Modification of the sterol composition of Trypanosoma (Schizotrypanum) cruzi epimastigotes by Δ24(25)-sterol methyl transferase inhibitors and their combinations with ketoconazole

Paracoccidioides brasiliensis: chemical and molecular tools for research on cell walls, antifungals, diagnosis, taxonomy

“…However, their actions were slightly different. AZA-1 impaired both SMR activity and the introduction of the D 22 bond in the sterol side chain, in agreement with previous studies [61,62]. On the other hand, AZA-2 was much more selective as a SMR inhibitor, due to the accumulation of ergosta-5,7,22,24(28)-tetraen-3b-ol (E); no interference with the metabolic transformation of the B-C ring system and side chain of the sterol molecule occurred with this azasterol analogue.…”

“…3a) [60]; additionally four sterol hydrazones, namely, 20-hydrazone-imidazolin-2-yl-5a-pregnan3b-ol (H1), 20-hydrazone-pyridin-2-yl-5a-pregnan-3b-ol (H2), 22-hydrazone-imidazolin-2-yl-chol-5-ene-3b-ol (H3) and 22-hydrazone-pyridin-2-yl-chol-5-ene3b-ol (H4) were also tested [Visbal et al manuscript under preparation]. AZA-1 (0.1-5 lM) inhibited P. brasiliensis growth in a dose-dependent fashion, reaching 100% growth arrest at the latter concentration and above [60], a result that is similar to those previously reported for parasites (Trypanosoma cruzi, Leishmania donovani) [61] and fungi (Pneumocystis carinii) [62]. AZA-2, instead, was only able to inhibit 60% growth at the highest concentration used in these experiments (10 lM), while AZA-3 was the most powerful drug, since a concentration of 0.5 lM was able to completely inhibit fungal growth in a fungicydal manner [60].…”

A class of sterol 14-demethylase inhibitors as anti- Trypanosoma cruzi agents

“…The analysis revealed accumulation of lanosterol and another major compound with a molecular weight of 440 (14 mass units larger than lanosterol). The latter compound is most likely 24-methylene-dihydrolanosterol (15). The data were consistent with a mechanism of sterol biosynthesis inhibition involving blockage of the enzyme sterol 14-demethylase, a heme-containing cytochrome P450 enzyme.…”

“…The HP-5MS column was used with helium carrier gas at constant f low of 1.1 ml͞min; injector temperature was 250°. We compared the spectra with reference data from National Institute of Standards and Technology͞Environmental Protection Agency͞National Institutes of Health 1998 Mass Spectral Library (Standard Reference Data Program: National Institute of Standards and Technology, Gaithersburg, MD) and published data (15).…”

“…Epimastigotes (1 ϫ 10 8 ) were cultured for 5 days in the presence of compound 2 in varying concentrations. Sterols were extracted from cell pellets (15) and dissolved in ethyl acetate, and 1 l was injected splitless into a Hewlett-Packard GC-MS system with a 6890 series GC and 5973 mass selective detector (70 eV electron impact ionization). The HP-5MS column was used with helium carrier gas at constant f low of 1.1 ml͞min; injector temperature was 250°.…”