Inhibitory Potential of New Phenolic Hydrazide-Hydrazones with a Decoy Substrate Fragment towards Laccase from a Phytopathogenic Fungus: SAR and Molecular Docking Studies

Abstract

Laccase from pathogenic fungi participates in both the delignification and neutralization of phytoantibiotics. Furthermore, it interferes with the hormone signaling in plants and catalyzes melanization. Infections of these pathogens contribute to loss in forestry, agriculture, and horticulture. As there is still a need to expand knowledge on efficient defense strategies against phytopathogenic fungi, the present study aimed to reveal more information on the molecular mechanisms of laccase inhibition with natural and natural-like carboxylic acid semi-synthetic derivatives. A set of hydrazide-hydrazones derived from carboxylic acids, generally including electron-rich arene units that serve as a decoy substrate, was synthesized and tested with laccase from Trametes versicolor. The classic synthesis of the title inhibitors proceeded with good to almost quantitative yield. Ninety percent of the tested molecules were active in the range of KI = 8–233 µM and showed different types of action. Such magnitude of inhibition constants qualified the hydrazide-hydrazones as strong laccase inhibitors. Molecular docking studies supporting the experimental data explained the selected derivatives’ interactions with the enzyme. The results are promising in developing new potential antifungal agents mitigating the damage scale in the plant cultivation, gardening, and horticulture sectors.

Discovery of Aryloxy-, Arylthio-, and Arylamino-Containing Acethydrazides as Fungicidal Agents

“… , Maniak reported that the fungicidal mechanism of phenolic hydrazide-hydrazones derived from coumarin hydrazine was inhibiting laccase (Figure ). Similarly, N -sulfonyl hydrazides based on PMDD-5Y design were also designated as laccase inhibitors by Zhang (Figure ). On the other hand, for the fungicidal acethydrazide compounds reported in the literature, the plasma membrane contraction and separation from the cell wall in the treated fungal cells could be clearly found by TEM observation, while the specific target was unclear (Figure ).…”

“…Food supply is related to global security and stability, while world grain output has declined due to various superimposed factors in 2022. Therein, phytopathogenic fungi, such as the troublesome filamentous fungi Fusarium graminearum, Rhizoctonia solani, and Pyricularia grisea, seriously affect grain yield and quality. − The application of fungicides is the most common method of controlling plant diseases and is essential to improve and secure food production. , In China, Shouguang and Shenxian are the two largest producing cities for facility vegetables. However, with the long-term use of traditional fungicides, the resistance of plant pathogens such as Botrytis cinerea and Colletotrichum gloeosporioides in facility vegetables has become more serious.…”

Evaluation of the Binding Relationship of the RdRp Enzyme to Novel Thiazole/Acid Hydrazone Hybrids Obtainable through Green Synthetic Procedure

“…Hydrazides are highly bioactive chemicals with broad biological activities, including glycogen phosphorylase inhibitors, insecticides, HIV inhibitors, myeloperoxidase inhibitors, and antituberculous medications (isoniazid) [ 21 ]. Furthermore, hydrazide-hydrazones are commonly utilized as enzyme inhibitors [ 22 ]. Some hydrazones, for example, have been examined as a new class of dual inhibitors of thymidine phosphorylase and cancer cell growth, which merits further investigation for anti-cancer drug development [ 23 , 24 ].…”

Design, Synthesis and Bioactivity of Sulfonyl Hydrazides and Hydrazides Containing Fragment 1,2,3,4-Tetrahydroisoquinoline

“…漆酶蛋白结构包含肽链、糖配基、四个铜离子反应 簇, 其晶体结构的解析为漆酶抑制剂的深入研究奠定了 基础 [5] . 当前已报道的漆酶抑制剂主要分为两类: (1)无 机化合物: 金属螯合剂、金属离子、卤素离子等 [6][7][8] ; (2) 有机化合物: 短醇 [9] 、肼腙 [10][11] 、缩氨基硫脲类 [12] 等. 这 些抑制剂可通过螯合铜原子、修饰氨基酸残基、改变糖 蛋白构象或与底物竞争性结合等方式影响漆酶活性.…”