Synthesis, fungicidal activity and molecular docking studies of tavaborole derivatives

He, Zhonghu; Huang, Dai-Chuan; Guo, Da‐Le; Deng, Fang; Sha, Qiang; Zhang, Ming-Zhi; Zhang, Weihua; Gu, Yu‐Cheng

doi:10.1016/j.aac.2023.05.004

Cited by 3 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plant pathogens seriously affect food security and yield, and the use of fungicides is the most direct and effective way to control crop diseases. , According to FRAC, more than 230 small-molecule fungicides are currently commercialized, providing a guarantee for a global food supply and social security and stability. However, with the long-term use of traditional chemical fungicides, pathogen resistance is becoming more and more serious, and the ecological environment is also under threat. − Therefore, the development of new, green, safe, and efficient fungicides is indispensable and also in line with the concept of green sustainable development.…”

Section: Introductionmentioning

confidence: 99%

Environmental Evaluation on Toxicity, Toxic Mechanism, and Hydrolysis Behavior of Potential Acethydrazide Fungicide Candidates

Chen,

Chang,

Wang

et al. 2024

J. Agric. Food Chem.

Self Cite

View full text Add to dashboard Cite

The evaluation of toxicity and environmental behavior of bioactive lead molecules is helpful in providing theoretical support for the development of agrochemicals, in line with the sustainable development of the ecological environment. In previous work, some acethydrazide structures have been demonstrated to exhibit excellent and broad-spectrum fungicidal activity; however, its environmental compatibility needs to be further elucidated if it is to be identified as a potential fungicide. In this project, the toxicity of fungicidal acethydrazide lead compounds F51, F58, F72, and F75 to zebrafish was determined at 10 μg mL −1 and 1 μg mL −1 . Subsequently, the toxic mechanism of compound F58 was preliminarily explored by histologic section and TEM observations, which revealed that the gallbladder volume of common carp treated with compound F58 increased, accompanied by a deepened bile color, damaged plasma membrane, and atrophied mitochondria in gallbladder cells. Approximately, F58-treated hepatocytes exhibited cytoplasmic heterogeneity, with partial cellular vacuolation and mitochondrial membrane rupture. Metabolomics analysis further indicated that differential metabolites were enriched in the bile formation-associated steroid biosynthesis, primary bile acid biosynthesis, and taurine and hypotaurine metabolism pathways, as well as in the membrane function-related glycerophospholipid metabolism, linolenic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism pathways, suggesting that the acethydrazide F58 may have acute liver toxicity to common carp. Finally, the hydrolysis dynamics of F58 was investigated, with the obtained half-life of 5.82 days. The above results provide important guiding significance for the development of new green fungicides.

show abstract

Section: Introductionmentioning

confidence: 99%

Environmental Evaluation on Toxicity, Toxic Mechanism, and Hydrolysis Behavior of Potential Acethydrazide Fungicide Candidates

Chen,

Chang,

Wang

et al. 2024

J. Agric. Food Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…6−9 Nevertheless, fungicides remain the most potent weapon to control crop pathogens. 10,11 Therefore, the search for new high-efficiency green fungicides is still needed.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Besides, the wide application of genetically modified crops protected by one or two innate resistance genes or/and partially protected from disease by single-target antifungals accelerates the emergence of new virulent and antifungal strains. , Various disease control strategies are proposed and applied, including the widespread spraying of antifungals and using crops carrying in-bred disease resistance genes . There is also considerable interest in introducing transgenic disease-resistant varieties, such as RNAi-based control strategies, and using microbial biological control agents (MBCA) to protect crops from plant pathogens. − Nevertheless, fungicides remain the most potent weapon to control crop pathogens. , Therefore, the search for new high-efficiency green fungicides is still needed.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Benzothiazol-2-ylthiophenylpyrazole-4-carboxamides as Novel Succinate Dehydrogenase Inhibitors

Yin,

Zhang,

Shang

et al. 2024

J. Agric. Food Chem.

View full text Add to dashboard Cite

Succinate dehydrogenase (SDH) has been considered an ideal target for discovering fungicides. To develop novel SDH inhibitors, in this work, 31 novel benzothiazol-2-ylthiophenylpyrazole-4-carboxamides were designed and synthesized using active fragment exchange and a link approach as promising SDH inhibitors. The findings from the tests on antifungal activity indicated that most of the synthesized compounds displayed remarkable inhibition against the fungi tested. Compound Ig N- (2-(((5-chlorobenzo[d]thiazol-2-yl)thio)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-yrazole-4-carboxamide, with EC 50 values against four kinds of fungi tested below 10 μg/mL and against Cercospora arachidicola even below 2 μg/mL, showed superior antifungal activity than that of commercial fungicide thifluzamide, and specifically compounds Ig and Im were found to show preventative potency of 90.6% and 81.3% against Rhizoctonia solani Kuḧn, respectively, similar to the positive fungicide thifluzamide. The molecular simulation studies suggested that hydrophobic interactions were the main driving forces between ligands and SDH. Encouragingly, we found that compound Ig can effectively promote the wheat seedlings and the growth of Arabidopsis thaliana. Our further studies indicated that compound Ig could stimulate nitrate reductase activity in planta and increase the biomass of plants.

show abstract

“…Benzoxaboroles have gained great popularity in the last decade due to their antimicrobial activity. [7], [8], [9], [10] Several years of clinical research resulted in the approval of Tavaborolethe first known antifungal drug of a benzoxaborole structure. [11], [12], [13], [14], [15], [16] This compound is currently used in the topical treatment of fungal infections called onychomycosis.…”

Section: Introductionmentioning

confidence: 99%

On the mode of anti-C. albicansactivity of a bis(benzoxaborole) analogue of Tavaborole

Gadakh,

Szczepińska,

Potoczna

et al. 2024

Preprint

View full text Add to dashboard Cite

We presented the pharmacodynamic relationship between benzoxaborole concentrations and C. albians blastoconidial population dynamics. Bis(benzoxaborole) analogue (2) and Tavaborole (ref.) showed comparable moderate effects against C. albicans. Benzoxaboroles inhibited the C. albicans growth with metabolic reduction (%R=64). BIC50=2 μg/mL is the lowest concentration that presented 50% inhibition of biofilm metabolic activity vs non-treated control. 2 displayed poor ability to inhibit morphogenesis. Safety and fungicidal activity are still in high demand against biofilm grown on fibroblasts and the zebrafish model in vivo. Benzoxaboroles displayed selectivity in cytotoxic effects. 2 exhibited significantly lower embryotoxicity vs ref. IC50>128 μg/mL for 2. Ref. at 256 μg/mL showed approximately 80% viability of VERO E6 cells. A higher selectivity of the ref to the pathogen than to the mammalian cells was observed. Ref. and 2 showed IC50=2 μg/mL against PBMCs. Antifungal development targets ergosterol binding. RNAseq data indicated that efflux pumps (MDR) were upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole. MDR1 upregulation by 2 was accompanied by the IFD6 (aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1 encoding putative nicotinic acid transporter). Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression of MDR1 and IDF6. Docking studies confirmed the proposed interactions of benzoxaborole adenosinemonophosphate adduct with LeuRS. C5_04480C_A (cell wall biogenesis, protein folding, modification, and destination) was negatively regulated in response to the benzoxaborole stress. Benzoxaborole-altering efflux inhibitors are important for the development of combination strategies in candidiasis. Innovative findings can inspire for designing new antifungals.

show abstract

Synthesis, fungicidal activity and molecular docking studies of tavaborole derivatives

Cited by 3 publications

References 34 publications

Environmental Evaluation on Toxicity, Toxic Mechanism, and Hydrolysis Behavior of Potential Acethydrazide Fungicide Candidates

Environmental Evaluation on Toxicity, Toxic Mechanism, and Hydrolysis Behavior of Potential Acethydrazide Fungicide Candidates

Discovery of Benzothiazol-2-ylthiophenylpyrazole-4-carboxamides as Novel Succinate Dehydrogenase Inhibitors

On the mode of anti-C. albicansactivity of a bis(benzoxaborole) analogue of Tavaborole

Contact Info

Product

Resources

About