Oh

Figure 17.17. Sordarin and notable derivatives.

tion and evaluation of a variety of alkyl-substi-tuted derivatives such as L-793,422 (160). Compounds of this type clearly demonstrate that a certain degree of lipophilicity on the side chain is important for optimal antifungal activity. Biological studies have confirmed that L-793,422 and GM 237354 share the same mode of action (161).

An enantio-specificsynthesis of the monocyclic core of sordarin has been achieved through the conversion of (+)-3,9-dibromoc-amphor into a 1,1,2,2,5-penta-substituted cy-clopentane bearing all of the key functionalities present in the natural product (162). In addition, preliminary reports describing the SAR of the sordarin class of antifungal agents have recently appeared (163, 164).

Recently, efforts have been directed toward the identification of new sordarin agents that display improved activity against Candida spp. other than C. albicans, and that possess improved pharmacological properties such as increased efficacy and decreased toxicity. To that end, a new class in which the traditional sugar moiety is replaced by a 6-methylmor-pholin-2-yl group with N-4' substituents, known as the azasordarins, has been identified. These compounds, highlighted by GW 471558 (Fig. 17.17), have the advantage of be-ingeasier to synthesize from fermentation-derived starting materials than from the parent class (165,166).

3.5.5.4 Pradimicins and Benanomycins. These compounds are dihydrobenzonaphtha-cene quinones conjugated with a D-amino acid and a disaccharide side chain (167). They bind to cell wall mannoproteins in a calcium-dependent manner that causes disruption of the plasma membrane and leakage of intracellular potassium. Spectroscopic studies on the interaction of BMS 181184 (Fig. 17.18), a water-soluble pradimicin derivative, suggest that two molecules of the compound bind one Ca2+ ion, and each compound binds two mannosyl residues (168,169). BMS 181184 possesses activity toward Aspergillus spp. in vitro, but is less potent than itraconazole or amphotericin B (170).In a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits, daily doses of 50 and 150 mg/kg of BMS 181184 were as effective as amphotericin B at 1 mg/kg/day (171).

3.5.5.5 N-Myristoy1 Transferase Inhibitors. N-myristoyl transferase (NMT) is a cytosolic enzyme that catalyzes the transfer of myris-tate from myristoylCoA to the N-terminal glycine amine of a variety of eukaryotic proteins, thereby facilitating protein-protein or pro-tein-lipid interactions involved in intracellular signal transduction cascades. The enzyme has been shown to be essential for the viability of both C. albicans and Cryptococcus neoformans (172, 173).

An approach to inhibit NMT by exploiting the peptide binding site has been reported. Remarkably, it proved possible to mimic four terminal aminoacids (ALYASKLS-NH2) of a weak octapeptide inhibitor of the substrate by use of an 11-aminoundecanoyl motif. Initial optimization of this lead gave a highly potent

Figure 17.1B. BMS 181184.

and selective agent (1, Fig. 17.19), which was shown to be a competitive inhibitor of C. albicans NMT with respect to the octapeptide substrate GNAASARR-NH,, with a ifi(app) value of 70 nM, and to exhibit 400-fold selectivity over the human enzyme (174). However, no whole-cell activity was observable. Addition of a second carboxylic acid (2) ameliorated the potency against the enzyme, but gave a compound with weak fungistatic activity, as did replacement of the remaining peptidic residues (3) (175). The crystal structure of an inhibitor in this series bound to NMT from S. cerevisiae has been published (176).

Two alternative structure-based drug design approaches, based on a lead identified through high throughput screening, have also been reported. In the first, a compound with weak but selective activity (4, Fig. 17.19; IC50 = 0.98 nM; 200-fold selectivity over the human enzyme) (177) was refined to afford highly potent agents with activity against C. albicans both in vitro and in a rat model of systemic candidiasis (5, 6) (178). Like compounds 1-3, these inhibitors interact with the key carboxylate residue (Leu451) implicated in the acyl transfer reaction.

In the second structure-based drug design approach (179,180), early leads based on screening hits that were competitive with the peptide substrate (e.g., 7, Fig. 17.19; IC50 = 0.5 /uM) were potent enzyme inhibitors but lacked whole-cell antifungal activity. Based on the premise that this was attributed to excessive hydrophi-licity, lipophilic substituents were added to the primary amino group. This effort culminated in the identification of a highly potent compound (8;IC„ =86 nAf; C. albicans MIC 0.09 jxg/mL) that was also shown to be fungicidal. A surprising lack of activity against Aspergillus fumiga-tus was attributed to a single change (Phe to Ser) in the binding pocket of the benzothiazole-carboxamide, and this was corroborated by site-directed mutagenesis studies in Candida.

3.5.5.6 Fungal Efflux Pump Inhibitors. It will be apparent from the above discussions on resistance that the inhibition of efflux pumps in pathogenic fungi would be expected to have a significant effect on the susceptibility of several clinically problematic Candida spp. toward several classes of antifungal drugs. The first reports of inhibitors of ABC-type pumps in C. albicans and C. glabrata have recently appeared (181). The agents lack antifungal activity and were characterized by their ability to increase intrinsic susceptibility to known pump substrates (azoles, terbinafine, rhodamine 6G), but not to agents not subject to efflux (amphotericin B). In a fluorescence assay, the compounds were shown to increase intracellular accumulation of rhodamine 6G. Such compounds can reverse CDR-mediated azole resistance in C. albicans (64- to 128-fold reduction in MIC of fluconazole or posaconazole) and reduce intrinsic resistance in C. glabrata (8- to 16-fold reduction in MIC). A representative of the class, milbemycin a-9 (MC-510,027, Fig. 17.20), was shown to dramatically reduce the MIC90 of a broad panel of clinical isolates of Candida (182).

Figure 17.19. nmt inhibitors.
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