- Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues
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Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14α-sterol demethylase and cruzain, and employing the bioisosterism and molecular hybridization approaches, four novel compounds were synthesized, characterized by melting point range, elemental analysis, IR and NMR spectroscopy. The compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds showed selectivity towards T. cruzi and showed trypanomicidal activity in low micromolar range. The compound 3 showed potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazole, thiosemicarbazonic and nitro group moieties for designing new efficient compounds, potentially for the chronic phase of Chagas disease.
- Silva, Fredson T.,Franco, Caio H.,Favaro, Denize C.,Freitas-Junior, Lucio H.,Moraes, Carolina B.,Ferreira, Elizabeth I.
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- Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections
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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.
- Xu, Hang,Yan, Zhong-zuo,Guo, Meng-bi,An, Ran,Wang, Xin,Zhang, Rui,Mou, Yan-hua,Hou, Zhuang,Guo, Chun
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- Preparation method of 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl)] acetophenone
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The invention provides a preparation method of 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl)] acetophenone. 2-chloro-2' 4'-difluoroacetophenone serving as a raw material reacts with 3-chloro-1, 2, 4-triazole to obtain 2-(3-chloro-1H-1, 2, 4-triazolyl-1-(2, 4-difluorophenyl) ethanone, and then palladium-on-carbon hydrogenation dehalogenation is carried out to obtain a final product 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl) acetophenone. The method for preparing 2' 4'-difluoro-2-[1-(1H-1, 2, 4-triazolyl)] acetophenone is simple in steps, convenient to operate, low in economic cost, suitable for industrial production, capable of bringing good social benefits and economic benefits and large in economic value potential.
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Paragraph 0028; 0035-0036
(2020/08/27)
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- Antibacterial drug and preparation method thereof
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The invention discloses an antibacterial drug. The antibacterial drug is 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(1H-1,2,3,4-tetrazol-1-yl)-2-propanol, the compound is obtained by modifyingfluconazole and introducing a tetrazole ring. Compared with fluconazole, the compound has wider antimicrobial activity spectrum. The invention also discloses a preparation method of the antibacterialdrug. The method comprises the step of introducing the tetrazole ring to obtain 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(1H-1,2,3,4-tetrazol-1-yl)-2-propanol on the basis of retaining moststructures with drug effects on fluconazole.
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- Synthesis, optimization, antifungal activity, selectivity, and cyp51 binding of new 2-aryl-3-azolyl-1-indolyl-propan-2-ols
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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.
- 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
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- Voriconazole and intermediate preparation method
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The present invention discloses a Voriconazole condensate isomer as raw materials for recovery under acidic conditions to obtain 4 - chloro - 6 - ethyl - 5 - fluoro pyrimidine and 2 '4' - difluoro - 2 - [1 - (1 H - 1, 2, 4 - triazolyl)] acetophenone, and can further be used for the preparation of Voriconazole. The method can greatly improve the prior art for preparing the utilization rate of the fu likang zuozuo original auxiliary materials, the cost is reduced.
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Paragraph 0013; 0030-0041
(2019/05/15)
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- Preparation method of voriconazole intermediate
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The invention discloses a preparation method of a voriconazole intermediate. The preparation method comprises the following steps of firstly, preparing 2,4-difluoro brmorobenzene (compound 2) into a format reagent; then reacting with 4-(2-chloracetyl)morpholine (compound 4), so as to obtain a compound, namely 2'-chloro-2,4-difluoroacetophenone (compound 5); finally, enabling the compound 5 to react with 1,2,4-sodium triazole, so as to obtain the voriconazole intermediate (compound 1). The preparation method has the advantages that the cost of the raw materials is low, and the obtaining is easy; the reaction conditions are moderate, the requirement on a reaction kettle is low, and the good industrialization prospect is realized.
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Paragraph 0041; 0042; 0044; 0046; 0048; 0050; 0052; 0054
(2018/04/03)
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- Novel carbazole-triazole conjugates as DNA-targeting membrane active potentiators against clinical isolated fungi
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A series of carbazole-triazole conjugates were designed, synthesized and characterized by IR, NMR, and HRMS spectra. Biological assay showed that most of the synthesized compounds exhibited moderate and even strong antifungal activities, especially 3,6-dibromocarbazolyl triazole 5d displayed excellent inhibitory efficacy against most of the tested fungal strains (MIC = 2–32 μg/mL) and effectively fungicidal ability towards C. albicans, C. tropicals and C. parapsilosis ATCC 22019 (MFC = 4–8 μg/mL). Its combination use with fluconazole could enhance the antifungal efficacy, and compound 5d also did not obviously trigger the development of resistance in C. albicans even after 10 passages. Preliminary mechanism study revealed that the active molecule 5d could depolarize fungal membrane potential and intercalate into DNA to possibly block DNA replication, thus possibly exhibiting its powerful antifungal abilities. Conjugate 5d could interact with HSA, which was constructive for the further design, modification and screening of drug molecules. Docking investigation demonstrated a non-covalent binding of 5d with CYP51 through hydrogen bond and hydrophobicity. These results strongly suggested that compound 5d could act as a potential template for the development of promising antifungal drugs.
- Zhang, Yuan,Tangadanchu, Vijai Kumar Reddy,Bheemanaboina, Rammohan R. Yadav,Cheng, Yu,Zhou, Cheng-He
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p. 579 - 589
(2018/06/20)
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- Triazole compound and application of triazole compound serving as fungicide
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The invention relates to a triazole compound with a general formula (I). In the general formula (I), X is selected from substituting groups including H, C1 to C4 linear-chain or branched-chain alkyl,halogen, nitryl, cyano, phenyl, trifluoromethyl, trichloromethyl, methoxyl and the like and the quantity is 1 to 3. (The formula (I) is shown in the description.) The compound shown as the general formula (I) is used as fungicide and can be used for preventing and controlling banded sclerotial blight, anthracnose, rape sclerotinia rot, watermelon wilt disease, wheat scab, phyricularia oryzae, tomato early blight, phytophthora capsici leonian, banana leaf spot disease, rice false smut, wheat rust, pear tree scab, apple tree altermaria leaf spot and powdery mildew. The compound synthesized by the invention has a novel structure, has higher or equivalent fungicidal activity on certain pathogenic fungi when being compared with commercial fungicide and has a relatively high commercial prospect.
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Paragraph 0023; 0025; 0026
(2018/06/28)
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- fukang zuo and its intermediate synthesis method
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The invention provides a synthesis method of efinaconazole. The method comprises the following steps: carrying out substitution reaction on a compound (8) and a compound (9) to obtain a compound (7), carrying out amidation reaction to obtain a compound (6), carrying out Grignard addition reaction on the compound (6) to obtain a compound (5), carrying out addition reaction on the compound (5) and nitroethane to obtain a racemic mixture (4), carrying out chiral resolution to obtain a compound (3), carrying out reduction reaction on the compound (3) to obtain a compound (2), and finally, carrying out substitution reaction on the compound (2) and a compound (10) to obtain the efinaconazole. The method provided by the invention is simple to operate, has the advantages of low production cost and favorable product quality, and is suitable for industrial production.
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Paragraph 0021; 0063-0065
(2017/07/07)
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- Synthesis and biological evaluation of new fluconazole β-lactam conjugates linked via 1,2,3-triazole
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Novel 1,2,3-triazole-linked β-lactam-fluconazole conjugates 12(a-l) were designed and synthesized. The compounds showed potent antifungal activity against two pathogenic Candida strains; Candida albicans ATCC 24433 and Candida albicans ATCC 10231 with MIC values in the range of 0.0625-2 μg mL-1. Compounds 12h, 12j and 12k showed promising antifungal activity against all the tested fungal pathogens except C. neoformans ATCC 34554 compared to fluconazole. Compound 12j in which the β-lactam ring was formed using para-anisidine and benzaldehyde was found to be more potent than fluconazole against all the fungal strains with an IC50 value of -1 for Candida albicans (ATCC 24433). Mechanistic studies for active compounds revealed that the antifungal action was due to ergosterol inhibition. Compounds 12h and 12j at a concentration of 0.125 μg mL-1 caused 91.5 and 96.8% ergosterol depletion, respectively, compared to fluconazole which at the same concentration caused 49% ergosterol depletion. The molecular docking study revealed that all the fluconazole β-lactam conjugates 12(a-l) could snugly fit into the active site of lanosterol 14α-demethylase (CYP51) with varying degrees of affinities. As anticipated, the binding energy for compound 12j (-58.961 kcal mol-1) was much smaller than that for fluconazole (-52.92 kcal mol-1). The synthesized compounds have therapeutic potential for the control of candidemia.
- Divse, Jaisingh M.,Mhaske, Santosh B.,Charolkar, Chaitanya R.,Sant, Duhita G.,Tupe, Santosh G.,Deshpande, Mukund V.,Khedkar, Vijay M.,Nawale, Laxman U.,Sarkar, Dhiman,Pore, Vandana S.
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p. 470 - 479
(2017/02/05)
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- Discovery of potential antifungal triazoles: Design, synthesis, biological evaluation, and preliminary antifungal mechanism exploration
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A series of triazoles as miconazole analogues was designed, synthesized and characterized by IR, NMR, MS and HRMS. All the newly prepared compounds were screened for their antifungal activities against five kinds of fungi. The bioactive assay showed that most of the synthesized compounds exhibited good or even stronger antifungal activities in comparison with the reference drugs miconazole and fluconazole. In particular, the 3,4-dichlorobenzyl derivative 5b showed a comparable or superior activity against all the tested fungal strains to standard drugs, and formed a supramolecular complex with CYP51 via the hydrogen bond between the 4-nitrogen of the triazole nucleus and the histidine residue. Preliminary experiments revealed that both of the active molecules 5b and 9c could intercalate into calf thymus DNAs, which might block DNA replication to exhibit their powerful antifungal abilities. Further studies indicated that compound 5b might be stored and transported by human serum albumin through hydrophobic interactions, specific electrostatic interactions and hydrogen bonds. These results strongly suggested that compound 5b could serve as a promising antifungal candidate.
- Zhang, Yuan,Damu, Guri L. V.,Cui, Sheng-Feng,Mi, Jia-Li,Tangadanchu, Vijai Kumar Reddy,Zhou, Cheng-He
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p. 1631 - 1639
(2017/08/22)
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- Design, synthesis, & biological activity of new triazole & nitro-triazole derivatives as antifungal agents
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In this study two series of fluconazole derivatives bearing nitrotriazole (series A) or piperazine ethanol (series B) side chain were designed and synthesized and then docked in the active site of lanosterol 14α-demethylase enzyme (1EA1) using the Autodock 4.2 program (The scripps research institute, La Jolla, CA, USA). The structures of synthesized compound were confirmed by various methods including elemental and spectral (NMR, CHN, and Mass) analyses. Then antifungal activities of the synthesized compound were tested against several natural and clinical strains of fungi using a broth microdilution assay against several standard and clinical fungi. Nitrotriazole derivatives showed excellent and desirable antifungal activity against most of the tested fungi. Among the synthesized compounds, 5a-d and 5g, possessing nitrotriazole moiety, showed maximum antifungal activity, in particular against several fluconazole-resistant fungi.
- Sadeghpour, Hossein,Khabnadideh, Soghra,Zomorodian, Kamiar,Pakshir, Keyvan,Hoseinpour, Khadijeh,Javid, Nabiollah,Faghih-Mirzaei, Ehsan,Rezaei, Zahra
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- Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design, synthesis and bioactive evaluation
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A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by 1H NMR, 13C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02 mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.
- Fang, Xian-Fu,Li, Di,Tangadanchu, Vijai Kumar Reddy,Gopala, Lavanya,Gao, Wei-Wei,Zhou, Cheng-He
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p. 4964 - 4969
(2017/10/23)
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- Synthetic method of efinaconazole intermediate
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The invention relates to a synthetic method of an efinaconazole intermediate and discloses a synthetic method of the efinaconazole intermediate (2R, 3S)-2-(2, 4-difluorophenyl)-3-methyl-2-((1H-1, 2, 4 triazol-group) methyl) ethylene oxide. The preparation method comprises the following steps: synthesizing alpha-(1H-1, 2, 4 triazol)-2, 4-difluoroacetophenone by substitution reaction of alpha-halogenated-2, 4-difluoroacetophenone and 1H-1, 2, 4-triazole, then reacting with a sulfur ylide reagent, and synthesizing 2-(2, 4-difluorophenyl)-3-methyl-2-((1H-1, 2, 4 triazol-group) methyl) ethylene oxide. The synthetic method has the advantages that the used materials are low in price and easy in obtaining, the conditions are mild, the operation is simple, the environmental pollution is less and the production cost is low, and the synthetic method is suitable for industrial production.
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Paragraph 0016; 0018
(2017/08/31)
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- Method for preparing philippines Kang Zuo
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The invention discloses a preparation method of efinaconazole (I). The preparation method comprises the following steps: performing asymmetric addition reaction on 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)aceton (II) and nitroethane in the presence of a catalyst cupreine and a promoter benzoic acid to generate (2R,3R)-3-nitro-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (III); performing nitro reduction reaction on the intermediate (III) to generate (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (IV); and performing cyclization reaction on the intermediate (IV) and 1,5-di-halogen-3-methylene pentane (V) to prepare efinaconazole (I). The preparation method is easily available in raw materials and concise in process, is economical and environment-friendly and is suitable for industrial production.
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Paragraph 0038-0040
(2017/02/09)
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- Synthetic method of fluconazole drug intermediate 2,4-dichloro-alpha-(1H-1,2,4-triazol-1-yl)acetophenone
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The invention relates to a synthetic method of fluconazole drug intermediate 2,4-dichloro-alpha-(1H-1,2,4-triazol-1-yl)acetophenone. The synthetic method comprises the following steps of adding 0.21mol of 1H-1,2,4-triazole, 0.11mol of hexane, 0.16mol of sodium sulfite, and 130ml of nitromethane into a reactor provided with a stirrer, a thermometer, a reflux condenser, controlling the stirring speed to be 130 to 160 rpm, lowering the solution temperature to be 5 to 9 DEG C, dropwise adding 0.26 to 0.29mol of alpha- amino-2,4-difluoroacetophenone, rising the solution temperature to be 40 to 45 DEG C after the completion of addition, reacting for 8 to 9h, filtering, performing reduced pressure distillation on a solution, recycling a solvent, adding 700ml of sodium bromide solution and 300ml of oxalic acid, stirring until a solid is fully dissolved, standing, then separating out an oil layer, extracting a water layer with methylbenzene for 3 to 5 times, adding potassium hydrogen sulfate to adjust the pH of the solution to be 4 to 5, separating out a white solid, performing suction filtration, washing with a salt solution, washing with nitroethane, and performing dehydration with a dehydrant, performing recrystallization in paraxylene so as to obtain the 2,4-dichloro-alpha-(1H-1,2,4-triazol-1-yl)acetophenone.
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Paragraph 0010; 0015-0016
(2017/02/17)
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- Voriconazole and intermediate preparation method (by machine translation)
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The invention provides a by the Voriconazole isomer preparation Voriconazole and intermediate preparation method. The method uses the Voriconazole isomer as the raw material, under the alkaline reaction conditions, in the 25 - 100 °C reaction under 1 - 24 hours, and then carry on the condensation reaction, the preparation obtained kang Zuoxiaofu Li racemic modification, to carry out a chiral racemic modification kang Zuoxiaofu Li obtained after the Voriconazole. The method of the invention can be recycled to a process generating a large amount of waste of Voriconazole isomer, avoiding the preparation fu Li conazole process the accessories and the waste of resources. Not only can greatly reduce the production cost, also can be the development of the cycle production, in order to save resources and the purpose of environmental protection. (by machine translation)
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Paragraph 0008; 0030; 0038; 0039
(2017/01/26)
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- Triazole compound as well as preparation method and application thereof
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The invention discloses a triazole compound as well as a preparation method and an application thereof. The triazole compound has a structural formula as shown in the specification, wherein R' is as shown in the specification. The triazole compound has functions of inhibiting bacteria, preventing mildew and preventing corrosion, is relatively good in leach resistance, and has a better effect and a longer usage time by use of an organic wood preservative.
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Paragraph 0028; 0029
(2017/01/17)
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- 2' - amidogen Zha Tongzuo kind compound and its pyrazoline and cyclopropyl azole derivative, preparation method and use thereof
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The invention relates to 2'-aminochalcone-zole compounds with structures shown in general formulas (I, II, III, IV and XIII) and pharmaceutically acceptable salts thereof, wherein amine groups are introduced onto chalcone skeletons while the zole-ring displacement of alpha-site can be realized; and the invention also relates to 2'-aminochalcone-zole compound-based pyrazoline derivatives with structures shown in the general formulas (V, VI, VII, VIII, XIV and XV) and pharmaceutically acceptable salts thereof, and relates to 2'-aminochalcone-zole compound-based cyclopropyl zole derivatives with structures shown in general formulas (IX, X, XI, XII, XVI and XVII) and pharmaceutically acceptable salts thereof. The invention relates to the antimicrobial activities and antitumor activities of the 2'-aminochalcone-zole compounds, the pyrazoline derivatives and cyclopropyl zole derivatives and the pharmaceutically acceptable salts. The invention also relates to medical applications of the compounds.
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Paragraph 0067-0069
(2019/02/02)
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- 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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- A model [...] fungal compound and its preparation method and application
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The invention provides a novel azole antifungal compound. According to the azole antifungal compound, a structural general formula is shown in the specification, wherein X is hydroxyl, Ar is 2,4-difluoro phenyl, and R is selected from hydrogen, alkyl, halogen, cyano-group, nitryl, amino or alkoxy and can be positioned at the ortho-position, meta-position or para-position of a benzene ring and can be mono-substituted or multi-substituted; the alkyl has 1 to 4 carbon atoms; the halogen is selected from F, Cl, Br and I; the amino is selected from -NH2, one or two aminos substituted by the alkyl and cyclic amino; and the alkoxy is selected from methoxyl, ethyoxyl and tert-butyl oxygroup. The invention also provides a method for preparing the compound and application of the compound to preparation of antifungal medicines. Compared with the conventional antifungal medicines which are applied clinically, the azole antifungal compound has the advantages of high antifungal activity on invasive fungi, high efficiency, low toxicity, broad spectrum and the like; and the method is simple and high in yield, and the prepared compound has a good antifungal effect.
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- Synthesis and biological evaluation of α-triazolyl chalcones as a new type of potential antimicrobial agents and their interaction with calf thymus DNA and human serum albumin
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A series of α-triazolyl chalcones were efficiently synthesized. Most of the prepared compounds showed effective antibacterial and antifungal activities. Noticeably, α-triazolyl derivative 9a exhibited low MIC value of 4 μg/mL against MRSA and Micrococcus luteus, which was comparable or even superior to reference drugs. The further research revealed that compound 9a could effectively intercalate into Calf Thymus DNA to form 9a-DNA complex which might block DNA replication to exert their powerful antimicrobial activities. Competitive interactions between 9a and metal ions to Human Serum Albumin (HSA) suggested the participation of Fe3+, K+ and Mg 2+ ions in 9a-HSA system could increase the concentration of free 9a, shorten its storage time and half-life in the blood, thus improving its antimicrobial efficacy.
- Yin, Ben-Tao,Yan, Cong-Yan,Peng, Xin-Mei,Zhang, Shao-Lin,Rasheed, Syed,Geng, Rong-Xia,Zhou, Cheng-He
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p. 148 - 159
(2014/01/06)
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- Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates
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A series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl dithiocarbamates as new analogs of fluconazole were synthesized and their antifungal activities were evaluated. Among these compounds, 2a-f and 3a-q exhibited higher activities than fluconazole against nearly all fungi tested except Aspergillus fumigatus. Noticeably, the in vitro biological activities of 2b, 3a, 3c, 3h-k, and 3o-q against Candida species were much better than those of fluconazole and ketoconazole. Also, 2a-d, 3a-d, 3e-f, 3h-k, 3p and 3q showed higher activities against A. fumi than fluconazole. Computational docking experiments indicated that the inhibition of CYP51 involved a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft.
- Zou, Yan,Yu, Shichong,Li, Renwu,Zhao, Qingjie,Li, Xiang,Wu, Maocheng,Huang, Ting,Chai, Xiaoxun,Hu, Honggang,Wu, Qiuye
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p. 366 - 374
(2014/02/14)
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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 phenacyl azoles
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A new N-(4-methoxyphenacyl)imidazole and three new substituted N-(phenacyl)triazoles were prepared by reaction of the heterocycle with a phenacyl halide. The former ketone and one example of the latter were reduced to the corresponding alcohols. All six compounds were screened in vitro for antifungal activity against two pathogenic fungal strains, Candida albicans (fluconazole-resistant) and Aspergillus fumigatus. The results revealed that most of the compounds showed activity against both strains at 100 μg mL-1and 80 μg mL-1, some comparable with control compound fluconazole. The alcohols were less active than the corresponding ketones.
- Nelson, Ronald,Kesternich, Vctor,Perz-Fehrmann, Marcia,Salazar, Fernanda,Marcourt, Laurence,Christen, Philippe,Godoy, Patricio
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p. 549 - 552
(2014/12/11)
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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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- 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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- 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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- New triazole derivatives as antifungal agents: Synthesis via click reaction, in vitro evaluation and molecular docking studies
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A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted- 2-propanols (5a-5y) which are analogues of fluconazole, have been designed and synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition on the basis of computational docking experiments to the active site of the cytochrome P450 14α-demethylase (CYP51). The in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi. Compound 5l showed the best antifungal activities.
- Zou, Yan,Zhao, Qingjie,Liao, Jun,Hu, Honggang,Yu, Shichong,Chai, Xiaoyun,Xu, Mingjuan,Wu, Qiuye
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p. 2959 - 2962
(2012/06/04)
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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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- Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents
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A series of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents were synthesized for the first time and screened for their antimicrobial efficacy against four Gram-positive bacteria, four Gram-negative bacteria and two fungi by two fold serial dilution technique. The bioactive assay indicated that most of the target compounds displayed broad antimicrobial spectrum and good antibacterial and antifungal activities with low MIC values ranging from 0.25 to 2 μg/mL against all the tested strains which exhibited comparable or even better efficiency in comparison with the reference drugs Chloramphenicol, Clinafloxacin and Fluconazole, respectively. Notably, some synthesized clinafloxacin triazoles showed stronger efficacy against methicillin-resistant Staphylococcus aureus than their parent Clinafloxacin.
- Wang, Yan,Damu, Guri L.V.,Lv, Jing-Song,Geng, Rong-Xia,Yang, Da-Cheng,Zhou, Cheng-He
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p. 5363 - 5366
(2012/09/22)
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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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- 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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- Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities
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A series of novel fluconazoliums were synthesized and their bioactive evaluation as potential antibacterial and antifungal agents were described. Some target compounds displayed good and broad-spectrum antimicrobial activities with low MIC values ranging from 0.25 to 64 μg/mL against all the tested strains, including three Gram-positive bacteria (Staphylococcus aureus, MRSA and Bacillus subtilis), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Bacillus proteus) as well as two fungi (Candida albicans and Aspergillus fumigatus). Among all tested title compounds, the octyl, dichlorobenzyl, naphthyl and naphthalimino derivatives gave comparable or even better antibacterial and antifungal efficiency in comparison with the reference drugs Fluconazole, Chloromycin and Norfloxacin.
- Zhang, Yi-Yi,Mi, Jia-Li,Zhou, Cheng-He,Zhou, Xiang-Dong
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p. 4391 - 4402
(2011/11/06)
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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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- 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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- 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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- 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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- 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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- 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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- 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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- Fluconazole analogues containing 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moieties, a novel class of anti-Candida agents
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As a part of our program to develop new antifungal agents, a series of fluconazole analogues was designed and synthesized wherein one of the triazole moieties in fluconazole was replaced with 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moiety. The new chemical entities thus synthesized were screened against various fungi and it was observed that the compounds 4a and 4i are potent inhibitors of Candida strains. The structure-activity relationship for these compounds is discussed.
- Borate, Hanumant B.,Maujan, Suleman R.,Sawargave, Sangmeshwer P.,Chandavarkar, Mohan A.,Vaiude, Sharangi R.,Joshi, Vinay A.,Wakharkar, Radhika D.,Iyer, Ramki,Kelkar, Ramesh G.,Chavan, Subhash P.,Kunte, Sunita S.
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experimental part
p. 722 - 725
(2010/06/12)
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- Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase
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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-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC80 values indicate that compounds 1a-n exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 2a-f, 3a-f showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times higher activity (with the MIC80 value of 0.0039 μg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In addition, the activity of the compounds would be enhanced when the side chains were shorter.
- Chai, Xiaoyun,Zhang, Jun,Hu, Honggang,Yu, Shichong,Sun, Qingyan,Dan, Zhigang,Jiang, Yuanying,Wu, Qiuye
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scheme or table
p. 1913 - 1920
(2009/09/30)
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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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