Design, synthesis, crystal structure, fungicidal activity, and mechanism of action of novel thiazole-based hydrazide derivatives containing the 4-aminoquinazoline moiety

A family of novel thiazole-based hydrazide derivatives bearing the 4-aminoquinazoline moiety were designed and synthesized by the molecular hybridization strategy, and assessed for their Antifungal activities in vitro and in vivo. Among these derivatives, the chemical structure of compound A26 was clearly confirmed via X-ray crystallography. The bioassay results revealed that some of the synthesized compounds exhibited significant inhibition effects against the tested phytopathogenic fungi. For example, in vitro EC₅₀ (half maximal effective concentration) values of compounds A19 and A26 against Rhizoctonia solani, A19 against Verticillium dahliae, A26 against Alternaria solani, and A17 against Colletotrichum gloeosporioides were all less than 3.0 μg/mL. In particular, compound A19 with a 2-fluorophenyl group had an EC₅₀ value as low as 2.87 μg/mL towards R. solani, comparable to that of Chlorothalonil (1.44 μg/mL) and slightly inferior to those of Carbendazim and Boscalid (0.85 and 0.83 μg/mL, respectively). In addition, in vivo assays using this compound displayed the curative and protective efficiencies of 48.4% and 59.6% against R. solani, respectively, at the concentration of 200 μg/mL. Moreover, the mechanistic studies indicated that compound A19 likely exerted its highly Antifungal effects by acting as an effective Succinate Dehydrogenase (SDH) inhibitor with an IC₅₀ value of 29.33 μM, based on SDH enzymatic inhibition assays and molecular docking studies. Meanwhile, the presence of compound A19 adversely impacted the integrity of cell membranes and mycelial morphologies of R. solani.

4-Aminoquinazoline; Antifungal activities; Antifungal mechanisms; Structure–activity relationship (SAR) analysis; Thiazole-based hydrazide.