Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections

Xu, Hui; Yan, Zhong-zuo; Guo, Mengbi; An, Ran; Wang, Xin; Zhang, Rui; Mou, Yanhua; Hou, Zhuang; Guo, Chun

doi:10.1016/j.ejmech.2021.113337

Cited by 20 publications

(22 citation statements)

References 22 publications

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“…Therefore, the minimum fungicidal concentration (MFC) and the time-kill curve against strain 904 were used to evaluate the in vitro fungicidal activity of the target compounds. 29,33 Time-kill curves were assayed to further evaluate the fungicidal activity of compounds A17 and C1 combined with FLC throughout 48 h. The gradient concentrations of compounds A17 and C1 (1× MIC, 2× MIC, and 4× MIC) were used in the time-kill curve assay.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Motivated by the MIC results of the combination of AUY-922 and FLC, we first carried out structural modification of its isopropyl moiety based on molecular docking to further enhance the inhibitory activity against FLC-resistant fungi while achieving species selectivity. To facilitate the subsequent activity screening process, we performed a checkerboard microdilution assay on AUY-922 and FLC for their combined activity against six FLC-resistant fungi isolated from the clinic − to determine the FLC concentration. The results revealed that when the FLC concentration was 2 μg/mL, the inhibition of drug-resistant fungi could be achieved, and follow-up screening was carried out at this concentration.…”

Section: Resultsmentioning

confidence: 99%

“…The experimental procedure was performed according to our previous methods with a few modifications. 29 A fungal suspension of C. albicans (strain 904, 1 × 10 6 CFU/mL) was prepared in RPMI 1640 medium. Then, the fungal suspension was moved to 96-well plates and incubated at 37 °C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…The growth curve assay was performed according to a previous method with a few modifications. 29 A fungal suspension of strain 904 (1 × 10 5 CFU/mL) was prepared in RPMI 1640 medium. The fungal suspension and different concentrations of samples were taken together to incubate at 35 °C for 48 h. The samples were taken at a specific time point (0, 6, 12, 24, and 48 h), diluted and coated on the SDA medium, and cultured at 35 °C for 48 h. Then, the CFU was counted.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Yin

Liu

et al. 2022

J. Med. Chem.

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Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

See 2 more Smart Citations

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Yin

Liu

et al. 2022

J. Med. Chem.

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“…The sterol composition analysis of fungal cells in the target compound (10a-2, 16b-3) treatment groups was performed with gas chromatography−mass spectrometry (GC−MS). 40 In the process, FLC was selected as a positive reference. C. alb.…”

Section: Change Analysis Of the Fungal Sterol Composition In C Alb (S...mentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Dual-Target COX-2/CYP51 Inhibitors for the Treatment of Fungal Infectious Diseases

Liu

Fan

et al. 2022

J. Med. Chem.

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The design of novel dual-target (COX-2/CYP51) inhibitors was proposed in the study, and three series of compounds were constructed though the pathway of skeleton screening and combination; their molecular structures were synthesized and evaluated. Most of the compounds exhibited significant antifungal ability. Among them, potential compounds (10a-2, 16b-3) with excellent antifungal and anti-drug-resistant fungal ability (MIC50, 0.125–2.0 μg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds could block the ergosterol biosynthesis pathway by inhibiting CYP51 and influence the internal physiological function of fungal cells, which included the increase of the ROS level, the anomaly of ΔΨm, and the emergence of an apoptotic state. On the other hand, these compounds also effectively showed COX-2 inhibition ability, eliminated the inflammatory reaction of the infected region, and activated the body’s immune function. In summary, this study not only provided a novel antifungal drug design pathway but also discovered excellent target compounds.

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1,2,4‐Triazole benzamide derivative TPB against Gaeumannomyces graminis var. tritici as a novel dual‐target fungicide inhibiting ergosterol synthesis and adenine nucleotide transferase function

Wang,

Song,

Cheng

et al. 2023

Pest Management Science

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BACKGROUNDIsopropyl 4‐(2‐chloro‐6‐(1H‐1,2,4‐triazol‐1‐yl)benzamido)benzoate (TPB) was a 1,2,4‐triazole benzoyl arylamine derivative with excellent antifungal activity, especially against Gaeumannomyces graminis var. tritici (Ggt). Its mechanism of action was investigated by transmission electron microscopy (TEM) observation, assays of sterol composition, cell membrane permeability, intracellular ATP and mitochondrial membrane potential, and mPTP permeability, ROS measurement, RNA sequencing (RNA‐seq) analysis.RESULTSTPB interfered with ergosterol synthesis, reducing ergosterol content, increasing toxic intermediates, and finally causing biomembrane disruption such as increasing cell membrane permeability and content leakage, and destruction of organelle membranes such as coarse endoplasmic reticulum and vacuole. Moreover, TPB destroyed the function of adenine nucleotide transferase (ANT), leading to ATP transport obstruction in mitochondria, inhibiting mPTP opening, inducing intracellular ROS accumulation and mitochondrial membrane potential loss, finally resulting in mitochondrial damage including mitochondria swelled, mitochondrial membrane dissolved, and cristae destroyed and reduced. RNA‐seq analyses showed that TPB increased the expression of ERG11, ERG24, ERG6, ERG5, ERG3 and ERG2 genes in ergosterol synthesis pathway, interfered with the expression of genes (NDUFS5, ATPeV0E, NCA2 and Pam17) related to mitochondrial structure, and inhibited the expression of genes (WrbA and GST) related to anti‐oxidative stress.CONCLUSIONSTPB exhibited excellent antifungal activity against Ggt by inhibiting ergosterol synthesis and destroying ANT function. So, TPB was a novel compound with dual‐target mechanism of action and can be considered a promising novel fungicide for the control of wheat Take‐all. The results provided new guides for the structural design of active compounds and powerful tools for pathogen resistance management. © 2023 Society of Chemical Industry.

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Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections

Cited by 20 publications

References 22 publications

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Design, Synthesis, and Biological Evaluation of Dual-Target COX-2/CYP51 Inhibitors for the Treatment of Fungal Infectious Diseases

1,2,4‐Triazole benzamide derivative TPB against Gaeumannomyces graminis var. tritici as a novel dual‐target fungicide inhibiting ergosterol synthesis and adenine nucleotide transferase function

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