- SMALL MOLECULE STIMULATORS OF THE CORE PARTICLE OF THE PROTEASOME
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This present disclosure relates to series compounds and methods of use for the treatment of a disease caused by abnormal regulation of the ubiquitin-proteasome system (UPS), and wherein said compound is an effective stimulator of the 20S core particle (CP) of the UPS. Composition matters and methods of uses are within the scope of this disclosure.
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Paragraph 00101
(2021/02/26)
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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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- Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies
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In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
- Zhou, You,Lu, Xin,Du, Chenxi,Liu, Yijun,Wang, Yifan,Hong, Kwon Ho,Chen, Yao,Sun, Haopeng
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- BuChE-IDO1 inhibitor as well as preparation method and application thereof
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The invention relates to the field of medicines, and particularly discloses a BuChE-IDO1 inhibitor as well as a preparation method and application thereof. The 7-chlorine-3-substituted benzothiophene part of sertaconazole is chemically modified, the influence of the 7-chlorine-3-substituted benzothiophene part of sertaconazole on the in-vitro inhibitory activity of AChE, BuChE and IDO1 is explored, the target compound is further optimized, and the technical problems that an existing BuChE-IDO1 inhibitor is poor in pertinence and safety are solved. What is explored is that an appropriate substituent group introduced to a 2-benzothiazole ring can form additional interaction with surrounding amino acids and heme iron, so that the binding affinity of the analogue with BuChE and IDO1 is increased, and a new idea is broadened for more efficient and targeted treatment of advanced AD diseases.
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- Azole antifungal compounds could have dual cholinesterase inhibitory potential according to virtual screening, enzyme kinetics, and toxicity studies of an inhouse library
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Recent advances in cholinesterase inhibitors opened new venues for the treatment of cognitive disorders like Alzheimer's disease. Certain azole antifungals like miconazole were reported to have cholinesterase inhibitory effects and hence ameliorate cognitive deficits. In this study, we tested a set of azole antifungal derivatives selected through virtual screening of an inhouse library for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects. Compound 61 showed potent and selective AChE inhibition (IC50 = 8.77 μM). The study also yielded dual AChE/BChE inhibitors in addition to a number of potent AChE inhibitors. Enzyme kinetics assays revealed that AChE inhibitors were competitive inhibitors. All the active compounds were imidazole derivatives and the modeling study showed that imidazole at protonated state contributed greatly to the binding interactions with some key residues of AChE and BChE active site. The active derivatives had negligible cytotoxic effects on murine fibroblast viability. According to our results, compounds featuring the classical scaffold of azole antifungal drugs could hold high potential for anticholinesterase drug design.
- Barut, Burak,Sari, Suat,Sabuncuo?lu, Suna,?zel, Arzu
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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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- A imidazole ethanol preparation method (by machine translation)
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The invention discloses a method for the preparation of imidazole ethanol, which belongs to the technical field of organic synthesis, comprising the following steps: to 1 - (2, 4 - dichlorophenyl) - 2 - chloro - ethanol and imidazole as raw materials, hexafluoro isopropanol as solvent, inorganic carrier KOH/A12 O3 As basic catalyst, through N - alkylation reaction, filtration, rotary evaporation, neutralization, filtration, recrystallization to obtain the imidazole alcohol; the invention mild reaction conditions, the reaction time is short, the solvent to reclaim, catalyst and not fully involved in the reaction of the imidazole can be recycled, is a green synthetic imidazole ethanol. (by machine translation)
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Paragraph 0030; 0033; 0035; 0037; 0039; 0041; 0043; 0045
(2019/01/16)
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- Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer's disease
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In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.
- Lu, Xin,He, Si-yu,Li, Qi,Yang, Hongyu,Jiang, Xueyang,Lin, Hongzhi,Chen, Yao,Qu, Wei,Feng, Feng,Bian, Yaoyao,Zhou, You,Sun, Haopeng
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p. 1665 - 1674
(2018/02/23)
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- Anti-staphylococcal biofilm activity of miconazoctylium bromide
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We designed and synthesized miconazole analogues containing a substituted imidazolium moiety. The structural modification of the miconazole led to a compound with high potency to prevent the formation and disrupt bacterial biofilms, as a result of accumulation in the biofilm matrix, permeabilization of the bacterial membrane and generation of reactive oxygen species in the cytoplasm.
- Tessier, Jérémie,Golmohamadi, Mahmood,Wilkinson, Kevin J.,Schmitzer, Andreea R.
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p. 4288 - 4294
(2018/06/22)
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- Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo
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UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates. After rounds of kinase and anti-proliferative activity screening, we discovered the small molecule, LYN-1604, to be the best candidate for a ULK1 agonist. Additionally, we identified that three amino acid residues (LYS50, LEU53, and TYR89) were key to the activation site of LYN-1604 and ULK1 by site-directed mutagenesis and biochemical assays. Subsequently, we demonstrated that LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. To further explore LYN-1604-induced autophagic mechanisms, we found some potential ULK1 interactors, such as ATF3, RAD21, and caspase3, by performing comparative microarray analysis. Intriguingly, we found that LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. Moreover, we demonstrated that LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy.
- Zhang, Lan,Fu, Leilei,Zhang, Shouyue,Zhang, Jin,Zhao, Yuqian,Zheng, Yaxin,He, Gu,Yang, Shengyong,Ouyang, Liang,Liu, Bo
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p. 2687 - 2701
(2017/04/06)
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- ULK1 micromolecule stimulant and application of stimulant in antitumor drug
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The invention relates to an ULK1 micromolecule stimulant and an application of the stimulant in an antitumor drug, which belong to the technical field of antitumor pharmacy. The invention provides a compound taken as the ULK1 micromolecule stimulant. The compound comprises the compound shown in a specification or its pharmaceutically acceptable salt. The compound or its pharmaceutically acceptable salt can be taken as the ULK1 stimulant, has certain antineoplastic activity, and effectively inhibits the growth of the cancer cells. The compound has obvious inhibition effect for a plurality of tumor cells, especially breast cancer cells.
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Paragraph 0102; 0103; 0104; 0105
(2017/07/31)
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- Synthesis of imidazole aromatic alcohol derivatives and the preparation thereof
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The invention discloses synthesis of imidazole aromatic alcohol derivatives and preparations of the imidazole aromatic alcohol derivatives. The imidazole aromatic alcohol derivatives are 1-[2-(2,4-dichlorophenyl)-2-[(2,6-dichlorophenyl)methoxy]ethyl-1H-imidzole nitrate, 1-[2-[(4-chlorphenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidzole, 1-[2-(4-chlorphenyl)-2-(2,6-dichlorophenyl methoxy)ethyl]-1H-imidzole nitrate, 1-[2-(2,4-dichlorophenyl)-2-{[4-phenyl sulfo]phenyl]methoxy]ethyl}-1H-imidzole nitrate, 1-[2-[(2-chlorine-3-thiophene methoxy)]-2-(2,4-dichlorophenyl)]ethyl imidazole, 1-[2-(7-cholorbenzo[b]thiophene-3-group)methoxy-2-(2,4-dichlorophenyl)ethyl]-1H-imidzole nitrate and (2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidzole nitrate. The synthetic route comprises the following steps of: performing N-alkylation reaction on halogenated acetophenone and imidazole to reduce carbonyl into corresponding alcohol; performing O-alkylation reaction on the corresponding benzyl halide in the presence of a phase transfer catalyst; reacting with acid to form a salt so as to obtain a target compound; and directly or indirectly adding a pharmaceutically acceptable excipient into the target compound by using the conventional process to prepare clinically acceptable formulations such as tablets, soft capsules, suppositories, emulsifiable paste, ointment, gel, liniments, lotion, aerosol and spray so as to exert curative effect better.
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- A facile synthesis of novel miconazole analogues and the evaluation of their antifungal activity
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Four novel miconazole analogues (8-11) were synthetized and evaluated for activity against four filamentous fungi (Mucor hiemalis, Aspergillus fumigatus, Trichosporon cutaneum, and Rhizopus oryzae) and eight species of Candida as yeast specimens. Compounds 9 and 10 showed very good activity when evaluated in yeast (MIC 0.112 and 0.163 μg/mL) compared to the reference compound, itraconazole (MIC 0.067 μg/mL). The best antifungal activity in filamentous strains was shown by compound 9. Hence compounds 9 and 10 represent new leads for further pharmacomodulation in this series.
- Ramírez-Villalva, Alejandra,González-Calderón, Davir,González-Romero, Carlos,Morales-Rodríguez, Macario,Jauregui-Rodríguez, Bertha,Cuevas-Yá?ez, Erick,Fuentes-Benítes, Aydeé
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p. 275 - 279
(2015/05/27)
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- Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
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Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.
- R?hrig, Ute F.,Majjigapu, Somi Reddy,Chambon, Marc,Bron, Sylvian,Pilotte, Luc,Colau, Didier,Van Den Eynde, Beno?t J.,Turcatti, Gerardo,Vogel, Pierre,Zoete, Vincent,Michielin, Olivier
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p. 284 - 301
(2014/08/05)
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- New copper(II) complexes with isoconazole: Synthesis, structures and biological properties
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There is an increasing demand for novel metal-based complexes with biologically relevant molecules in technology and medicine. Three new Cu(II) coordination compounds with antifungal agent isoconazole (L), namely mononuclear complexes [CuCl2(L)2] (1), and [Cu(O2CMe) 2(L)2]·2H2O (2) and coordination polymer [Cu(pht)(L)2]n (3) (where H2pht-o-phthalic acid) were synthesized and characterized by IR spectroscopy, thermogravimetric analysis and X-ray crystallography. X-ray analysis showed that in all complexes, the isoconazole is coordinated to Cu(II) centres by a N atom of the imidazole fragment. In complex 1, the square-planar environment of Cu(II) atoms is completed by two N atoms of isoconazole and two chloride ligands, whereas the Cu(II) atoms are coordinated by two N atoms from two isoconazole ligands and two O atoms from the different carboxylate residues: acetate in 2 and phthalate in 3. The formation of an infinite chain through the bridging phthalate ligand is observed in 3. The biosynthetic ability of micromycetes Aspergillus niger CNMN FD 10 in the presence of the prepared complexes 1-3 as well as the antifungal drug isoconazole were studied. Complexes 2 and 3 accelerate the biosynthesis of enzymes (β-glucosidase, xylanase and endoglucanase) by this fungus. Moreover, a simplified and improved method for the preparation of isoconazole nitrate was developed.
- Dulcevscaia, Galina M.,Kravtsov, Victor Ch.,Macaev, Fliur Z.,Duca, Gheorghe G.,Stingachi, Eugenia P.,Pogrebnoi, Serghei I.,Boldescu, Veaceslav V.,Clapco, Steliana F.,Tiurina, Janeta P.,Deseatnic-Ciloci, Alexandra A.,Lipkowski, Janusz,Liu, Shi-Xia,Decurtins, Silvio,Baca, Svetlana G.
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p. 106 - 114
(2013/06/05)
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- The "reverse-tethered" ruthenium (II) catalyst for asymmetric transfer hydrogenation: Further applications
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The attachment of a tethering group from the basic nitrogen atom to the arene ligand of a ruthenium(II) catalyst greatly improves its ability to catalyze asymmetric transfer hydrogenation (ATH) reactions. In this paper, we describe further applications of this versatile system to an extended substrate range.
- Morris, David J.,Hayes, Aidan M.,Wills, Martin
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p. 7035 - 7044
(2007/10/03)
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- N-[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F1F0 ATP hydrolase
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A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F1F0 ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
- Atwal, Karnail S.,Ahmad, Saleem,Ding, Charles Z.,Stein, Philip D.,Lloyd, John,Hamann, Lawrence G.,Green, David W.,Ferrara, Francis N.,Wang, Paulina,Rogers, W. Lynn,Doweyko, Lidia M.,Miller, Arthur V.,Bisaha, Sharon N.,Schmidt, Joan B.,Li, Ling,Yost, Kenneth J.,Lan, Hsi-Jung,Madsen, Cort S.
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p. 1027 - 1030
(2007/10/03)
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- Synthesis, antifungal activity, and molecular modeling studies of new inverted oxime ethers of oxiconazole
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Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, C=N-O, of oxiconazole 6 is in an inverted atomic sequence, were synthesized and tested for their antifungal activities. Among them, the type 7 compounds, such as the N-ethoxy-morpholino-substituted derivatives 71-o (Table 1), showed good antifungal properties against the Candida strains tested, with minimum inhibitory concentration (MIC) values similar to those of the reference drug 6. A remarkable result was obtained with these types of azoles, which had shown a cidal character against Candida albicans, while the reference drug oxiconazole was only fungistatic in the same tests. This fact may be seen from a comparison of the MIC values with those of the minimum fungicidal concentration (MFC) values for most of the type 7 compounds assayed that have shown differences between the MIC and the MFC, which are lower than three double diluitions. A simple molecular modeling of the P450 14-α-sterol demethylase from C. albicans (Candida P450DM) was built in order to understand how the structural differences between type 7 compounds and oxiconazole 6 can induce different antifungal profiles. The results of this work seem to confirm that it is possible to reverse the atomic sequence of the methyleneaminoxy group, C=N-O, of 6, obtaining new imidazoles possessing good antifungal properties.
- Rossello, Armando,Bertini, Simone,Lapucci, Annalina,Macchia, Marco,Martinelli, Adriano,Rapposelli, Simona,Herreros, Esperanza,Macchia, Bruno
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p. 4903 - 4912
(2007/10/03)
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- Chiral imidazole fungicidal compositions and methods for their use
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Chiral fungicides and compositions containing the same are provided. Also provided are methods for using the compositions of the present invention for inhibiting the growth of fungi, including phytotoxic fungi. The use of a single isomer in treating particular plant species and against particular fungi allows for selective inhibition of fungal growth with reduced fungicidal phytotoxic effects.
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- A new series of miconazole analogs: Synthesis and in vitro antifungal and antimycobacterial activities
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The synthesis and antimicrobial activity of new miconazole analogs are reported. All compounds showed good antimycobacterial activity; some of them were also active against some strains of Candida albicans and Candida sp.. Of the synthesized compounds, two showed good activity both against some strains of Mycobacterium and some strains of Candida. Structure-activity relationships are discussed.
- Fioravanti, Rossella,Biava, Mariangela,Porretta, Giulio Cesare,Lampis, Giorgio,Deidda, Delia,Pompei, Raffaello
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p. 162 - 175
(2007/10/03)
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- Substituted dibenzyl ethers and pharmaceutical compositions containing said ethers for the treatment of infections
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There are provided 2,4-dichloro-4'-phenyl-α-(N-imidazolyl-methyl)-dibenzyl ether, 2,4-dichloro-4'-phenylthio-α-(N-imidazolyl-methyl)-dibenzyl ether and pharmaceutically acceptable acid addition salts thereof. These compounds show activity against some fungi, yeasts and gram positive aerobic and anaerobic bacteria. The new compounds can be prepared by condensing 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol with 4-chloromethyl-biphenyl, 4-bromomethyl-biphenyl, 1-phenylthio-4-chloromethyl-benzene or 1-phenylthio-4-bromomethyl-benzene in a solvent, most preferably dimethylsulphoxide.
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