Azole sterol inhibitors

TABLE II, Azole sterol Inhibitors and their ED q concentrations for selected sensitive fungi... 

Since research on the growth and biochemical responses, as well as resistance, to sterol inhibitors has been recently reviewed (8-14) this information will be covered here only insofar as necessary to establish the background for a discussion on the molecular basis for fungal growth inhibition by these substances. Since most of the work has been conducted with C-14 demethylation inhibitors, emphasis will be given to them, particularly the azoles. 

Antifungal azoles, names, 270-27It Aphelenchus avenae. ecdysteroids, 214 Apis melllfera. effect of sterols on brood production, 183 Artemisia absinthium, sesquiterpene Inhibitor production, 104 Ascaris. sterol biosynthesis, 202-203 Ascarls suum, ecdysteroids, 214 Aspergillus nldulans, studies of sterol inhibitors, 276-277 Aspergillus nlger. studies of fatty acids, 222,223... 

Podust, L. M., Poulos, T. L., and Waterman, M. R. (2001) Crystal structure of cytochrome P450 14alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc. Natl. Acad. Sci. USA 98, 3068-3073. 

Ji, H., Zhang, W., Zhang, M., et al. (2003) Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specific for lano-sterol 14alpha-demethylase of fungi. J. Med. Chem. 46, 474—485. 

In addition to the trifluoromethylphenyl sterol biosynthesis inhibitors discussed in Section 2.1.1.3, a number of fluorine phenyl-containing azoles were introduced in the years 1984 through 1993. Though these molecules share some common structural features, such as the triazole heterocycle and a 4-fluorophenyl ring in at least three of the four fungicides shown below, each also has unique chemical features. For instance, in the case of flusilazole (Punch , Nustar , Triumph , Olymp ) [164], a silicon atom is present. This represented that first time silicon... 

The azole antifungal drugs act by inhibiting the synthesis of the sterol components of the fungal membrane (see also Chapter 4). They are inhibitors... 

In summary, prochloraz, like other azoles, is an ergosterol biosynthesis inhibitor (i.e. it is an EB1) and it does this by blocking 14-demethylation (such compounds are sometimes referred to as demethylation inhibitors, or DMIs). As is now well known, these molecules bind to the sterol binding site of the demethylase enzyme in such a way as to allow the azole to bind to an iron atom in the active site (see below). The normal physiological reaction is therefore prevented. 

Many of the enzymes in the sterol biosynthesis pathway have selective-inhibitors (Fig. 3). These include some extremely important classes of drugs such as Statins , used to treat high cholesterol, bisphosphonates, used to treat osteoporosis, allylamines (e.g., terbinafine) and azoles used to treat fungal infections, and morpholines which are used as fungicidal agrochemicals. 

The current clinical studies have not established a dear role for using either ketooonazole or itraconazole for treatment of patients with Chagas disease, althou it is possible that there may be a marginal therapeutic benefit with itraconazole. Based on the encouraging data with newer azole drugs in animal modds (dearly with superior activity than ketoconazole or itraconazole), one has to be hopefid that aditional dinical smdies will be performed with more aaive sterol l4-demethylase inhibitors in the near future. 

As monotherapy in mice, the best sterol 14-demethylase inhibitors appear to be at least as effective as benznidazole or nifurtimox for treating T. cruzi infections. Three azole compounds deserve special notice are posaconazole, ravuconazole, andTAK-187. A fourth compound, D0870 had excellent activity, but was discontinued from clinical development due to serious side effects in clinical trials for fiu infections. 

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