Discovery of Novel Quinazoline-2-Aminothiazole Hybrids Containing a 4-Piperidinylamide Linker as Potential Fungicides against the Phytopathogenic Fungus Rhizoctonia solani

Abstract

A total of 29 novel quinazoline-2-aminothiazole hybrids containing a 4-piperidinylamide linker were designed, synthesized, and evaluated for their anti-microbial properties against phytopathogenic fungi and bacteria of agricultural importance. The anti-fungal assays indicated that some of the target compounds exhibited excellent inhibitory effects in vitro against Rhizoctonia solani. For example, 11 compounds within this series (including 4a, 4g, 4h, 4j, 4o, 4s, 4t, 4u, 4v, 4y, and 4b′) were found to possess EC50 values (effective concentration for 50% activity) ranging from 0.42 to 2.05 μg/mL against this pathogen. In particular, compound 4y with a 2-chloro-6-fluorophenyl substituent displayed a potent anti-R. solani efficacy with EC50 = 0.42 μg/mL, nearly threefold more effective than the commercialized fungicide Chlorothalonil (EC50 = 1.20 μg/mL) and also slightly superior to the other fungicide Carbendazim (EC50 = 0.53 μg/mL). Moreover, compound 4y could efficiently inhibit the growth of R. solani in vivo on the potted rice plants, displaying an impressive protection efficacy of 82.3% at 200 μg/mL, better than those of the fungicides Carbendazim (69.8%) and Chlorothalonil (48.9%). Finally, the mechanistic studies showed that compound 4y exerted its anti-fungal effects by altering the mycelial morphology, increasing the cell membrane permeability, and destroying the cell membrane integrity. On the other hand, some compounds demonstrated good anti-bacterial effects in vitro against Xanthomonas oryzae pv. oryzae (Xoo). Overall, the presented results implied that 4-piperidinylamide-bridged quinazoline-2-aminothiazole hybrids held the promise of acting as lead compounds for developing more efficient fungicides to control R. solani.

Design, synthesis, crystal structure, and antimicrobial activities of new quinazoline derivatives containing both the sulfonate ester and piperidinylamide moieties

“…The synthetic route of target compounds III‐1–III‐35 is outlined in Scheme 1. In brief, quinazoline‐substituted piperidine‐4‐carboxylic acid I was prepared according to the procedure reported previously, 42 using quinazolin‐4‐one as the starting material. Subsequently, acid I was converted into the corresponding acid chloride using SOCl 2 as the chlorinating agent, which was immediately condensed with 2‐aminophenol in dry THF with Et 3 N as a catalyst at room temperature to generate phenol II in 47% yield.…”

“…A thionyl chloride (SOCl 2 ) solution (15 mL) containing acid I 42 (500 mg, 1.94 mmol) and dimethylformamide (DMF, 0.2 mL) was stirred at room temperature for 8 h. Then, excess SOCl 2 was removed under reduced pressure to generate the corresponding acid chloride, which was immediately reacted with 2‐aminophenol (212 mg, 1.94 mmol) in dry tetrahydrofuran (THF, 20 mL) with dry triethylamine (Et 3 N, 0.5 mL) as a catalyst. After stirring at room temperature for 6 h, the reaction mixture was poured into water, and the resultant precipitates were filtered, washed with water, and dried to afford phenol II.…”

Heterocycle-Substituted α-Methylene-γ-Butyrolactones Derivatives Synthesis, Antifungal Activity, and 3D-QSAR

“…Effect of Compound 38 on the Cell Membrane Permeability of V. Mali. 34 The activated V. mali was inoculated into 100 mL of PDB; after shaking at 28 °C for 2 days, the wet mycelia were filtered and washed with distilled water. 500 mg of mycelia was put into a 50 mL centrifuge tube, and the drug-containing distilled water was added to make the suspension with gradient concentrations.…”

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

“…The in vivo anti-R. solani effects of lead compounds 7d and 12b were determined on rice leaves using the widely used detached leaf assay. 39,40 For the curative activity assay, R. solani was inoculated into the healthy leaves of rice and cultivated at 25 °C for 24 h before being sprayed with test compounds (100 μg/mL), respectively. For the protective activity assay, fungal inoculation was conducted after spraying the test compounds.…”