Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors

An, Yunfei; Liu, Wenxia; Xie, Hua; Fan, Haiyan; Han, Jun; Sun, Bin

doi:10.1016/j.ejmech.2021.113950

Cited by 15 publications

(13 citation statements)

References 33 publications

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“…l -Phenylglycine ethyl ester ( 5 ) was selected as the starting material, and its ester group was first reduced to a hydroxyl structure ( 6 ). Subsequently, the amino structure was further protected with BOC anhydride ( 7 ), and transformed into the key intermediate 8 by introduction of the sulfonamide structure . Under alkaline conditions, the intermediate was replaced with the different kind of azole groups to generate intermediates 9a / b .…”

Section: Resultsmentioning

confidence: 99%

Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

Liu

Sheng

et al. 2022

J. Med. Chem.

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Dual-target drug design was considered as the more reasonable antifungal strategy. In this study, three different series of novel compounds were designed using the skeleton screening and splicing method based on dual-target enzyme features, and their structures were synthesized and characterized. Among them, target compounds 5a-1-2, 14b-1-2, and 14c-2-1 with excellent antifungal activity (0.125−2.0 μg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds blocked the ergosterol biosynthesis pathway by inhibiting the core enzyme CYP51, which effectively induced rapid accumulation of reactive oxygen species, damaged the mitochondrial function, and eventually led to the occurrence of fungal apoptosis. On the other hand, these compounds also inhibited the inflammatory inducible enzyme cyclooxygenase-2, which further affected the expression of inflammatory factors and body's immune function. In conclusion, this study discovered potential target compounds, which could accelerate the rehabilitation process of the infected region.

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Section: Resultsmentioning

confidence: 99%

Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

Liu

Sheng

et al. 2022

J. Med. Chem.

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“…Compounds P163-0892 and FLC were predicted using DS-ADMET and DS-TOPKAT modules . The operation process is performed as follows: The structures of target compounds were drawn by Chemdraw, the generated structure files were imported into the program, and “ADMET descriptors” and “Toxicity Prediction” modules were selected, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Compounds P163-0892 and FLC were predicted using DS-ADMET and DS-TOPKAT modules. 27 The operation process is performed as follows: The structures of target compounds were drawn by Chemdraw, the generated structure files were imported into the program, and "ADMET descriptors" and "Toxicity Prediction" modules were selected, respectively. The prediction items, including aqueous solubility, blood−brain barrier penetration, intestinal absorption, plasma protein binding, FDA rodent carcinogenicity, Ames mutagenicity, Skin_Irritancy, and Skin_sensitization, were selected in the parameter browser, respectively.…”

Section: Adme/t Predictionmentioning

confidence: 99%

Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Cryptococcus Species

Zhu

et al. 2022

J. Med. Chem.

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Cryptococcus neoformans and Cryptococcus gattii can cause fatal invasive infections, especially in immunocompromised patients. However, few antifungal drugs are available to help treat cryptococcosis. In this study, by compound library screening, we presented the first report of hit compound P163-0892, which had potent in vitro and in vivo antifungal activity against Cryptococcus spp. In vitro tests showed that P163-0892 was not cytotoxic and had highly selective and strong antifungal activities against Cryptococcus spp. with MIC values less than 1 μg/mL. Synergism of P163-0892 and fluconazole was also observed in vitro. The in vivo antifungal efficacy of P163-0892 was assessed in a wax moth larval fungal infection model, and treatment with 10 mg/kg P163-0892 caused a significant reduction in fungal burden and significant extension of the survival time. Taken together, our data indicate that the hit compound P163-0892 warrants further investigation as a novel anti-Cryptococcus agent.

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“…Apigenin, rutin, and palmitic acid downregulated the expression of ERG11 [ 56 , 104 ]. Other studies targeted ergosterol biosynthesis by applying tormentic acid [ 105 ], benzodioxane derivatives [ 106 ], honokiol and magnolol [ 107 ], and cold atmospheric plasma [ 108 ].…”

Section: Recent Update On Antifungal Targets and Strategiesmentioning

confidence: 99%

Emerging Antifungal Targets and Strategies

Ivanov

Ćirić

Stojković

2022

IJMS

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Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since those currently available are limited and do not completely provide safe and secure protection. Since the current knowledge regarding the physiology of fungal cells and the infection mechanisms is greater than ever, we have the opportunity to use this for the development of novel generations of antifungals. In this review, we selected and summarized recent studies describing agents employing different antifungal mechanisms. These mechanisms include interference with fungal resistance, including impact on the efflux pumps and heat shock protein 90. Additionally, interference with virulence factors, such as biofilms and hyphae; the impact on fungal enzymes, metabolism, mitochondria, and cell wall; and antifungal vaccines are explored. The agents investigated belong to different classes of natural or synthetic molecules with significant attention given also to plant extracts. The efficacy of these antifungals has been studied mainly in vitro with some in vivo, and clinical studies are needed. Nevertheless, there is a large quantity of products employing novel antifungal mechanisms that can be further explored for the development of new generation of antifungals.

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Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors

Cited by 15 publications

References 33 publications

Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Cryptococcus Species

Emerging Antifungal Targets and Strategies

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