Furan carboxamide fungicides: Structure-activity relationships with the succinate dehydrogenase complex in mitochondria from a wild-type strain and a carboxin-resistant mutant strain of Ustilago maydis

Abstract

The structure-activity relationships were tested between a broad structural range of substituted mono-, di-, and trimethylfuran carboxamides and the succinate dehydrogenase complex (SDC, complex II) activity in mitochondria isolated from sporidia of a wild-type strain and a moderately carboxin-resistant mutant strain of Ustilago maydis (corn smut). A variety of molecular structures were found to be potent inhibitors of both wild-type and carboxin-resistant SDCs. As with other classes of heterocyclic carboxanilides, certain substituent groups, primarily at the 3′-position on the phenyl ring of the parent anilide, gave analogs with high inhibitory activities. Of prime importance was that a molecular diversity of 4′-substituent groups on the parent carboxanilide produced compounds more inhibitory to the mutant SDC than to the wild-type enzyme complex. These ranged from groups as small as 4′-bromo to larger substituents such as 4′-benzoyl and 4′-phenyl. The 4′-phenyl analog of 2,4,5-trimethylfuran-3-carboxanilide (TCF) had a spectacularly high affinity for the mutant SDC being some 813 times more active on the latter SDC than on the wild-type enzyme complex. With 4′-phenyl TCF, as for some other 4′-substituted analogs, the compound was more active on the mutant enzyme complex than was carboxin to the wild-type SDC. The type of heterocyclic ring also appears to be a factor involved in the degree of specificity of 4′-phenyl substituted carboxamides for both the wild-type and mutant SDCs. The 3′-hydroxy analogs of 2,4-dimethylfuran-3-carboxanilide and TCF showed a slight specificity for the mutant SDC as did several furan carboxamides with thiazol-2-yl, benzothiazol-2-yl, and pyrimidin-2-yl rings. With some exception, furan carboxamides which strongly inhibited the wild-type SDC of U. maydis were active inhibitors of Rhizoctonia solani growth. Most 4′-substituted and N-n-alkyl furan carboxamides were poor inhibitors possibly due to limited cell membrane permeability. More than a single site of action and/or conversion to an active metabolite may account for the strong inhibition of R. solani growth and the weak inhibition of SDC activity noted with furan carboxamides such as the R-i-propyl, methylenefuran-2-yl, and 4-morpholino analogs of 2-methylfuran-3-carboxanilide. © 1988.