Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents

Ni, Tingjunhong; Chi, Xiaochen; Xie, Fei; Li, Liping; Wu, Hao; Yang, Hao; Wang, Xiaobo; Zhang, Dazhi; Jiang, Yuanying

doi:10.1016/j.ejmech.2022.115007

Cited by 17 publications

(16 citation statements)

References 16 publications

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“…Compared with ketoconazole, compounds 8 , 11 , 15 , 24 , and 25 showed relatively lower inhibitory effects on CYP3A4 with IC 50 values of 8.04, 15.2, 19.8, 2.90, and 5.18 μM, respectively. We determined that the halogen-containing compounds 8 , 24 , and 25 showed relatively strong inhibitory activities against the two enzymes CYP2C19 and CYP2D6, which is consistent with the data from our previous study . Notably, compounds 11 , 15 , and 24 showed no inhibition of CYP1A2 with IC 50 values of >100 μM.…”

Section: Resultssupporting

confidence: 90%

“…The general synthetic route for the preparation of the target compounds ( 5 – 35 ) is depicted in Scheme . As a key intermediate of our designed compounds, alkyne 2 was synthesized according to the literature, ,, and the absolute configuration of 2 was confirmed by X-ray crystallographic analysis . Intermediate 3 was prepared by cycloaddition of 2 with TMSCHN 2 at a high temperature.…”

Section: Resultsmentioning

confidence: 99%

“…The intermediate compound 2 was synthesized by a known procedure as previously reported, ,, and the specific experimental operation details can be found in the Supplementary Material.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of Novel Tetrazoles Featuring a Pyrazole Moiety as Potent and Highly Selective Antifungal Agents

Chi

Zhang

et al. 2023

ACS Omega

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In pursuit of developing novel azole antifungals with potent activity and high selectivity, a series of (2R,3S)-3-(substituted-1H-pyrazol-3-yl)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previous work. All compounds exhibited excellent in vitro antifungal activities against Candida spp. and Cryptococcus neoformans H99 with minimum inhibitory concentration values ranging from <0.008 to 4 μg/mL, with some even showing moderate activity against Aspergillus fumigatus 7544. The most active compounds (8, 11, 15, 24, and 25) displayed outstanding antifungal activity against six fluconazole-resistant C. auris clinical isolates and showed a potent inhibitory effect on biofilm formation of C. albicans SC5314 and C. neoformans H99. In addition, compounds 11 and 15 showed no inhibition of human CYP1A2 and low inhibitory activity against CYP3A4, indicating minimal risk of drug−drug interactions. Taken together, these promising tetrazoles with high in vitro potency and good safety profiles warrant further investigation.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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Discovery of Novel Tetrazoles Featuring a Pyrazole Moiety as Potent and Highly Selective Antifungal Agents

Chi

Zhang

et al. 2023

ACS Omega

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“…Furthermore, certain newly discovered CYP51 inhibitors, namely the novel triazoles PC945 and VT1598, have exhibited remarkable antifungal efficacy against C. auris, in comparison to fluconazole [134,135]. The 5-aryl-3-mercapto-1,2,4-triazole derivative compound 10 h, which contains an isoxazole moiety, was tested for its activity against fluconazole-resistant C. auris isolates and indicated remarkable in vivo efficacy against not only C. auris but also C. albicans and C. neoformans [136]. According to molecular docking studies, sertraline has been postulated to exhibit potential binding affinity toward CYP51 and prevent the formation of biofilms in C. auris however, experimental evidence is insufficient to support this hypothesis [137].…”

Section: Combination Therapies To Enhance Azole Efficacymentioning

confidence: 99%

Azole resistance in Candida auris: mechanisms and combinatorial therapy

Jangir,

Kalra,

Tanwar

et al. 2023

APMIS

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Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is associated with nosocomial infections that cause invasive candidiasis in immunocompromised patients. Several antifungal drugs with distinct mechanisms of action are clinically approved for the treatment of fungal infections. The high rates of intrinsic and acquired drug resistance, particularly to azoles, reported in characterized clinical isolates of C. auris make treatment extremely problematic. In systemic infections, azoles are the first‐line treatment for most Candida species; however, the increasing use of drugs results in the frequent emergence of drug resistance. More than 90% of the clinical isolates of C. auris is shown to be highly resistant to azole drugs especially fluconazole, with some strains (types) resistant to all three classes of commonly used antifungals. This presents a huge challenge for researchers in terms of completely understanding the molecular mechanism of azole resistance to develop more efficient drugs. Due to the scarcity of C. auris therapeutic alternatives, the development of successful drug combinations provides an alternative for clinical therapy. Taking advantage of various action mechanisms, such drugs in combination with azole are likely to have synergistic effects, improving treatment efficacy and overcoming C. auris azole drug resistance. In this review, we outline the current state of understanding about the mechanisms of azole resistance mainly fluconazole, and the current advancement in therapeutic approaches such as drug combinations toward C. auris infections.

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“…Invasive fungal infections (IFIs), especially in the last three decades, pose a serious global threat. Especially immunocompromised patient groups (those living with HIV-AIDS, cancer, organ transplant recipients and autoimmune patients) face this threat . It is estimated that the number of invasive fungal infections associated deaths is as high as 1.5 to 2 million worldwide each year .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antifungal Activities, Molecular Docking and Molecular Dynamic Studies of Novel Quinoxaline-Triazole Compounds

Osmaniye,

Baltacı Bozkurt,

Levent

et al. 2023

ACS Omega

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Uncontrolled use of antifungal drugs affects the development of resistance to existing drugs. Azole antifungals constitute a large part of antifungal therapy. Therefore, there is a need for new azole antifungals. Within the scope of this study, 17 new triazole derivative compounds were synthesized. Structure determinations were clarified by spectroscopic analysis methods ( 1 H-NMR, 13 C-NMR, HRMS). In addition, structure matching was completed using two-dimensional NMR techniques, HSQC, HMBC and NOESY. The antifungal effects of the compounds were evaluated on Candida strains by means of in vitro method. Compound 5d showed activity against Candida glabrata with a MIC 90 = 2 μg/mL. Compound 5d showed activity against Candida krusei with a MIC 90 = 2 μg/mL. This activity value, which is higher than fluconazole, is promising. In addition, the biofilm inhibition percentages of the compounds were calculated. Molecular docking and molecular dynamics simulations performed with compound 5d are in harmony with activity studies.

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Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents

Cited by 17 publications

References 16 publications

Discovery of Novel Tetrazoles Featuring a Pyrazole Moiety as Potent and Highly Selective Antifungal Agents

Discovery of Novel Tetrazoles Featuring a Pyrazole Moiety as Potent and Highly Selective Antifungal Agents

Azole resistance in Candida auris: mechanisms and combinatorial therapy

Synthesis, Antifungal Activities, Molecular Docking and Molecular Dynamic Studies of Novel Quinoxaline-Triazole Compounds

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