Discovery of Novel Thiazole Carboxamides as Antifungal Succinate Dehydrogenase Inhibitors

Abstract

To contribute molecular diversity for novel fungicide development, a series of novel thiazole carboxamides were rationally designed, synthesized, and characterized with the succinate dehydrogenase (SDH) as target. Bioassay indicated that compound 6g showed the similar excellent SDH inhibition as that of Thifluzamide with IC 50 of 0.56 mg/L and 0.55 mg/L, respectively. Some derivatives displayed improved in vitro fungicidal activities against Rhizoctonia cerealis and Sclerotinia sclerotiorum with EC 50 of 1.2−16.4 mg/L and 0.5−1.9 mg/L. Surprisingly, 6g showed promising in vitro fungicidal activities against R. cerealis and S. sclerotiorum with EC 50 of 6.2 and 0.6 mg/L, respectively, which was superior to Thifluzamide with the EC 50 of 22.1 and 4.4 mg/L, respectively. Additionally, compounds 6c and 6g displayed excellent in vivo fungicidal activities against S. sclerotiorum on Brassica napus L. leaves with protective activity of 75.4% and 67.3% at 2.0 mg/L, respectively, while Thifluzamide without activity at 5.0 mg/L. Transcriptomic analysis of S. sclerotiorum treated with 6g by RNA sequencing indicated the down-regulation of succinate dehydrogenase gene SDHA and SDHB, and the inhibition of the TCA-cycle.

Studies on the novel pyridine sulfide containing SDH based heterocyclic amide fungicide

“…The SDH was extracted from Botrytis cinerea hyphae, treated with the inhibitors, wileyonlinelibrary.com/journal/ps and the enzyme activities were measured using the method of enzyme-linked immune-sorbent assay (ELISA) according to the manufacturer's instructions (Shanghai Enzyme-linked Biotechnology Co., Ltd, Shanghai, China). 11 The inhibitor concentrations ranged from 0.625 to 10 μg L −1 , and each experiment was repeated at least three times. The absorbance [optical density (OD) value] was determined at 450 nm and used to calculate the half maximal inhibitory concentration (IC 50 ) values.…”

“…Furthermore, the recent studies on the structural modification of amide SDHI fungicides mainly focused on the substituents in aromatic ring and polar moiety. [7][8][9][10][11][12][13][14] Recently, several literatures reported the effect of changes in the amide bridge on fungicidal activity, such as ⊍-hydroxy and ⊍-carbonyl chiral amide ( Fig. 1).…”

Synthesis, Bioactivity Evaluation,3D‐QSAR, and Molecular Docking of Novel Pyrazole‐4‐carbohydrazides as Potential Fungicides Targeting Succinate Dehydrogenase

“…[ 5 ] SDH is widely found in the mitochondria of eukaryotic cells and a variety of prokaryotic cells, which provides electrons for their aerobic respiratory chains. [ 6‐7 ] Succinate dehydrogenase inhibitors (SDHIs) combine with SDH's ubiquinone reduction site and disrupt the mitochondrial respiration chain, thus leading to the fungal death, [ 8 ] which has a unique mechanism of action and has no cross‐resistance with other types of fungicides, such as benzimidazoles, strobilurins and aminopyridines. Therefore, SDHIs are excellent candidates for overcoming fungicide resistance and improving plant disease control.…”

The potential of respiration inhibition as a new approach to combat human fungal pathogens

“…Inhibitors of Complex II include 2-thenoyltrifluoroacetone (TTFA) which inhibits its quinone reduction activity, and 3-nitropropionate, a succinate analogue which inhibits succinate oxidation activity. Succinate dehydrogenase inhibitors are a fast-growing class of fungicides against plant fungal pathogens, which act by binding the (Qp) ubiquinone binding site (Sierotzki and Scalliet 2013; Guo et al 2019; Amiri et al 2019). The role of Complex II in the virulence of human fungal pathogens is not well understood, and thus its inhibition has not yet been explored as an antifungal therapy.…”