Chemical fungicides play a vital role in protecting plants and are considered one of the most cost-effective and efficient measures. Over the years, various types of chemical fungicides have been developed and marketed [1]. Among, succinate dehydrogenase inhibitors (SDHIs) are one of the popular chemical fungicides in recent years, due to their broad antifungal spectrum and excellent antifungal activities. More than 20 commercial SDHIs have been commercialized [2]. SDHIs work on succinate dehydrogenase (SDH) to affect the tricarboxylic acid cycle of pathogenic fungi [3], [4], [5]. hinder normal energy metabolism of pathogenic fungi and inhibit fungal growth for controlling plant diseases [6]. Unfortunately, the problem of fungal drug resistance is becoming increasingly serious due to the frequent use and misuse of SDHIs [7], [8], [9]. Therefore, there is an urgent need to develop novel SDHIs in response to the challenge of fungal drug resistance.

It is well known that the chemical structures of most SDHIs include an amide bond as a linker, a polar component, and a hydrophobic tail [10], [11]. Recent studies have focused on the modified amine fraction while retaining the polar component of commercial SDHIs [12], [13], [14], which results in all commercial SDHIs having similar scaffolds that are susceptible to cross-resistance [15], [16], [17]. The search for novel scaffolds to avoid fungal cross-resistance has become urgent. Thiazole is a five-membered heteroaromatic ring that is commonly used in plant protection due to the pharmaceutical activities of its derivatives, including antifungal [18], antibacterial [19], antidepressant [20], antidiabetic [21] and antiviral properties [22]. Therefore, in this study, thifluzamide with thiazole ring was used as a lead compound for design modification.

In a pesticide or a pharmaceutical drug development process, the structural optimization of lead compounds was carried out through the design strategies of scaffold hopping [23], [24], [25] and bioisosterism [26], [27], [28], which can improve the pharmacological properties of lead compounds and reduce the risk of cross-resistance. In this work, thifluzamide was selected as the lead compound for development. Firstly, by transferring the amide bond from the 5th position to the 2nd position of the thiazole by a scaffold hopping and inverting the amide group based on the concept of bioisosterism. During the synthesis of thiazol-2-ylbenzamide using the pyridine and phosphorus oxychloride, we observed the conversion of the amide group to an imidoyl chloride group, which was similar to that reported in the literature [29]. By consulting the literature, it is found that imidoyl chloride scaffold has found widespread use in the pharmaceutical field [30], [31]. However, apart from studies by Douglas L. Rector and others in 1973 [29], there are few reports about the application of imidoyl chloride scaffolds in plant protection. Therefore, by controlling the reaction conditions, the derivatives of thiazol-2-ylbenzamide and thiazole-2-ylbenzimidoyl chloride were designed and selectively synthesized to respond the challenge of fungal cross-resistance. (Fig. 1).