Dieter Berg

Test Methods for Antifungal Agents—a Critical Review/ Wirksamkeitsuntersuchungen an antimykotischen Substanzen

Summary: The research for new antimycotic agents is markedly hampered by a lack of alternative fungus‐specific test methods in vitro and a limited number of reproducible infection models in vivo.

Antimycotic sterol biosynthesis inhibitors

Abstract The last decade or so has seen the development and increased use of the antifungal azoles. D. Berg and colleagues describe the pharmacology and medicinal chemistry of these compounds which has allowed research in this field to move towards the development of analogues with reduced toxicity suitable for oral and parenteral administration.

Bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-yl-methyl)-germane, a germanium analogue of the agricultural fungicide flusilazole: Synthesis and biol

Abstract Bis(4-fluorophenyl)methyl(1 H -1,2,4-triazol-1-yl-methyl)germane ( 2 ), a germanium analogue of the agricultural fungicide flusilazole ( 1 ), has been synthesized from Cl 3 GeCH 2 Cl ( 3 ) by both a three-step and a four-step synthesis ( 3 → ( p -F-C 6 H 4 ) 2 Ge(CH 2 Cl)Br ( 4 ) → ( p -F-C 6 H 4 ) 2 Ge (CH 2 Cl)CH 3 ( 5 ) → 2 ; 5 → ( p -F-C 6 H 4 ) 2 Ge(CH 2 I)CH 3 ( 6 ) → 2 ). The fungicidal properties of 2 have been compared with those of the parent silicon compound 1 (studies on Si/Ge bioisosterism). In various test systems, the Si/Ge analogues 1 and 2 showed comparable fungicidal properties (in activity against plant pathogenic fungi: in ag

Sterol Biosynthesis Inhibitors

Sterol biosynthesis inhibitors such as the imidazoles and 1,2,4-triazoles are generally regarded as inhibitors of sterol C-14 demethylation. Neither the MIC values nor the data for direct interaction with the cytochrome P-450 responsible for oxidative C-14 methyl removal, however, fully explain the observed in vivo efficacy. The first generation of azoles, which includes clotrimazole and miconazole, has been supplemented by a second generation, and azoles of the new generation are capable of additional effects on sterol biosynthesis. With the new azoles, for example, delta 5 sterols may accumulate, the accumulation being due to additional sites of inhibition in sterol biosynthesis or to direct membrane-azole interactions. Ketoconazole, itraconazole, and vibunazole are representative of the azoles of the second generation. Finally, a third generation of azoles has been discovered. Azoles of this generation, which include fluconazole, show almost negligible in vitro potency against saprophytically grown fungi but excellent in vivo efficacy. These compounds specifically affect parasitic forms of fungi, thus blocking invasion processes, and interfere directly with the plasma membrane, as shown in leakage experiments. Such secondary effects obviously enhance in vivo potency.

Action Mechanisms of Cell-Division-Arresting Benzimidazoles and of Sterol Biosynthesis-Inhibiting Imidazoles, 1, 2, 4-Triazoles, and Pyrimidines

Summary: In spite of a formal similarity between benzimidazoles and azoles, two completely different action mechanisms are in operation, namely inhibition of tubuline association by the benzimidazoles, and inhibition of ergosterol biosynthesis at the stage of C14 demethylation by imidazoles, 1, 2, 4‐triazoles, and pyrimidines.

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF PHENOXY-TRIAZOLYL-METHANES AS INHIBITORS OF STEROL BIOSYNTHESIS

Abstract Triadimefon is a known potent inhibitor of ergosterol biosynthesis in yeasts and fungi and belongs to the Phenoxy-triazolyl-methane group We report on quantitative structure-activity relationship studies according to Hansch in the phenoxy-triazolyl-methane series based on MIC-values against Saccharomycopsis lipolytica in the agar diffusion test and, in comparison, based on 50% inhibition-values for ergosterol biosynthesis in the same yeast. The correlation deduced show that principally pI50-values of ergosterol biosynthesis inhibition in yeast and fungi are of value as biological data in quantitative structure-activity studies in this azole group.

Naramycin B, an Antibiotic from Streptomyces griseus Strain 587 with Herbicidal Properties-Fermentation, Isolation, and Identification

Abstract From the culture filtrate of Streptomyces griseus strain 587 a herbicidal active fraction was isolated by adsorption on Lewapol® , methanolic desorption, and chromatography on Sephadex® LH-20. Further purification was achieved by HPLC. The pure product was characterized by TLC and different colour reactions. By MS, 1H-NM R, IR and ORD spectroscopy the herbicidal compound could be identified as naramycin B. Naramycin B is an optical isomer of cycloheximide (naramycin A, Actidione®, Acti-Aid®). This communication reports on the fermentative production of naramycin B with strain 587, its isolation, identification, and herbicidal activity.

Chemistry, stereochemistry and biological properties of KWG 4168

KWG 4168 (8-tert-butyl-1,4-dioxaspiro[4,5]decan-2-ylmethyl(ethyl)(propyl)amine; proposed common name spiroxamine) is a new fungicide consisting of four biologically active isomers (two diastereomers, four enantiomers). The four isomers were separated by preparative HPLC on a chiral stationary phase. The diastereoisomers were synthesised from the corresponding chirally pure glycerol derivatives and were separated by preparative HPLC. COSY, HSQC and NOESY NMR spectroscopy were used to asign the configuration of the amino residue relative to the cyclohexyl ring. Studies of the activity against wheat powdery mildew, as well as the inhibition of sterol biosynthesis in fungi by the four stereoisomers, indicate the contribution of each isomer to the biological activity of spiroxamine.