58905-16-1Relevant articles and documents
Phototransformation of propiconazole in aqueous media
Vialaton,Pilichowski,Baglio,Paya-Perez,Larsen,Richard
, p. 5377 - 5382 (2001)
The photolysis of propiconazole in pure water, in water containing humic substances, and in natural water was investigated. The reaction rates were determined, and the main photoproducts were identified with the help of HPLC-mass spectrometry and by NMR.
Development of a stability-indicating UPLC method for terconazole and characterization of the acidic and oxidative degradation products by UPLC-Q-TOF/MS/MS and NMR
Chavan, Balasaheb B.,Prasanna, G. Lakshmi,Radhakrishnanand,Kosuri, Eswara Raju,Kalariya, Pradipbhai D.,Talluri, M.V.N. Kumar
, p. 10761 - 10773 (2018)
Terconazole, a triazole antifungal drug, is used to treat infections in the form of a cream or suppositories. A simple, rapid, precise and accurate ultra high performance liquid chromatography method has been developed for the quantitative determination of the terconazole drug substance in the presence of process impurities and degradation products. The method showed adequate separation of terconazole, process impurities and degradation products on a CSH C18 (100 × 2.1 mm, 1.7 μm) column. The mobile phase used was ammonium acetate (10 mM; pH 7.5) and acetonitrile was used as an organic modifier. Terconazole was subjected to forced degradation studies and found to be degraded in acid hydrolytic and oxidative conditions, whereas it was stable under basic, neutral, photolytic and thermal conditions. LC/electrospray ionization and/or LC/atmospheric pressure chemical ionization coupled with quadrupole time-of-flight mass spectrometry have been utilized for identification and structural characterization of the degradation products. The major oxidative degradation products were isolated by preparative HPLC and their structures were confirmed using 1H NMR and 13C NMR. The probable mechanistic explanation is given for the formation of the degradation products. The method was validated in terms of specificity, linearity, accuracy, precision and robustness as per the International Conference on Harmonisation guidelines.
Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections
Xu, Hang,Yan, Zhong-zuo,Guo, Meng-bi,An, Ran,Wang, Xin,Zhang, Rui,Mou, Yan-hua,Hou, Zhuang,Guo, Chun
, (2021/03/16)
A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 μg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 μg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.
Triazole compound containing dioxolame and preparation method of intermediate of triazole compound
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Paragraph 0020-0021, (2021/09/04)
The invention relates to a preparation method of a dioxolane-containing triazole compound and an intermediate thereof, and the method comprises the following steps: reacting a compound shown as a formula (V) with a compound shown as a formula (IV) in the presence of Lewis acid to prepare a compound shown as a formula (III); reacting the compound shown in the formula (III) with a compound shown in the formula (II) to prepare the compound shown in the formula (I). According to the technical scheme, a triazole group is introduced into 1H-1, 2, 4-triazole-1-acetic acid, generation of an isomer 1, 3, 4-triazole byproduct is avoided, the reaction yield is increased, and the method has the advantages of being simple and convenient in process route, few in reaction step, simple in process, low in production cost, environmentally friendly, green and safe; the post-treatment of the product only needs a simple solvent crystallization process, a nitric acid salifying method and a high-temperature distillation method do not need to be adopted, the requirements on equipment are reduced and the cost is reduced under the condition of improving the yield and content of the product, and the method is suitable for industrial production.
Novel triazole derivatives containing different ester skeleton: Design, synthesis, biological evaluation and molecular docking
Han, Xiaoyan,Ren, Liwen,Song, Yali,Sun, Xiaoyang,Wang, Jinhua,Wang, Shumin,Xiao, Bin,Zhang, Na
, p. 64 - 69 (2020/02/03)
Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity are in an urgent need. In this study, a novel series of triazole derivatives containing different ester skeleton were designed and synthesized. Microdilution broth method was used to investigate antifungal activity. Significant inhibitory activity of compounds 5c, 5d, 5e, 5f, 5m and 5n was evaluated against the Candida albicans (I), Candida albicans clinical isolate (II), Candida glabrata clinical isolate (I), and Candida glabrata (II) with minimum inhibitory concentrations (MIC80) values ranging from 2 to 16μg/mL. Notably, compounds 5e and 5n showed the best inhibition against Candida albicans (II), Candida glabrata (I), and Candida glabrata (II) at the concentrations of 2 and 8μg/mL, respectively. Molecular docking study revealed that the target compounds interacted with CYP51 mainly through hydrophobic and van der Waals interactions. The results indicated that these novel triazole derivatives could serve as promising leads for development of antifungal agents.
Design and Synthesis of Tetrazole- And Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors
Cheng, Zhiqiang,Head, Sarah A.,Li, Ruo-Jing,Li, Yingjun,Liu, Jun O.,Liu, Wukun,Pasunooti, Kalyan Kumar,Peng, Hanjing,Shi, Wei Q.
, p. 1111 - 1117 (2020/07/04)
Itraconazole, a widely used antifungal drug, was found to possess antiangiogenic activity and is currently undergoing multiple clinical trials for the treatment of different types of cancer. However, it suffers from extremely low solubility and strong interactions with many drugs through inhibition of CYP3A4, limiting its potential as a new antiangiogenic and anticancer drug. To address these issues, a series of analogs in which the phenyl group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound 24 has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound 24 inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2. It also induced cholesterol accumulation in the endolysosome and demonstrated binding to the sterol-sensing domain of NPC1 in a simulation study. These results suggested that compound 24 may serve as an attractive candidate for the development of a new generation of antiangiogenic drug.
insecticide compositions, insecticidal products containing them and methods of eradicating pests using them
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Paragraph 0267-0271, (2021/01/29)
Styryltriazole compounds having activity as antiparasitic hormone antagonists. Provided are an insecticide composition comprising an isomer or a pharmaceutically acceptable salt thereof, an insecticide product comprising the same, and a method for combating pests using the same.
Synthesis, optimization, antifungal activity, selectivity, and cyp51 binding of new 2-aryl-3-azolyl-1-indolyl-propan-2-ols
Lebouvier, Nicolas,Pagniez, Fabrice,Na, Young Min,Shi, Da,Pinson, Patricia,Marchivie, Mathieu,Guillon, Jean,Hakki, Tarek,Bernhardt, Rita,Yee, Sook Wah,Simons, Claire,Lézé, Marie-Pierre,Hartmann, Rolf W.,Mularoni, Angélique,Le Baut, Guillaume,Krimm, Isabelle,Abagyan, Ruben,Pape, Patrice Le,Borgne, Marc Le
, p. 1 - 32 (2020/08/17)
A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (?)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 0.000256 μg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 μg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 μg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (?)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.
Antifungal activity, mode of action variability, and subcellular distribution of coumarin-based antifungal azoles
Elias, Rebecca,Benhamou, Raphael I.,Jaber, Qais Z.,Dorot, Orly,Zada, Sivan Louzoun,Oved,Pichinuk, Edward,Fridman
supporting information, p. 779 - 790 (2019/07/10)
Azole antifungals inhibit the biosynthesis of ergosterol, the fungal equivalent of cholesterol in mammalian cells. Here we report an investigation of the activity of coumarin-substituted azole antifungals. Screening against a panel of Candida pathogens, including a mutant lacking CYP51, the target of antifungal azoles, revealed that this enzyme is inhibited by triazole-based antifungals, whereas imidazole-based derivatives have more than one mode of action. The imidazole-bearing antifungals more effectively reduced trailing growth associated with persistence and/or recurrence of fungal infections than triazole-based derivatives. The imidazole derivatives were more toxic to mammalian cells and more potently inhibited the activity of CYP3A4, which is one of the main causes of azole toxicity. Using live cell imaging, we showed that regardless of the type of azole ring fluorescent 7-diethylaminocoumarin-based azoles localized to the endoplasmic reticulum, the organelle that harbors CYP51. This study suggests that the coumarin is a promising scaffold for development of novel azole-based antifungals that effectively localize to the fungal cell endoplasmic reticulum.
Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents
Thamban Chandrika, Nishad,Shrestha, Sanjib K.,Ngo, Huy X.,Tsodikov, Oleg V.,Howard, Kaitlind C.,Garneau-Tsodikova, Sylvie
, p. 158 - 173 (2018/02/10)
The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.
