Chemistry and biology of novel amine fungicides: Attempts to improve the antifungal activity of fenpropimorph

Abstract

In spite of considerable efforts by many workers, there has been a lack of progress in the area of amine fungicides since fenpropimorph. Random synthesis of a large variety of different amine compounds, as well as intelligent structural modification of the lead structure fenpropimorph (well over 15 000 amines have been screened at BASF alone) have not led to a new market product so far. Further work has been focused on the reported mode of action of fenpropimorph, notably on the inhibition of the sterol Δ14‐reductase. Although some doubt has to be cast on the hypothesis that fenpropimorph behaves as a sterol mimic, the concept of ‘high energy intermediate’ inhibitors has been employed successfully. Rational drug design of azasterol mimics has led to a number of very potent inhibitors of the sterol Δ14‐reductase which also displayed high fungicidal activity in the greenhouse. Although many of these compounds are more powerful reductase inhibitors than fenpropimorph, under field conditions none showed significant advantages over this established fungicide. Most likely, fenpropimorph already exhibits the maximum fungicidal activity which can be attained by blocking the sterol Δ14‐reductase. This would mean that, with the development of the ‘second generation’ amine fungicide fenpropimorph, this class of compounds has already virtually been optimized.

Different approaches toward an automatic structural alignment of drug molecules: Applications to sterol mimics, thrombin and thermolysin inhibitors

“…Inhibitors of the ergosterol biosynthesis are potent fungicides [33]. Two enzymes, A14-sterol reductase and AS~AY-isomerase, are involved in the ergosterol transformation (Fig.…”

“…fenpropimorph, Fig. 2) inhibit both enzymes [33]. Due to their basic character, they are protonated under physiological conditions.…”

“…In the reductase, the positive charge should be delocalized between C8, C9 and C14; in the isomerase it should be located at C8. However, various molecular frameworks can be imagined to mimic the geometry of this cationic transition state [33]. Similar volume requirements and a positive charge are exhibited by a protonated nitrogen present in the different types of sterol mimics shown in Fig.…”

“…The potency of these derivatives increases with growing size of the side chain at nitrogen (see Fig. 3; I50 values of A14-reductase from Ustilago maydis [33]). For the structural comparison the 3,3-dimethylcyclohexyl derivative (1) has been used.…”

Rationally Designed Guanidine and Amidine Fungicides

“…Extensive studies aimed at optimising the activity of the morpholine/piperidine fungicides based on this model have been published. 4 Although the level of activity at the enzyme level was signiÐcantly increased, no compounds were shown to have any advantage over fenpropimorph in the Ðeld.…”