Design, synthesis, and biological evaluation of novel spiro[pyrrolidine-2,3′-quinolin]-2′-one derivatives as potential chitin synthase inhibitors and antifungal agents

Wu, Hu; Du, Chuanbiao; Xu, Yajie; Liu, Lige; Zhou, Xin; Ji, Qinggang

doi:10.1016/j.ejmech.2022.114208

Cited by 10 publications

(4 citation statements)

References 38 publications

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“…Consequently, quinolin‐2(1 H )‐one derivatives have been extensively studied and exploited for a long time. Various derivatives with biological activities have been discovered 25–28 . For all that, the research and development of quinolin‐2(1 H )‐one derivatives have been scarcely reported in the realm of agricultural chemistry.…”

Section: Introductionmentioning

confidence: 99%

“…Namely, it contains both quinoline moiety and amide scaffold. Moreover, quinolin-2(1H)-one derivatives possess various biological activities, including inhibiting activities against pathogenic fungi: Trichophyton rubrum, 24 Epidermophyton floccosum, 24 Aspergillus flavus, 25 Cryptococcus neoformans, 26 Aspergillus fumigatus 27 and Candida albicans 25,26 (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

“…Various derivatives with biological activities have been discovered. [25][26][27][28] For all that, the research and development of quinolin-2(1H)-one derivatives have been scarcely reported in the realm of agricultural chemistry. More importantly, it is the first time that their inhibitory activities have been reported against SDH.…”

Section: Introductionmentioning

confidence: 99%

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Novel quinolin‐2(1H)‐one analogues as potential fungicides targeting succinate dehydrogenase: design, synthesis, inhibitory evaluation and molecular modeling

Wang

Xiao

et al. 2023

Pest Management Science

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BACKGROUNDSuccinate dehydrogenase is an important target of fungicides. Succinate dehydrogenase inhibitors (SDHIs) have widely been used to combat destructive plant pathogenic fungi because they possess efficient and broad‐spectrum antifungal activities and as well as unique mode of action. The research and development of novel SDHIs have been ongoing.RESULTSThirty‐six novel quinolin‐2(1H)‐one derivatives were designed, synthesized and characterized. The single crystal structure of compound 3c was determined through the X‐ray diffraction of single crystals. The bioassay results displayed that most compounds had good antifungal activities at 16 μg mL−1 against Rhizoctonia cerealis, Erysiphe graminis, Botrytis cinerea, Penicillium italicum and Phytophthora infestans. Compounds 6o, 6p and 6r had better antifungal activities than the commercialized fungicide pyraziflumid against Botrytis cinerea. Their half maximal effective concentration (EC50) values were 0.398, 0.513, 0.205 and 0.706 μg mL−1, respectively. Moreover, the inhibiting activities of the bioactive compounds were tested against succinate dehydrogenase. The results indicated that they possessed outstanding activities. Compounds 6o, 6p and 6r also exhibited better inhibiting activities than pyraziflumid against succinate dehydrogenase. Their half maximal inhibitory concentration (IC50) values were 0.450, 0.672, 0.232 and 0.858 μg mL−1, respectively. The results of molecular dynamic (MD) simulations indicated that compound 6r displayed stronger affinity to succinate dehydrogenase than pyraziflumid.CONCLUSIONThe results of the present study displayed that quinolin‐2(1H)‐one derivative could be one scaffold of potential SDHIs and will provide some valuable information for the research and development of new SDHIs. © 2022 Society of Chemical Industry.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel quinolin‐2(1H)‐one analogues as potential fungicides targeting succinate dehydrogenase: design, synthesis, inhibitory evaluation and molecular modeling

Wang

Xiao

et al. 2023

Pest Management Science

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“…Consequently, targeting biofilm is an ideal strategy for antifungal drugs. Echinocandin is a successful example, as it exhibits better selectivity and lower toxicity by specifically targeting fungal biofilms [14].…”

Section: Introductionmentioning

confidence: 99%

Exploration of Baicalein-Core Derivatives as Potent Antifungal Agents: SAR and Mechanism Insights

Zhou,

Yang,

et al. 2023

Molecules

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Baicalein (BE), the major component of Scutellaria Baicalensis, exhibited potently antifungal activity against drug-resistant Candida albicans, and strong inhibition on biofilm formation. Therefore, a series of baicalein-core derivatives were designed and synthesized to find more potent compounds and investigate structure–activity relationship (SAR) and mode of action (MoA). Results demonstrate that A4 and B5 exert a more potent antifungal effect (MIC80 = 0.125 μg/mL) than BE (MIC80 = 4 μg/mL) when used in combination with fluconazole (FLC), while the MIC80 of FLC dropped from 128 μg/mL to 1 μg/mL. SAR analysis indicates that the presence of 5-OH is crucial for synergistic antifungal activities, while o-dihydroxyls and vic-trihydroxyls are an essential pharmacophore, whether they are located on the A ring or the B ring of flavonoids. The MoA demonstrated that these compounds exhibited potent antifungal effects by inhibiting hypha formation of C. albicans. However, sterol composition assay and enzymatic assay conducted in vitro indicated minimal impact of these compounds on sterol biosynthesis and Eno1. These findings were further confirmed by the results of the in-silico assay, which assessed the stability of the complexes. Moreover, the inhibition of hypha of this kind of compound could be attributed to their effect on the catalytic subunit of 1,3-β-d-glucan synthase, 1,3-β-d-glucan-UDP glucosyltransferase and glycosyl-phosphatidylinositol protein, rather than inhibiting ergosterol biosynthesis and Eno1 activity by Induced-Fit Docking and Molecular Dynamics Simulations. This study presents potential antifungal agents with synergistic effects that can effectively inhibit hypha formation. It also provides new insights into the MoA.

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Expedient Access to Enantioenriched 1‐Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement

Panda

Ghorai

2023

Angewandte Chemie

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Leveraging the unexplored regions of chemical space, the integration of spirocyclic cyclobutane in a molecular scaffold opens up a new vista in modern drug discovery. Despite recent advancements in achieving the synthesis of such motifs, strategies for their asymmetric construction have not been well-recognized and remain a formidable challenge. Herein, for the first time, we have demonstrated a chiral Brønsted acid-catalyzed enantioselective synthesis of 1-azaspiro cyclobutanone enabled by an unusual reactivity of enamine that explore the potentiality of Heyns rearrangement upon electrophilic modification. This design strategy offers viable access to a wide range of cyclobutanone containing spiroindoline and spiropyrrolidine derivatives in good yields with excellent stereoselectivities (up to > 99 % ee, > 20 : 1 dr). Furthermore, the practicality of this methodology has been shown by a scale-up synthesis of spirocyclic products and their facile post-synthetic modifications.

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Design, synthesis, and biological evaluation of novel spiro[pyrrolidine-2,3′-quinolin]-2′-one derivatives as potential chitin synthase inhibitors and antifungal agents

Cited by 10 publications

References 38 publications

Novel quinolin‐2(1H)‐one analogues as potential fungicides targeting succinate dehydrogenase: design, synthesis, inhibitory evaluation and molecular modeling

Novel quinolin‐2(1H)‐one analogues as potential fungicides targeting succinate dehydrogenase: design, synthesis, inhibitory evaluation and molecular modeling

Exploration of Baicalein-Core Derivatives as Potent Antifungal Agents: SAR and Mechanism Insights

Expedient Access to Enantioenriched 1‐Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement

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