Tridemorph

Although termed "SI" or "EBI" compounds, the latter referring to ergosterol biosythesis inhibitors, these compounds do not all inhibit ergosterol biosynthesis at the same metabolic site (Fig. 2). For instance, the fungicide tridemorph, unlike most EBI compounds, does not inhibit demethylation at C-14 but rather it apparently prevents the A A isomerization resulting in the accumulation of A containing sterols in treated cells (3). 

Morpholines such as tridemorph (9.112) attack sterol biosynthesis via A -reductase enzyme inhibition and are valuable agricultural fungicides. 

A8,7 Isomerase and A14 Reductase. Before the appearance of resistance to azole fungicides in cereal powdery mildew the A8,7 isomerase and A14 reductase inhibitors were of minor importance because of their limited spectrum. Only seven examples of this group have shown commercial potential fenpropimorph, fenpropidin, tridemorph, dode-morph, aldimorph, piperalin, the first member of the series, introduced by Eli Lilley (now Dow Agrosciences) in 1960, and spiroxamine, the latest addition (Figure 4.5). 

R.I. Baloch, E.L Mercer, T.E. Wiggins and B.C. Baldwin, Inhibition of Ergosterol Biosynthesis in Saccharomyces cerevisiae and Ustilago maydis by Tridemorph, Fenpropimorph and Fenpropidin , Phytochemistry, 1984, 23, 2219-2226. 

Some saturated heterocycles also inhibit ergosterol biosynthesis, but probably at a point later in the pathway. Fenpropimorph (44) (80AGIEH84) is the most potent, superseding the older tridemorph (45). Triforine (46) (B-77MI10712) contains a piperazine ring, but the activity is believed to be associated with the 2,2,2-trichloro-l-formamidoethyl moiety rather than the heterocycle. 

The third group of EBI s are the pyrimidine derivatives nuari-mol, fenarimol, and triarimol (Figure 6). All of these compounds are closely related chemically. The commonality they have with the triazoles and imidazoles is the nitrogen heteroatom in the 3-position from the central carbon. The fourth most interesting group of EBI s are the morpholines which are represented by just two compounds, tridemorph and fenpropimorph (Figure 7). 

Figure 13. Gas chromatography of sterols from Pyricularia oryzae treated with tridemorph.

Figure 14. Distribution of sterols in Pyricularia oryzae after application of tridemorph and fenpropimorph.

Figure 15. Biosynthetic pathway of ergosterol in Pyricularia oryzae indicating the sites of inhibiton by tridemorph and fenpropimorph.

Ergosterol biosynthesis inhibitors differ in their molecular modes of action. This is especially true for the morpholine derivative tride-morph and fenpropimorph. In Pyricularia oryzae, tridemorph inhibits the A to A7 -isomerization reaction in ergosterol synthesis,... 

Selectivity is brilliantly displayed by a multiplicity of compounds developed for the control of powdery mildews. For 148 years from 1803 until 1951 sulfur was the only significant fungicide for powdery mildew. In 1949 a new fungicide appeared with the publication of 6-(1-methylheptyl)-2,4 dinitro-phenyl crotonate (8). Two years later Yarwood reported (9) its anti-powdery mildew properties. It went on to worldwide usage and thus stimulated a vast search for others. Now we have many effective compounds, including benomyl, binapacryl, dodemorph, folpet, parinol, piperalin, pyrazophos, thiophanate, tridemorph, triforine, and dthers. 

Caid chlorophacinone Caliber simazine Caldon dinoseb Calirus benodanil Calixin tridemorph Catnpogran furmecyclox Caparol prometryn Caragard terbumeton Caramba metconazole Carbamult promecab Carbicron dicrotophos Carbyne barban Caryne barban... 

Figure 2.27 The fungicides tridemorph 99 (n = 12 is the major component, but n = 10, 11, and 13 are present in minor amounts) and fenpropimorph 100 are picomolar a, receptor ligands which still await their optimization to drug candidates.

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