The Crocacins: Novel Natural Products as Leads for Agricultural Fungicides

Abstract

Septoria nodorum (wheat glume blotch). We also confirmed their mode of action as inhibition of mitochondrial respiration at complex III in beef heart and the model fungus Neurospora crassa.With their novel structures, interesting mode of action and significant fungicidal activity, the crocacins were attractive leads for synthesis, although ambitious targets as agrochemicals due to their relatively complex structures. We therefore decided to embark on a programme of chemistry to see if simpler, more active and more stable compounds could be found.For practical use on crops in the field, fungicides must have reasonable stability on leaf surfaces so that they can kill incoming fungal spores over a period of 1-2 weeks as well as those that are already present. Both crocacin A (1) and D (4) were shown to have low levels of photostability, with 50% of the parent compound being lost in 7 and 37 min, respectively, as thin films on glass slides in a simulated sunlight test in the laboratory. This low photostability is not surprising in view of the number of double bonds the crocacins contain, and would undoubtedly lead to very poor persistence of fungicidal activity on plants, severely limiting the activity that these compounds could show in the field.There was no significant aqueous hydrolysis of the glycine methyl ester group of crocacin A (1) at pH 4 and 7 at 39 o C, but addition of pig liver esterase under these CROP PROTECTION RESEARCH 685Abstract: A short route to the synthesis of analogues of the antifungal but unstable natural product crocacin D was developed. A wide range of compounds were made in which the complex side chain was replaced by simple aromatic units, and many of them showed high activity in a mitochondrial beef heart respiration assay. Some of these compounds were active against plant pathogenic fungi of agricultural importance in glasshouse tests. In order to find compounds with greater stability than the natural crocacins, the photolabile (Z)-enamide was replaced with many different moieties, but none gave rise to useful fungicidal activity.

The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D

“…In our first analogues, we replaced the whole the side chain with simple n-alkyl chains 27,28. We were gratified to find that certain analogues, for example, 12 (Table 4), were very active in the beef heart mitochondrial respiration assay but unfortunately showed no fungicidal activity.…”

“…However, 24 was only very weakly active on the NADH oxidase assay (see Table 5). Another approach that had been employed with the β-methoxyacrylates, was incorporation of the cis -double bond into a benzene ring,27 as in 25 , but this type of analogue was completely inactive. This was consistent with our model, which shows that there is no space for an additional ring.…”

Use of natural products in the crop protection industry

“…Thus, at Syngenta several simplified analogues were prepared to overcome these potential limitations (Crowley et al 2003). It was demonstrated that the complex side chain could be simplified significantly by replacing the side chain with bisarylethers as in 33, or by benzylaryl groups as in 34, whilst maintaining biological activity in vitro and in vivo (Fig.…”

“…Crocacin B (30) and crocacin C (31) did not exhibit significant biological activity (Crowley et al 2003).…”

Sínteses totais das crocacinas A, C e D: novos antibióticos isolados de Chondromyces crocatus e Chondromyces pediculatus

“…O modo de ação apresentado pelas crocacinas A (1) e D (4) sobre o crescimento de fungos despertou o interesse de Crowley e colaboradores 18 em sintetizar análogos nos quais a alta complexidade da cadeia lateral foi substituída por subunidades aromáticas mais simples e contendo funcionalidades que pudessem mimetizar as encontradas nas estruturas das crocacinas. Apesar dos análogos apresentarem maior estabilidade fotoquímica que os produtos naturais, eles continuaram a ter tempos de meia-vida relativamente curtos na superfície das plantas, o que provavelmente se deve à instabilidade fotoquímica da função (Z)-enamida e infelizmente nenhum dos compostos foi ativo o suficiente para estudos posteriores.…”