- Isopropyl amino azole antifungal compound, and preparation method and application thereof
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The invention relates to the technical field of medicine, and in particular, relates to a new azole alcohol antifungal compound having the following chemical structural general formula defined in the specification, and a preparation method and an application thereof, wherein R is selected from the group consisting of halogen, alkyl, nitro and cyano group. The compound has good antifungal activity on various superficial and deep fungi, has the advantages of high efficiency, low toxicity, wide antifungal spectra and the like compared with current clinical applied antifungal drugs, and can be used for preparation of antifungal drugs.
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- Propylaminoazole antifungal compounds, and preparation method and application thereof
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The invention relates to the technical field of medicines, and specifically relates to a type of novel azole alcohol antifungal compounds with a chemical structural general formula shown in the description. In the formula, R is selected from alkyl, halogen, nitro or cyano. The compounds provided by the invention have good antifungal activities on various superficial and deep fungi. Compared with existing clinically applied antifungal medicines, the compounds have the advantages of high efficiency, low toxicity, wide antifungal spectrum, and the like. The compounds can be used for preparing antifungal medicines.
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- Allylamine substituted azole antifungal compound and preparation method and application thereof
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The invention relates to the technical field of medicine, in particular to a novel azole-alcohol antifungal compound with a chemical structural general formula shown in the description and a preparation method and application. The chemical structural general formula is shown in the description, wherein R is selected from alkyl or halogens or nitryl or a cyano group. The compound has good antifungal activity in various superficial fungi and deep fungi. Compared with an existing antifungal drug applied in clinic, the novel azole-alcohol antifungal compound has the advantages of being efficient, low in toxicity, wide in antifungal spectrum and the like and can be used for preparing antifungal drugs.
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- Triazole alcohol antifungal compound with piperidine oxadiazole side chain and preparation method for compound and application of compound
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The invention relates to the medical technical field and provides 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(piperidine oxadiazole side chain substituted)-2-propanol compounds in one category. The compound comprises cis-trans-isomers thereof and any mixtures in the forms or pharmaceutical salts thereof. The chemical structural formula of the compound is represented by a formula (I). The invention further provides a preparation method for the compound and an application of the compound in preparing antifungal drugs. From an antifungal experiment, the compound provided by the invention has a very strong antifungal effect on various superficial fungi and deep fungi. Compared with existing clinically applied antifungal drugs such as fluconazole, the compound has the advantages of being efficient, low in toxicity and wide in antifungal spectrum, has relatively good activity on fluconazole drug-resistant bacteria and can be used for preparing antifungal drugs. The formula is shown in the description.
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Paragraph 0062; 0100; 0101
(2016/10/07)
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- Design, synthesis and antifungal activity of novel triazole derivatives containing substituted 1,2,3-triazole-piperdine side chains
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Due to increasing incidence of invasive fungal infections and severe drug resistance to triazole antifungal agents, a series of novel antifungal triazoles with substituted triazole-piperidine side chains were designed and synthesized. Most of the target compounds showed good inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds 8t and 8v were highly active against Candida albicans and Cryptococcus neoformans with MIC values in the range of 0.125 μg/mL to 0.0125 μg/mL. They represent promising leads for the development of new generation of triazole antifungal agents. Molecular docking studies revealed that the target compounds interacted with CACYP51 mainly through hydrophobic and Van der Waals interactions.
- Jiang, Zhigan,Gu, Julin,Wang, Chen,Wang, Shengzheng,Liu, Na,Jiang, Yan,Dong, Guoqiang,Wang, Yan,Liu, Yang,Yao, Jianzhong,Miao, Zhenyuan,Zhang, Wannian,Sheng, Chunquan
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p. 490 - 497
(2014/07/07)
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- Synthesis and antifungal activity of the novel triazole compounds
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A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted- 2-propanols (1a-o) which are analogues of fluconazole, have been designed and synthesized for the first time by the click reaction on the basis of computational docking experiments to the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H NMR, 13C NMR and HRMS. The in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi.
- Yu, Shichong,Chai, Xiaoyun,Wang, Nan,Cui, Hong,Zhao, Qingjie,Hu, Honggang,Zou, Yan,Sun, Qingyan,Wu, Qiuye
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p. 704 - 708
(2013/06/05)
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- Synthesis and antifungal activity of the novel triazole derivatives containing 1,2,3-triazole fragment
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A series of fluconazole analogues containing 1,2,3-triazole fragment have been designed and synthesized on the basis of the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H NMR, 13C NMR and LC-MS. The MIC80 values indicate that the target compounds 1a-r showed higher activities against nearly all the fungi tested to some extent except against Aspergillus fumigatus. Compounds 1c, e, f, l and p showed 128 times higher activity (with the MIC 80 value of 0.0039 mg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls.
- Yu, Shichong,Wang, Nan,Chai, Xiaoyun,Wang, Baogang,Cui, Hong,Zhao, Qingjie,Zou, Yan,Sun, Qingyan,Meng, Qingguo,Wu, Qiuye
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p. 1215 - 1222
(2013/11/06)
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- Discovery of highly potent triazole antifungal derivatives by heterocycle-benzene bioisosteric replacement
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On the basis of our previously discovered triazole antifungal lead compounds, heterocycle-benzene bioisosteric replacement was used to improve their pharmacokinetic profile. The designed new triazole derivatives have good antifungal activity toward a wide range of pathogenic fungi. Their binding mode with the target enzyme was clarified by molecular docking. The MIC value of the highly potent compound 8f against Candida albicans, Candida tropicalis, and Cryptococcus neoformans is 0.016 μg/mL, 0.004 μg/mL, and 0.016 μg/mL, respectively. Moreover, preliminary pharmacokinetic studies revealed that it showed improved oral absorption as compared to the lead compound iodiconazole and deserved for further evaluations.
- Jiang, Zhigan,Wang, Yan,Wang, Wenya,Wang, Shengzheng,Xu, Bo,Fan, Guorong,Dong, Guoqiang,Liu, Yang,Yao, Jianzhong,Miao, Zhenyuan,Zhang, Wannian,Sheng, Chunquan
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- Molecular docking, design, synthesis and antifungal activity study of novel triazole derivatives containing the 1,2,3-triazole group
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A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[N-propyl-N- ((1-substituted-1H-1,2,3-triazol-4-yl)methyl)amino]-2-propanols which are analogues of fluconazole, have been designed and synthesized on the basis of computational docking experiments to the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H NMR, 13C NMR and HR ESI MS. The MIC80 values indicate that the target compounds 1a-o showed higher activities against nearly all the fungi tested to some extent except against A. fum. and T. rub. All of the target compounds exhibited higher activities against C. alb. SC5314 and C. alb. Y0109 than all of the six positive controls.
- Yu, Shichong,Wang, Lunuan,Wang, Yanwei,Song, Yang,Cao, Yongbing,Jiang, Yuanying,Sun, Qingyan,Wu, Qiuye
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p. 13486 - 13490
(2013/09/02)
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- Synthesis and biological evaluation of novel triazole derivatives as antifungal agents
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A series of 1-(benzylamino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1- yl)propan-2-ols compounds were synthesized and evaluated for their antifungal activities in vitro. The results showed that compounds 6A and 6B exhibited good antifungal activity. Compound 6A8 showed the strongest antifungal activity, which was significantly higher than that of the lead compounds and positive-control drugs Fluconazole and Itraconazole. In particular, the antifungal activity of compound 6A8 against Candida albicans and Candida krusei (MIC80 both at 0.00097 μg/mL) was 515 and 64 times that of Fluconazole, respectively. The structure-activity relationships of the synthesized compounds were discussed, and the docking model of the target compounds with fungal lanosterol 14α-demethylase (CYP51) was analyzed.
- Tang, Hui,Zheng, Can-Hui,Ren, Xiao-Hui,Liu, Jia,Liu, Na,Lv, Jia-Guo,Zhu, Ju,Zhou, You-Jun
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p. 219 - 222
(2013/06/27)
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- Design, synthesis, and biological evaluation of novel 1, 2, 4-triazole derivatives as antifungal agent
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A series of novel 1, 2, 4-triazole derivatives (9a-p) have been designed and synthesized as the potential antifungal agents. All compounds were characterized by 1H-NMR, 13C-NMR, and LCMS. Their antifungal activities against seven human pathogenic fungi were evaluated in vitro by measuring the minimal inhibitory concentrations. Most of the tested compounds were found to be more potent against Candida albicans than the control drug fluconazole.
- Chai, Xiaoyun,Yu, Shichong,Jiang, Yongwei,Zou, Yan,Wu, Qiuye,Zhang, Dazhi,Jiang, Yuanying,Cao, Yongbing,Sun, Qingyan
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p. 1895 - 1901
(2013/04/24)
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- Synthesis and Biological Evaluation of Triazole Derivatives as Potential Antifungal Agent
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A series of triazole antifungal agents with piperidine side chains were designed and synthesized. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum. Moreover, a molecular model for the binding between compound 12 and the active site of CACYP51 was provided based on the computational docking results. The side chain of the compound 12 is oriented into substrate access channel 2 (FG loop) and forms hydrophobic and van der waals interactions with surrounding hydrophobic residues. The phenyl group of the side chain can interact with the phenyl group of Phe380 through the formation of π-π face-to-edge interaction. A series of triazole antifungal agents with piperidine side chains were synthesized. And a molecular model for the binding between compound 12 and the active site of CACYP51 was provided based on the computational docking results.
- Chai, Xiaoyun,Yang, Guang,Zhang, Jun,Yu, Shichong,Zou, Yan,Wu, Qiuye,Zhang, Dazhi,Jiang, Yuanying,Cao, Yongbing,Sun, Qingyan
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p. 382 - 387
(2012/09/08)
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- Synthesis and antifungal activity of novel triazole derivatives
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A series of novel azoles (a-v), which are analogues of fluconazole, have been designed and synthesized as potential antifungal agents by the click reaction. The click reaction approach toward the synthesis of novel 1,2,3-triazolyl linked triazole antifungal derivatives a-v was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of propargylated intermediate 5 with substituted azidomethyl benzene. In addition, the target compounds tested can increase antifungal activity.
- Yan, Yongzheng,Yu, Shichong,Chai, Xiaoyun,Hu, Honggang,Wu, Qiuye
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p. 1649 - 1656
(2012/03/26)
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- Design synthesis and biological evaluation of 3-substituted triazole derivatives
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Based on the active site of lanosterol 14α-demethylase of azole antifungal agents, sixteen 1-(1H-1,2,4-triazole-1-yl)- 2-(2,4-difluorophenyl)-3- (N-n-butyl-N-1-substitutedbenzyl-4-methylene-1H-1,2,3-triazole)-2-propanols have been designed, synthesized and evaluated as antifungal agents. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that some of the compounds exhibited excellent activities with broad spectrum.
- Wang, Bao Gang,Yu, Shi Chong,Chai, Xiao Yun,Yan, Yong Zheng,Hu, Hong Gang,Wu, Qiu Ye
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p. 519 - 522
(2012/01/05)
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- Structure-Based Design, Synthesis, and Antifungal Activity of New Triazole Derivatives
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A series of new antifungal triazole derivatives with phenylacetamide side chain were rational designed and synthesized on the basis of the structural information of lanosterol 14-demethylase (CYP51). In vitro antifungal activity assay indicated that several compounds showed higher activity than fluconazole. Especially, compound 8h showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans (MIC=0.0156μg/mL), suggesting that it is a promising lead for the development of novel antifungal agents. The binding mode of compound 8h was investigated by flexible molecular docking. It interacted with CACYP51 through hydrophobic and van der Waals interactions. A series of phenylacetamide-containing new azoles with good in vitro antifungal activity were rationally designed and synthesized.
- Sheng, Chunquan,Che, Xiaoying,Wang, Wenya,Wang, Shengzheng,Cao, Yongbing,Yao, Jianzhong,Miao, Zhenyuan,Zhang, Wannian
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p. 309 - 313
(2012/05/05)
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- Design, synthesis and antifungal evaluation of 1-(2-(2,4-difluorophenyl)-2- hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one
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Based on the structure of the active site of cytochrome P450 14α-demethylase (CYP51) and the conclusions of the structure-activity relationships of azole antifungals, a series of 1-(2-(2,4-difluoro-phenyl)-2- hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one of fluconazole analogs was synthesized. All compounds were characterized by IR, HRMS, 1HNMR and 13C NMR spectroscopic analysis. Results of preliminary antifungal in vitro test using eight human pathogenic species showed that some compounds displayed comparable or even better antifungal activities than reference drug fluconazole and that compound 3i exhibited significant activity against Candida albicans being worthy of further optimization.
- Jiang, Yongwei,Cao, Yongbin,Zhang, Jun,Zou, Yan,Chai, Xiaoyun,Hu, Honggang,Zhao, Qingjie,Wu, Qiuye,Zhang, Dazhi,Jiang, Yuanying,Sun, Qingyan
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p. 3135 - 3141
(2011/07/08)
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- Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism
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The incidence of life-threatening fungal infections is increasing dramatically. In an attempt to develop novel antifungal agents, our previously synthesized phenoxyalkylpiperazine triazole derivatives were used as lead structures for further optimization. By means of structure-based bioisosterism, triazolone was used as a new bioisostere of oxygen atom. This type of bioisosteric replacement can improve the water solubility without loss of hydrogen-bonding interaction with the target enzyme. A series of triazolone-containing triazoles were rationally designed and synthesized. As compared with fluconazole, several compounds showed higher antifungal activity with broader spectrum, suggesting their potential for further evaluations.
- Sheng, Chunquan,Che, Xiaoying,Wang, Wenya,Wang, Shengzheng,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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p. 5276 - 5282
(2011/12/03)
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- Synthesis and antifungal evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase
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A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted- 2-propanols (1a-v, 2a-w), which are analogues of fluconazole, have been designed and synthesized as the potential antifungal agents by the click reaction. Click reaction approach toward the synthesis of two sets of novel 1,2,3-triazolyl linked triazole antifungal derivatives 1a-v, 2a-w was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of propargylated intermediate 8 with substituted azidomethyl benzene. The 1,2,3-triazolyl group was inserted into the side chain of the target molecule which can increase the antifungal activity of compounds.
- Yu, Shichong,Chai, Xiaoyun,Hu, Honggang,Yan, Yongzheng,Guan, Zhongjun,Zou, Yan,Sun, Qingyan,Wu, Qiuye
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scheme or table
p. 4435 - 4445
(2010/10/19)
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- Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives
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In an attempt to find novel azole antifungal agents with improved activity and broader spectrum, computer modeling was used to design a series of new azoles with piperidin-4-one O-substituted oxime side chains. Molecular docking studies revealed that they formed hydrophobic and hydrogen-bonding interactions with lanosterol 14α-demethylase of Candida albicans (CACYP51). In vitro antifungal assay indicates that most of the synthesized compounds showed good activity against tested fungal pathogens. In comparison with fluconazole, itraconazole and voriconazole, several compounds (such as 10c, 10e, and 10i) show more potent antifungal activity and broader spectrum, suggesting that they are promising leads for the development of novel antifungal agents.
- Xu, Yulan,Sheng, Chunquan,Wang, Wenya,Che, Xiaoying,Cao, Yongbing,Dong, Guoqiang,Wang, Shengzheng,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 2942 - 2945
(2010/08/19)
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- Improved model of lanosterol 14α-demethylase by ligand-supported homology modeling: Validation by virtual screening and azole optimization
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Lanosterol 14α-demethylase (CYP51) is an important target for antifungal drugs. An improved three-dimensional model of CYP51 from Candida albicans (CACYP51) was constructed by ligand-supported homology modeling and molecular dynamics simulations. The accuracy of the constructed model was evaluated by its performance in a small-scale virtual screen. The results show that known CYP51 inhibitors were efficiently discriminated by the model, and it performed better than our previous CACYP51 model. The active site of CACYP51 was characterized by multiple copy simultaneous search (MCSS) calculations. On the basis of the MCSS results, a series of novel azoles were designed and synthesized, and they showed good in vitro antifungal activity with a broad spectrum. The MIC80 value of four of these compounds against C. albicans is 0.001 μgmL-1, indicating that they are promising leads for the discovery of novel antifungal agents.
- Sheng, Chunquan,Wang, Wenya,Che, Xiaoying,Dong, Guoqiang,Wang, Shengzheng,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 390 - 397
(2010/11/18)
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- Novel conformationally restricted triazole derivatives with potent antifungal activity
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In continuation of our work on azole antifungal agents, a series of new conformationally restricted triazole derivatives possessing benzylpiperidin-4-yl methyl amino side chains were designed and synthesized. All the new azoles showed moderate to excellent in vitro antifungal activity against most of the tested pathogenic fungi. Several compounds (such as 12e, 12f, 12h and 12n) showed higher antifungal activity against Candida albicans than fluconazole. Moreover, compounds 12g-i also showed good activity against Aspergillus fumigatus with their MIC80 on the level of 1 μg/mL. Flexible molecular docking was used to analyze the binding mode of the designed compounds. They interact with CACYP51 through hydrophobic and van der Waals interactions.
- Wang, Wenya,Wang, Shengzheng,Liu, Yang,Dong, Guoqiang,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian,Sheng, Chunquan
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scheme or table
p. 6020 - 6026
(2011/01/13)
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- Design, synthesis, and antifungal activity of novel conformationally restricted triazole derivatives
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A series of new triazole derivatives were designed and synthesized on the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51). 2-(2,4-Difluorophenyl)-3-(methyl-(3-phenoxyalkyl)amino)-1- (1H-1,2,4-triazol-1-yl)propan-2-ols show excellent in-vitro activity against most of the tested pathogenic fungi. The MIC80 value of compound 8a against Candida albicans is 0.01 μM, which provides a good starting template for further structural optimization. The binding modes of the designed compounds were investigated by flexible molecular docking. The compounds interacted with CACYP51 through hydrophobic, van-der-Waals, and hydrogenbonding interactions.
- Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 732 - 739
(2010/06/11)
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- Discovery of highly potent novel antifungal azoles by structure-based rational design
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On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC80 value of compounds 8c, 8i and 8n against C. albicans is 0.001 μg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.
- Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 5965 - 5969
(2010/07/04)
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- Design, synthesis, and biological evaluation of novel 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted benzylamino-2-propanols
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Based on the results of computational docking to the active site of the cytochrome P450 14α-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted benzylamino-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum.
- Chai, Xiaoyun,Zhang, Jun,Yu, Shichong,Hu, Honggang,Zou, Yan,Zhao, Qingjie,Dan, Zhigang,Zhang, Dazhi,Wu, Qiuye
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scheme or table
p. 1811 - 1814
(2009/11/30)
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- Rapid synthesis of some new propanol derivatives analogous to fluconazole under microwave irradiation in solventless system
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Fluconazole and a series of 2-(2,4-difluorophenyl)-1-(1H-1,2,4 triazol-1-yl- methyl)-3-(substituted heterocycl)-propan-2-ol which are analogous to fluconazole,were synthesized via the reaction of 2-(2,4-difluorophenyl)-2- [1-(1,2,4-triazolmethide)]oxiran with various heterocyclic system under microwave irradiation in solventless system.
- Heravi, Majid M.,Motamedi, Radineh
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- Antifungal S-ethers of 2-aryl-3-mercapto-1-(1H-1,2,4-triazol-1-yl) propan-2-ols and corresponding sulfoxides and sulfones
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Compounds of the general formula: STR1 wherein R is naphthyl, biphenylyl, phenyl or substituted phenyl; n is 0, 1 or 2; and R1 is H, C1-6 alkyl, C3-7 cycloalkyl, C2-4 alkanoyl, or C1-2 alkyl substituted by C2-4 alkenyl with the provisos that when R1 is H or C2-4 alkanoyl, n is 0; and when n is 2, R1 is C1-3 alkyl; and their pharmaceutically acceptable salts are antifungal agents useful in combatting fungal infections in animals, including humans.
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- Triazole antifungal agents
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Triazole antifungal agents of the formula: STR1 and their O-esters and O-ethers, where R is a phenyl group optionally substituted by 1 to 3 substituents each independently selected from halo, CF3, C1 -C4 alkyl and C1 -C4 alkoxy; R1 is selected from (a) STR2 (C1 -C4 alkyl), (b) --SO2 (C1 -C4 alkyl), (C) --SO2 NR2 R3 where either R2 and R3 are both C1 -C4 alkyl, or R2 and R3 together with the N atom to which they are attached represent piperidino, (d) --NHSO2 (C1 -C4 alkyl) and (e) --CONR4 R5 where either R4 is H or C1 -C4 alkyl and R5 is C1 -C4 alkyl, or R4 and R5 together with the N atom to which they are attached represent piperidino; and n is 1 or 2 with the proviso that n is 2 when R1 is --NHSO2 (C1 -C4 alkyl); and their pharmaceutically acceptable salts. The compounds are useful as human and agricultural fungicides.
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