Simple Analogues of Quaternary Benzo[<i>c</i>]phenanthridine Alkaloids: Discovery of a Novel Antifungal 2-Phenylphthalazin-2-ium Scaffold with Excellent Potency against Phytopathogenic Fungi

Self Cite

As our further research, a series of new 7-chloro-9-methyl-2-phenyl-3,4-dihydro-β-carbolin-2-iums were designed and synthesized. Twelve compounds were found with excellent inhibition activity in vitro on three to five out of six phytopathogenic fungi, superior to standard drugs thiabendazole and/or azoxystrobin. Especially, 18 displayed the highest activity against three out of the fungi and the highest comprehensive activity for all of the fungi. The test in vivo revealed that 18 at 50 μg/mL was able to completely control Physalospora piricola infections in apples over 8 days. Scanning/transmission electron microscopic observations found that 18 could damage the hyphal integrity and cell membrane structure of P. piricola. The safety evaluation showed that 18 had no effect on the germination rate of cowpea seed at ≤200 μg/mL. The SAR revealed that the combination of 7-Cl and 2′- or 4′-alkyl is conducive to improvement of the activity. Thus, 7-chloro-9-methyl-2-phenyl-3,4-dihydro-β-carbolin-2-ium is a promising antifungal lead scaffold.

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

New 7-Chloro-9-methyl-2-phenyl-3,4-dihydro-β-carbolin-2-iums as Promising Fungicide Candidates: Design, Synthesis, and Bioactivity

Yang

et al. 2022

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“…Based on the above-mentioned considerations and our continuing interest in the development of anti-microbial agents using the quinazoline-piperidine backbone, ,,− we envisaged that a combination of the quinazoline backbone and the 2-aminothiazole heterocycle via the 4-piperidinylamide linker may be a feasible strategy , to discover new anti-microbial agents in agriculture (Figure ). Herein, a series of novel quinazoline-2-aminothiazole hybrids having a 4-piperidinylamide linker were rationally designed, facilely synthesized, and systematically evaluated for their in vitro and in vivo anti-microbial efficacies against ten fungi and three bacteria of agricultural importance.…”

Section: Introductionmentioning

confidence: 99%

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

Ding

Lin

et al. 2022

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.

“…Based on all of the aforementioned considerations and our persistent interest in the development of the 1,2,4-triazole thioether derivatives as agricultural antimicrobial agents, ,,− herein, we designed and synthesized a series of the 1,2,4-triazole thioether and thiazolo[3,2- b ]-1,2,4-triazole derivatives containing both the 6-fluoroquinazolinyl moiety and the piperidinyl linker based on the molecular hybridization strategy , (Figure ). To the best of our knowledge, this is the first report on the utilization of thiazolo[3,2- b ]-1,2,4-triazole-quinazoline hybrid compounds as agrochemical agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural Characterization, and Antibacterial and Antifungal Activities of Novel 1,2,4-Triazole Thioether and Thiazolo[3,2-b]-1,2,4-triazole Derivatives Bearing the 6-Fluoroquinazolinyl Moiety

Ding

Wan

et al. 2021

A total of 52 novel 1,2,4-triazole thioether and thiazolo[3,2-b]-1,2,4-triazole derivatives bearing the 6-fluoroquinazolinyl moiety were designed, synthesized, and evaluated as antimicrobial agents in agriculture based on the molecular hybridization strategy. Among them, molecular structures of compounds 5g and 6m were further confirmed via the single-crystal X-ray diffraction method. The bioassay results indicated that some of the target compounds possessed excellent antibacterial activities in vitro against the pathogen Xanthomonas oryzae pv. oryzae (Xoo). For example, compound 6u demonstrated a strong anti-Xoo efficacy with an EC50 value of 18.8 μg/mL, nearly 5-fold more active than that of the commercialized bismerthiazol (EC50 = 93.6 μg/mL). Moreover, the anti-Xoo mechanistic studies revealed that compound 6u exerted its antibacterial effects by increasing the permeability of bacterial membrane, reducing the content of extracellular polysaccharide, and inducing morphological changes of bacterial cells. Importantly, in vivo assays revealed its pronounced protection and curative effects against rice bacterial blight, proving its potential as a promising bactericide candidate for controlling Xoo. Moreover, compound 6u had a good pesticide-likeness based on Tice’s criteria. More interestingly, compound 6u with high anti-Xoo activity also demonstrated a potent inhibitory effect of 80.8% against the fungus Rhizoctonia solani at 50 μg/mL, comparable to that of the commercialized chlorothalonil (85.9%). Overall, the current study will provide useful guidance for the rational design of more efficient agricultural antimicrobial agents using the thiazolo[3,2-b]-1,2,4-triazole derivatives bearing the 6-fluoroquinazolinyl moiety as lead compounds.