This work has been digitalized and published in 2013 by Verlag Zeitschrift für Naturforschung in cooperation with the Max Planck Society for the Advancement of Science under a Creative Commons Attribution 4.0 International License. Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschung in Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht: Creative Commons Namensnennung 4.0 Lizenz. Anticandidial Effect of Phenylbutene Derivatives and Their Interaction with Ergosterol Svoboda Tabakova3, Iliya Manolovb, Todor Kantardjievc, Grisha Mateevd, Kon stantin Stoichkove, Anna Braykova3, Victoria Vakhan 3 and Evgeny Golovinsky3 a Institute of Molecular Biology, The Bulgarian Academy of Sciences, Sofia, Bulgaria b Department of Organic Chemistry, Faculty of Pharmacy, Higher Medical Scholl, Sofia, Bulgaria c Microbiological Department, National Centre of Infectious and Parasitic Diseases, Sofia, Bulgaria d Department of Dermatology, Higher Medical School, Sofia, Bulgaria e Clinic of Dermatology, National Centre of Oncology, Sofia, Bulgaria Z. Naturforsch. 54c, 61-64 (1999); received May 8 /August 28, 1999 Phenylbut-3-en-2-one Derivatives, Anticandidial, Ergosterol, UV Spectroscopy This paper reports the effect of phenylbut-3-en-2-one, of its analogues, bearing 3-nitro, 4- nitro, 4-chloro- and 4-dimethylamino substituents at the phenyl moiety, and of the hydrazide, phenylhydrazide and oxime of 4-nitrophenylbut-3-en-2-one on the growth and germ-tube formation of Candida spp., as well as their ability to interact with ergosterol in water/dimeth- ylformamide (DMF) solution and their acute toxicity for mice. 3-Nitro-, 4-nitro- and 4-chloro- phenylbut-3-en-2-ones inhibit candidial growth in vitro in concentrations ranging from 0.01 to >0.4 mM and their activity is comparable to that of ketoconazole (in mg/1) and lower than that of amphotericin B. The rest of the compounds are inactive at >0.4 mM. Germ-tube forma tion of C.albicans is inhibited at 0.04 mM 4-nitrophenylbut-3-en-2-one and at 0.005 mM of the 3-nitro isomer. A decrease in the absorption maxima in ergosterol mixtures with 4-dimethyl amino, 3-nitrophenylbut-3-en-2-one and the oxime of the 4-nitrophenylbut-3-en-2-one was observed, indicative of interaction in water/DMF solutions, while no changes in the UV spectra of the remaining compounds were detectable. That suggests that the growth inhibiting effect is not in correlation with their ability to interact with ergosterol, despite the resem blance to polyenes. LD 50 for mice is 367 mg/kg for 4-nitrophenylbut-3-en-2-one and 398 mg/ kg for the 3-nitro isomer. The increase in the incidence of infections, caused by yeast-like fungi from species Candida (Pfaller, 1994; Miller and Wenzel, 1987) , the emerging of strains resistant or cross-resistant towards currently available drugs (e.g. 5-fluorocy- tosine, fluconazole, (Speller and Davis, 1972, Nolte et al., 1997)), the narrow therapeutic index of agents for the treatment of systemic infections (e.g. amphotericin B, 5-fluorocytosine (Jullien et al., 1990)), as well as the low serum concentrations of some azole derivatives prompted the search for anticandidial drugs for either systemic or local ap plication, belonging to new chemical classes (Graybill, 1992). We were interested in the anticandidial effect of a series of phenylbutene derivatives, a group of Reprint requests to Dr. Svoboda Tabakova, Institute of Molecular Biology, Acad. G. Bonchev str. Bl. 21, 1113 Sofia, Bulgaria. E-mail: svt@bas.bg compounds that have a system of conjugated double bonds in which the delocalised pi-electrons originate both from the aliphatic chain and the benzene ring. It was previously reported that some of them (4-nitro- and 3-nitrophenylbut-3-en-2- one) exhibit an antibacterial effect and inhibit pro tein synthesis in E. coli (Tabakova et al., 1994). These two nitro derivatives were also effective against S. cerevisiae (Tabakova, unpublished data) and it was expected that they may act against yeast-like fungi as well. Since the nitrophenylbu- tenones did not affect protein synthesis in the yeast strains it was obvious that the mechanisms of growth inhibition in bacteria and baker’s yeasts would be different. The unsaturated character of the phenylbutene derivatives makes them similar to pecilocin - a polyene antibiotic (Reiner, 1982) and one possibility is that the phenylbutenes in teract with ergosterol and that the anti-yeast effect of this series is associated with the unsaturated character of the molecule. 0939-5075/99/0100-0061 $ 06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com • D