic fungi, it becomes obvious that there are at least four pathogen-specific steps to be inhibited. 

Ergosterol biosynthesis inhibitors differ in their molecular modes of action. This is especially true for the morpholine derivative tride-morph and fenpropimorph. In Pyricularia oryzae, tridemorph inhibits the A to A7 -isomerization reaction in ergosterol synthesis,... 

Oxiconazole, an ergosterol synthesis inhibitor possessing antifungal activity, is used for topical treatment of dermal infections caused by Trichophyton rubrum and T. men-tagrophytes (tinea pedis, tinea cruris, and tinea corporis). 

Cooper, A.B., J.J. Wright, A.K. Ganguly, J. Desai, D. Loenberg, R. Parmegiani et al. (1989). Synthesis of 14-a-aminomethyl substituted lanosterol derivatives inhibitors of fungal ergosterol biosynthesis. J. Chem. Soc., Chem. Commun. 898-900. 

Fungicide research receives less attention by synthesis chemists in the United States than do the herbicide and insecticide disciplines. Overseas chemists find a much greater market for fungicides than do their American counterparts. One of the chapters indicates the interest of the Japanese in fungicides. Two chapters attest to England s contributions to fungicide chemistry. These ergosterol biosynthesis inhibitors continue to attract effort from around the world as evidenced by these workers and the reports from American authors. 

Recently Kerkenaar and Kaars Sijpesteijn (1979) demonstrated that inhibition of respiration cannot be the primary cause of growth inhibition, and that the action of tridemorph is similar to that of known sterol biosynthesis inhibitors. Their study seems to favour in lipid biosynthesis, possibly ergosterol biosynthesis, as a primary mode of action of tridemorph, and would agree with the rather late interference of this compound with protein and RNA synthesis (Kerkenaar et al., 1979, 1981). 

However, there are other changes. There is an increase in sterol (chiefly ergosterol) and a shift in the relative proportions of carotenoids (8). These effects are prevented by the protein synthesis inhibitor cycloheximide (9). Since carotenoids and sterols share a common biosynthesis to farnesyl pyrc hosphate, the hormones must act by derepressing the synthesis of enzjnnes early in this pathway. Preliminary experiments have shown that mevalonate kinase activities are unaffected by trisporic acid, indicating that this is Unlikely to be the limiting enzjnae a more likely candidate is 3-hydroxy-3 ethylglutaryl CoA reductase. 

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