- Chalcone-Benzotriazole Conjugates as New Potential Antimicrobial Agents: Design, Synthesis, Biological Evaluation and Synergism with Clinical Drugs
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A series of chalcone-benzotriazole conjugates as new potential antimicrobial agents were synthesized and characterized by 1H NMR, 13C NMR, IR and HRMS spectra. Antimicrobial assay manifested that some target compounds gave moderate to good antibacterial and antifungal activities. The N-1 derived benzotriazole 5e and N-2 derived benzotriazole 6a exhibited valuable inhibitory efficacy against some tested strains. Especially, derivative 6a gave superior antifungal efficacies against C. utilis, S. cerevisiae and A. flavus (MIC=0.01, 0.02, 0.02 μmol/mL, respectively) to Fluconazole. The drug combination of compound 5e or 6a with antibacterial Chloromycin, Norfloxacin and antifungal Fluconazole respectively showed stronger antimicrobial efficiency with less dosage and broader antimicrobial spectrum than their separated use alone. The preliminary interaction with calf thymus DNA revealed that compound 6a could intercalate into DNA to form 6a-DNA supramolecular complex which might be a factor to exert its powerful bioactivity. Molecular docking study indicated strong binding of compound 6a with DNA gyrase. The structural parameters such as molecular orbital energy and molecular electrostatic potential of compound 6a were also investigated, which provided better understanding for its good antimicrobial activity.
- Liu, Hanbo,Gopala, Lavanya,Avula, Srinivasa Rao,Jeyakkumar, Ponmani,Peng, Xinmei,Zhou, Chenghe,Geng, Rongxia
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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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- Design, synthesis, and biological evaluation of novel miconazole analogues containing selenium as potent antifungal agents
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Herein, based on the theory of bioisosterism, a series of novel miconazole analogues containing selenium were designed, synthesized and their inhibitory effects on thirteen strains of pathogenic fungi were evaluated. It is especially encouraging that all the novel target compounds displayed significant antifungal activities against all tested strains. Furthermore, all the target compounds showed excellent inhibitory effects on fluconazole-resistant fungi. Subsequently, preliminary mechanistic studies indicated that the representative compound A03 had a strong inhibitory effect on C.alb. CYP51. Moreover, the target compounds could prevent the formation of fungi biofilms. Further hemolysis test verified that potential compounds had higher safety than miconazole. In addition, molecular docking study provided the interaction modes between the target compounds and C.alb. CYP51. These results strongly suggested that some target compounds are promising as novel antifungal drugs.
- An, Ran,Guo, Chun,Guo, Meng-bi,Hou, Zhuang,Mou, Yan-hua,Su, Xin,Xu, Hang
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- Novel triazole derivatives containing different ester skeleton: Design, synthesis, biological evaluation and molecular docking
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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.
- Han, Xiaoyan,Ren, Liwen,Song, Yali,Sun, Xiaoyang,Wang, Jinhua,Wang, Shumin,Xiao, Bin,Zhang, Na
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- A new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antibacterial agents: Design, synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV
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This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV–DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.
- Wang, Liang-Liang,Battini, Narsaiah,Bheemanaboina, Rammohan R. Yadav,Ansari, Mohammad Fawad,Chen, Jin-Ping,Xie, Yun-Peng,Cai, Gui-Xin,Zhang, Shao-Lin,Zhou, Cheng-He
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p. 166 - 181
(2019/07/02)
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- Method for synthesizing azaconazole through 4-amino-4H-1,2,4-triazole alkylation
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The invention discloses a method for synthesizing azaconazole through 4-amino-4H-1,2,4-triazole alkylation. The method comprises step 1, preparing a raw material which is shown in a following image; step 2, synthesizing 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone; step 3, synthesizing azaconazole. The method disclosed by the invention has the advantages that development of a novel azaconazole bactericide successfully fills the blank in China, synthesis researches of similar derivatives based on the azaconazole bactericide will be in the ascendant, and successful development andindustrial implementation of varieties of novel bactericides have a far-reaching influence on national economy development. The method disclosed by the invention is an azaconazole synthesizing method.
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- Synthesis and evaluation of novel benzene-ethanol bearing 1,2,4-triazole derivatives as potential antimicrobial agents
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The azole pharmacophore is still regarded as a viable lead structure for the synthesis of more efficacious and broad-spectrum antimicrobial agents. In this study, a novel series of triazole derivates that are structurally related to the famous antimicrobial azole pharmacophore were synthesized and the structures of them were characterized by spectral (IR, 1H NMR, 13C NMR, and MS spectra) analysis. Antimicrobial activity was measured against both bacteria and fungus. In vitro antimicrobial evaluation showed that five compounds had growth inhibitory effects on the tested Gram-positive bacteria and fungus with special efficacy. Potential antibacterial and antifungal activities are incorporated in these triazole compounds. Results of antimicrobial activities also revealed that compounds (5a–i) were the potent antibacterial and antifungal agents as compared to standard drugs (ciprofloxacin and itraconazole), and thus could be promising new lead molecules.
- Li, Bochao,Zhang, Dawei,Zhang, Yumin,Dan Jiang,Li, Shuang,Lei, Wei,Wang, Huiying,Lin, Feng
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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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- Synthetic method of miconazole medicament intermediate 2,4-dichlorophenyl chloromethyl ketone
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The invention provides a synthetic method of a miconazole medicament intermediate 2,4-dichlorophenyl chloromethyl ketone. The method comprises the following steps: (I) 0.4mol of 1,3-dichlorobenzene (2) and 0.53-0.55mol of stannous chloride are added into a reaction container which is provided with a stirrer, a thermometer, a reflux condenser and a dropping funnel, a stirring speed is controlled at 150-170rpm, 0.46-0.48mol of chloroacetamide is slowly added, dropwise adding time is controlled at 80-90 minutes, a solution temperature is raised to 60-65 DEG C, a reaction is carried out for 4-5 hours, reactants are poured into 900mol of a potassium chloride solution, the solution temperature is reduced to 5-7 DEG C, a light yellow solid precipitates, after filtering, washing with salting liquid, recrystallization with a hexane solution, and decolouring with a molecular sieve, the solution temperature is reduced to 3-4 DEG C, a sheet shaped yellow crystal precipitates, and after pumping filtration, washing with a methylamine solution, and dehydration with a desiccant, 2,4-dichlorophenyl chloromethyl ketone is obtained; the mass fraction of the potassium chloride solution in the step (i) is 20-25%, and the salting liquid in the step (i) is any one between sodium carbonate and sodium bicarbonate.
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Paragraph 0014; 0015
(2016/10/31)
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- Method for synthesizing Luliconazole
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The invention relates to a method for synthesizing Luliconazole. The method comprises the steps of subjecting m-dichlorobenzene to Friedel-Crafts acylation with chloroacetyl chloride, catalytic chiral reduction with (S)-2-methyl-CBS-oxazaborolidine and esterification with methylsulfonyl chloride so as to obtain (S)-2,2',4'-ethyl trichlorobenzene methanesulfonate, and finally, subjecting (S)-2,2',4'-ethyl trichlorobenzene methanesulfonate to a reaction with carbon disulfide and imidazolyl acetonitrile, thereby obtaining Luliconazole. According to the method, the total yield is about 30%.
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Paragraph 0003; 0007
(2016/10/09)
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- PROCESS FOR PREPARATION OF LULICONAZOLE
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A process for the preparation of luliconazole and salts thereof is disclosed.
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Paragraph 0120
(2016/11/07)
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- Synthesis and bioactive evaluations of novel benzotriazole compounds as potential antimicrobial agents and the interaction with calf thymus DNA
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A novel series of benzotriazole derivatives were synthesized and characterized by NMR, IR and MS spectra. The bioactive assay manifested that most of the new compounds exhibited moderate to good antibacterial and antifungal activities against the tested strains in comparison to reference drugs chloromycin, norfloxacin and fluconazole. Especially, 2,4-dichlorophenyl substituted benzotriazole derivative 6f displayed good antibacterial activity against MRSA with MIC value of 4 μg/mL, which was 2-fold more potent than Chloromycin, and it also displayed 3-fold stronger antifungal activity (MIC = 4 μg/mL) than fluconazole (MIC = 16 μg/mL) against Beer yeast. The preliminary interactive investigations of compound 6f with calf thymus DNA revealed that compound 6f could effectively intercalate into DNA to form compound 6f-DNA complex which might block DNA replication to exert antimicrobial activities. Molecular docking experiments suggested that compound 6f projected into base-pairs of DNA hexamer duplex forming two hydrogen bonds with guanine of DNA. The theoretical calculations were in accordance with the experimental results.
- Ren, Yu,Zhang, Hui Zhen,Zhang, Shao Lin,Luo, Yun Lei,Zhang, Ling,Zhou, Cheng He,Geng, Rong Xia
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p. 2251 - 2260
(2016/01/09)
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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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scheme or table
p. 5363 - 5366
(2012/09/22)
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- α-Halogenation of carbonyl compounds: Halotrimethylsilane-nitrate salt couple as an efficient halogenating reagent system
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A mixture of chloro/bromotrimethylsilane and nitrate salt is found to be an effective reagent system for the α-chlorination/bromination of carbonyl compounds. The reaction occurs under mild conditions yielding the products in moderate to good yields.
- Prakash, G.K. Sxurya,Ismail, Rehana,Garcia, Jessica,Panja, Chiradeep,Rasul, Golam,Mathew, Thomas,Olah, George A.
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experimental part
p. 1217 - 1221
(2011/03/22)
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- 1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors
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A novel series of 1,2,3-thiadiazole thioacetanilide (TTA) derivatives have been designed, synthesized and evaluated for its anti-HIV activities in MT-4 cells. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Among them, 2-[4-(2,4-dichlorophenyl)-1,2,3-thiadiazol-5-ylthio]-N-(2-nitrophenyl)acetamide 7d2 was identified as the most promising compound (EC50 = 0.059 ± 0.02 μM, CC50 > 283.25 μM, SI > 4883). The structure-activity relationship (SAR) of these novel structural congeners is discussed. Crown Copyright
- Zhan, Peng,Liu, Xinyong,Cao, Yuan,Wang, Yan,Pannecouque, Christophe,De Clercq, Erik
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scheme or table
p. 5368 - 5371
(2009/06/18)
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- Chemoenzymatic synthesis of enantiomerically pure terminal 1,2-diols
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A new practical method for the enzymatic synthesis of 1,2-diols has been developed by employing a lipase catalyzed one-pot transesterification protocol. A series of substituted α-acetoxyphenylethanones 3a-g have been reduced to the corresponding alcohols under mild conditions employing sodium borohydride and moist neutral alumina, and further subjected for lipase catalyzed irreversible transesterification in the same pot to give mono- and diacetate diols (R)-4 and (S)-5, which on hydrolysis afforded terminal 1,2-diols, (R)- and (S)-6 in high enantiomeric excess.
- Kamal, Ahmed,Sandbhor, Mahendra,Ahmed, Kaleem,Adil,Shaik, Ahmad Ali
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p. 3861 - 3866
(2007/10/03)
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- Synthesis and fungicidal activity of 2-imino-3-(4-arylthiazol-2-yl)- thiazolidin-4-ones and their 5-arylidene derivatives
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Five derivatives of 2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones and a series of their 5-arylidene derivatives have been synthesized and tested for antifungal activity against seven agricultural fungi. 2-Imino-3-(2,4-dichloro-5- fluorophenylthiazol-2-yl)-4-thiazolidi-none and 2-imino-3-(2,4- dichlorophenylthiazol-2-yl)-4-thiazolidione, both of them new compounds, exhibited higher fungicidal effects than the other compounds prepared.
- Liu, Hui-Ling,Li, Zongcheng,Anthonsen, Thorleif
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p. 1055 - 1061
(2007/10/03)
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- One-pot Synthesis of α-chloroketones from Secondary Benzylic Alcohols Using m-Chloroperbenzoic Acid/HCl/DMF System
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The one-pot reaction of the oxidation and chlorination of sec-benzylic alcohols by using m-CPBA/HCl/DMF system led to the corresponding α-chloroketones in good yields.
- Kim, Hak Jin,Kim, Hyoung Rae,Ryu, Eung K.
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p. 1625 - 1629
(2007/10/02)
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