Dual-active antifungal agents containing strobilurin and SDHI-based pharmacophores

Abstract

Crop disease management often implies repeated application of fungicides. However, the increasing emergence of fungicide-resistant pathogens requires their rotation or combined use. Tank-mix combinations using fungicides with different modes of action are often hard to manage by farmers. An alternative and unexploited strategy are bifunctional fungicides, i . e . compounds resulting from conjugation of the pharmacophores of fungicides with different mechanisms of action. In this paper we describe a new approach to antifungal treatments based on the synthesis of dual agents, obtained by merging the strobilurin and succinate dehydrogenase inhibitor pharmacophores into a new entity. The compounds were tested against important fungal plant pathogens and showed good inhibition of Pyricularia oryzae and Sclerotinia sclerotiorum with activity comparable to commercial fungicides. The inhibition of the cytochrome bc 1 and the succinate dehydrogenase enzyme activity confirmed that the new molecules are endowed with a dual mechanism of action. These results were further supported by molecular modelling which showed that selected compounds form stable complexes with both cytochrome b subunit and succinate dehydrogenase enzyme. This work can be considered an important first step towards the development of novel dual-action agents with optimized structure and improved interaction with the targets.

The cytochrome bc1 complex as an antipathogenic target

“…As above, dual‐site (Q o /Q i ) fungicidal activity would seem to offer the best chances against developing viable resistant strains, particularly if the issue of G143A resistance can be bypassed by the development of non‐strobilurin‐based inhibitors, occupying the b L ‐distal region of Q o . The recent exciting development of ‘hybrid’ bifunctional fungicides also deserves close observation [93]. Finally, we note that in the absence of suitable AOX inhibitors, the spread of respiratory bypass‐based inhibition must be carefully monitored, and the necessity of the energetic role played by AOX during the various developmental stages of fungal growth.…”

“…Such compounds are thus capable of targeting both cyt bc 1 and succinate dehydrogenase (an additional antipathogenic target). These hybrid compounds have demonstrated notable efficacy against the plant pathogens Pyricularia oryzae and Sclerotinia sclerotiorum under laboratory conditions [93].…”

Chitosan and postharvest decay of fresh fruit: Meta‐analysis of disease control and antimicrobial and eliciting activities

“…The control of the causal fungal pathogens is therefore critical to extend the shelf‐life of these fresh products (Arah, Amaglo, Kumah, & Ofori, 2015; Prusky, 2011). Despite the efficacy of synthetic fungicides in the control of postharvest decay, public concerns about chemical and toxic residues in food (Belden, McMurry, Smith, & Reilley, 2010; Gonçalves et al., 2019; Liu, Yamdeu, Gong, & Orfila, 2020; Mebdoua, 2018) and the increase in drug‐resistant strains of many pathogens (Zuccolo et al., 2019) indicate the need for development of new strategies. Over the last few decades, there has been an increasing interest in the study of postharvest control methods that make use of natural resources (Ebrahimzadeh & Abrinbana, 2019; Guimarães, Abrunhosa, Pastrana, & Cerqueira, 2018; Liu et al., 2019; Liu et al., 2020; Palou, Smilanick, & Droby, 2008; Souza, Yuk, Khoo, & Zhou, 2015; Talibi, Boubaker, Boudyach, & Ait Ben Aoumar, 2014).…”

Structural Investigation and Molecular Modeling Studies of Strobilurin-Based Fungicides Active against the Rice Blast Pathogen Pyricularia oryzae

“…Compound 7 was prepared by reacting (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate [ 18 ] with tert-butyl 2-hydroxyphenylcarbamate 16 , followed by removal of the Boc protecting group and acylation of the resulting compound 18 with 2-methylbenzoic acid. The same synthetic strategy was used to obtain the isomer 8 starting from tert-butyl 4-hydroxyphenylcarbamate 19 ( Scheme 1 ).…”

“…The synthesis of compounds 9–13 started from the common precursor 22 [ 18 ] , which was coupled with the suitable carboxylic acid using EDC·HCl and HOBt as coupling reagents and DIPEA at 0 °C ( Scheme 2 ).…”