α-Hydroxyarylacetamides: A New Class of Fungicidally Active Compounds

Abstract

The synthesis and subsequent discovery of fungicidally active a-hydroxyarylacetamides originated from a report that phenyltartronic acid amides exhibited insecticidal activity.1 The slow-acting nature of this activity led us to speculate that these compounds might be metabolically activated via hydrolysis and then decarboxylation of one of the amide moieties. Subsequently, a synthesis programme looking at a wide range of ahydroxy-arylacetamides was instigated. This yielded, not a new insecticide, but a novel class of fungicidally active compounds of which compound 1 (Fig. 1) was an early example.2,3 A systematic study of the optimal substitution patterns in the two phenyl rings indicated that, while various electron-withdrawing groups in the 4-or 3,4-position of the mandelic acid ring gave good activity, very little change was allowed in the phenethylamine ring. One of the best analogues was compound 3 * To whom correspondence should be addressed which showed very good activity ([95% control at 50 mg litre~1) against both vine downy mildew (Plasmopara viticola Berl. & De Toni) and potato late blight (Phytophthora infestans (Mont.) de Bary.During the next stage of our optimisation studies we systematically sought to modify the bridge connecting the two phenyl rings. This work resulted in the discovery of the biologically interesting methyl-substituted analogues 4 and 5. The phenylisopropylamide 5 showed the best overall activity seen to date, and we were keen to investigate whether or not there was any biological discrimination between the four stereoisomers. The isomers were separated using chiral HPLC and the highest activity with respect to late blight was found to be associated with the two isomers possessing the RconÐguration at the phenylisopropylamide centre (Table 1). This suggests that, for this pathogen, this chiral centre is biologically more important than that associated with the mandelamide end of the molecule. The absolute conÐguration of the phenylisopropylamine was assigned via an asymmetric synthesis.4The two aryl groups of the a-hydroxyarylacetamide structure are joined by six bonds, of which only one, the amide bond, has any conformational restriction on rotation. When such a non-rigid molecule binds at an enzyme or receptor there is an entropy penalty which must be paid in terms of lowered binding affinity due to loss of free rotation. Consequently, reducing the number of free rotations, for example by introducing a double bond into a chain, can lead to an increased binding affinity at the molecular site of action.5 The preferred conformations of our compounds were studied using 331 1997 SCI. Pestic. Sci. 0031-613X/97/$17.50. Printed in Great Britain (

Synthesis and fungicidal activity of N‐2‐(3‐methoxy‐4‐propargyloxy)phenethyl amides. Part II: Anti‐oomycetic mandelamides

“…Mandelamides bearing a 3,4-dioxy-substituted phenethylamine as amine part have been known for almost 10 years to be active against oomycetes diseases. 5,6 In this paper we have demonstrated that the introduction of propargyloxy functions into the benzylic position of the mandelic acid moeity and into the para position of the phenethylamine leads to an enormous increase in fungicidal efficacy. Mandipropamid (5), the development compound selected on the basis of the in-depth optimisation study, displays outstanding activity against late blight diseases of potato and tomato (P. infestans), combined with excellent efficacy on downy mildew diseases of grape (P. viticola) and cucumber (Pseudoperonospora cubensis Rostow).…”

“…The hydroxy function of the mandelic acid moiety of 10 can be alkylated with activated alkyl halides. Thus the introduction of a second propargyl group leads to mandipropamid (5), which can also be prepared by direct coupling of 6 with 4-chloromandelic acid and subsequent double propargylation.…”

“…The introduction of small lipophilic groups such as halogen (5 and 19), alkyl (20 and 23) or alkoxy (21 and 24) into the meta and/or para position of the mandelic acid phenyl ring was usually essential for good biological activity. However, surprisingly, the unsubstituted mandelamide 17 was the second most active compound after the para-chloro-substituted mandipropamide (5), which showed outstanding control of both of these important oomycetes diseases. However, ortho substituents other than hydrogen clearly have a negative effect on the fungicidal efficacy (as demonstrated by 18 and 25), with fluorine as the only exception (26).…”

“…3, 4 and mandelamides such as SX 623509 (4). 5,6 We found the broad chemical scope with retained biological activity to be intriguing, particularly for the mandelamides which have so far not been well explored. In this paper we summarise our in-depth derivatisation study of 4, which finally led to the discovery of our new development product mandipropamid (5; ISO-proposed common name).…”

“…Variation of the phenyl substituent in the mandelic acid moiety of mandipropamid(5) The introduction of a carbamate function instead of the successful ether and ester groups leads to a dramatic drop in biological activity (see 38).…”