Design, synthesis, and biological evaluation of novel miconazole analogues containing selenium as potent antifungal agents

Xu, Hui; X, Su; Guo, Mengbi; An, Ran; Mou, Yanhua; Hou, Zhuang; Guo, Chun

doi:10.1016/j.ejmech.2020.112360

Cited by 53 publications

(35 citation statements)

References 23 publications

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“…They were further nucleophilic substituted with azoles under alkaline conditions to generate intermediates 3a-1 / 2 and 3b-2 . Their carbonyl groups were reduced to hydroxyl structures ( 4a-1 / 2 and 4b-2 ) by sodium borohydride . Finally, the target compounds 5a-1, 5a-2-1 / 2 / 3 / 4 , and 5b-2-1 / 2 / 3 / 4 were synthesized by the esterification reaction of NSAIDs (KP, FP, NP, and PP) and intermediates 4a-1 / 2 and 4b-2 .…”

Section: Resultsmentioning

confidence: 99%

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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%

“…Their carbonyl groups were reduced to hydroxyl structures (4a-1/2 and 4b-2) by sodium borohy-dride. 34 Finally, the target compounds 5a-1, 5a-2-1/2/3/4, and 5b-2-1/2/3/4 were synthesized by the esterification reaction of NSAIDs (KP, FP, NP, and PP) and intermediates 4a-1/2 and 4b-2.…”

Section: Design Of Dual-target Compoundsmentioning

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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“…[26] In support of this, mode of action studies [27] with the organoselenium compound ebselen identified pathways leading to alteration of fungal cell redox homeostasis culminating in the attenuation of cellular glutathione and aberrant production of reactive oxygen species. Several groups [6,[28][29][30][31][32] have also described the antifungal properties of structurally diverse organoselenium agents, providing optimism that this class of compounds is uniquely positioned to complement fluconazole-and amphotericin-based anti-fungal therapies for which resistance development is an ongoing concern. [33,34] The Table 3.…”

Section: Chemistryselectmentioning

confidence: 99%

Synthesis, Structures and Antifungal Activity of Selenoglycolurils

et al. 2023

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A synthetic method for the preparation of selenoglycolurils is reported. Target compounds were obtained by two‐stage transformation of unsubstituted, 1‐substituted and 1,3‐disubstituted thioglycolurils by S‐methylation with MeI to the corresponding isothiouronium salts (Step 1) followed by selenation with NaHSe generated in situ from grey Se and NaBH4 (Step 2). Selenoglycolurils possessed potent antifungal activity against Candida albicans and Cryptococcus neoformans (MIC 0.25–0.125 μg/mL) with no discernable toxicity against mamallian cells, supporting the unique role of organoselenium compounds as novel antifungal agents.

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“…When these reactions were carried out in the same system (K 2 CO 3 –MeCN) without KI at room temperature, divergent yields were reported (27–85%) [ 54 , 55 ]. Moreover, both mentioned azoles can be N -alkylated at reflux in an NaHCO 3 -toluene system (yields 42–87%) [ 4 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], NEt 3 -DMF [ 63 ], or NEt 3 -MeOH [ 64 ]. Triazole can also be efficiently alkylated with 2,4-difluorophenacyl chloride in an K 2 CO 3 –CH 2 Cl 2 system at rt (yield of 70%) [ 65 , 66 , 67 ].…”

Section: Introductionmentioning

confidence: 99%

N-Phenacyldibromobenzimidazoles—Synthesis Optimization and Evaluation of Their Cytotoxic Activity

et al. 2022

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Antifungal N-phenacyl derivatives of 4,6- and 5,6-dibromobenzimidazoles are interesting substrates in the synthesis of new antimycotics. Unfortunately, their application is limited by the low synthesis yields and time-consuming separation procedure. In this paper, we present the optimization of the synthesis conditions and purification methods of N-phenacyldibromobenzimidazoles. The reactions were carried out in various base solvent-systems including K2CO3, NaH, KOH, t-BuOK, MeONa, NaHCO3, Et3N, Cs2CO3, DBU, DIPEA, or DABCO as a base, and MeCN, DMF, THF, DMSO, or dioxane as a solvent. The progress of the reaction was monitored using HPLC analysis. The best results were reached when the reactions were carried out in an NaHCO3–MeCN system at reflux for 24 h. Additionally, the cytotoxic activity of the synthesized compounds against MCF-7 (breast adenocarcinoma), A-549 (lung adenocarcinoma), CCRF-CEM (acute lymphoblastic leukemia), and MRC-5 (normal lung fibroblasts) was evaluated. We observed that the studied cell lines differed in sensitivity to the tested compounds with MCF-7 cells being the most sensitive, while A-549 cells were the least sensitive. Moreover, the cytotoxicity of the tested derivatives towards CCRF-CEM cells increased with the number of chlorine or fluorine substituents. Furthermore, some of the active compounds, i.e., 2-(5,6-dibromo-1H-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone (4f), 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trichlorophenyl)ethanone (5g), and 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trifluorophenyl)ethanone (5j) demonstrated pro-apoptotic properties against leukemic cells with derivative 5g being the most effective.

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Design, synthesis, and biological evaluation of novel miconazole analogues containing selenium as potent antifungal agents

Cited by 53 publications

References 23 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

Synthesis, Structures and Antifungal Activity of Selenoglycolurils

N-Phenacyldibromobenzimidazoles—Synthesis Optimization and Evaluation of Their Cytotoxic Activity

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