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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.

An unequivocal synthesis of (&) -0-methylaversin [ (h) -tri-0-methylversicolorin B] is described. Aversin i s s how n to 2,3,3a, 1 2 a -tetra h y d r o -4h y d r oxy -6,8d i met h ox y a n t h ra [ 2,3b] New syntheses of 1,3,6,8-tetramethoxyanthraquinone and tri-O-methylemodin are also described. be THE mould, Aspergillus versicolor (Vuillemin) Tiraboschi, produces an array of anthraquinonoid pigments 2-9 including aversin 2 and the versicolorins A, B, and C.Sn Analytical and spectroscopic investigations had previously led us to assign structure (1; R1 = H, R2 = Me) or (2) to aversin. Acting on a suggestion by Dr. J. S. E. Holker,lo we repeated some of our lH n.m.r. measurements (using a more advanced type of spectrometer and a more suitable solvent-see Experimental section) ; the results have necessitated the alteration of the first-mentioned structure to (1;

Biochemical studies on mode of action enable the chemist to optimize biologically active chemical structures. As a case study we describe the optimization process of fungicides inhibiting sterol biosynthesis. The spiroketalamines obtained represent new chemicals with various modes of action on sterol biosynthesis. These examples demonstrate that biochemixal studies allow directed pesticide design. The value of biochemistry in pesticide discovery has to be seen in a stepwise optimization rather than in "de-novo"-design.

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