- Preparation method of posaconazole intermediate
-
The invention relates to the technical field of medicine preparation, and especially relates to a preparation method of a posaconazole intermediate. The preparation method comprises the following steps: reacting a compound as shown in a formula II, serving as a raw material, with 1, 2, 4-triazole to obtain a compound as shown in a formula III, and then reacting with air or oxygen under the action of a catalyst 1 to obtain a compound as shown in a formula IV; reacting the compound as shown in the formula IV with dimethyl malonate to obtain a compound as shown in a formula V; reacting the compound shown in the formula V under the action of a reducing agent to obtain a compound shown in a formula VI; and finally, carrying out intramolecular etherification reaction on the compound shown in the formula VI, and carrying out sulfonylation reaction on the obtained product to obtain a target product I. The method has the advantages of cheap and easily available raw materials, mild reaction conditions, few reaction steps, high yield and high purity of the obtained product.
- -
-
Paragraph 0060; 0065-0066; 0069-0070; 0073-0076
(2021/11/21)
-
- Voriconazole synthesis process
-
The invention discloses a synthesis process of voriconazole bulk drug, which comprises the following steps: preparing halogenated ethyl fluorouracil and carrying out Grignard reaction. 2 - (2, 4 - Difluorophenyl) -3 - (1, 2, 4 - triazol -1 -yl) -1, 2 - propylene glycol was oxidized to give a propylene oxide compound. The Grignard reagent and the propylene oxide compound are mixed and reacted to obtain voriconazole. To the synthesis process, the reaction steps can be simplified, the dehydrochlorination and hydrogenolysis of palladium carbon are not needed, the reaction period is shortened, and furthermore, the energy consumption is reduced, the cost is reduced, and voriconazole and the racemate thereof are obtained with higher yield.
- -
-
Paragraph 0074-0077
(2021/09/08)
-
- Azole-triphenylphosphonium conjugates combat antifungal resistance and alleviate the development of drug-resistance
-
Azole antifungals are commonly used to treat fungal infections but have resulted in the occurrence of drug resistance. Therefore, developing azole derivatives (AZDs) that can both combat established drug-resistant fungal strains and evade drug resistance is of great importance. In this study, we synthesized a series of AZDs with a fluconazole (FLC) skeleton conjugated with a mitochondria-targeting triphenylphosphonium cation (TPP+). These AZDs displayed potent activity against both azole-sensitive and azole-resistant Candida strains without eliciting obvious resistance. Moreover, two representative AZDs, 20 and 25, exerted synergistic antifungal activity with Hsp90 inhibitors against C. albicans strains resistant to the combination treatment of FLC and Hsp90 inhibitors. AZD 25, which had minimal cytotoxicity, was effective in preventing C. albicans biofilm formation. Mechanistic investigation revealed that AZD 25 inhibited the biosynthesis of the fungal membrane component ergosterol and interfered with mitochondrial function. Our findings provide an alternative approach to address fungal resistance problems.
- Wang, Xin,Liu, Jun,Chen, Jinyao,Zhang, Ming,Tian, Chuan,Peng, Xiaoping,Li, Gang,Chang, Wenqiang,Lou, Hongxiang
-
-
- TRIAZOLE DERIVATIVES WITH ANTIFUNGAL ACTIVITY
-
Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, Q2, L1 and n are as defined herein. The compounds have antifungal properties and are useful in the treatment of fungal infections, including infections that are resistant to conventions anti-fungal agents. Q1 is selected from: (Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik) wherein * indicates the point of attachment to L1.
- -
-
Paragraph 00294
(2021/08/14)
-
- Triazole compounds, preparation method and application of triazole compounds in antifungal drugs
-
The invention discloses a series of novel triazole compounds obtained by coupling a triazole drug skeleton and diversified lipophilic cations through different chains, and also discloses a preparationmethod of the compounds and application of the compound
- -
-
Paragraph 0030; 0036-0038
(2020/09/20)
-
- Antibacterial drug and preparation method thereof
-
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.
- -
-
Paragraph 0028; 0041-0043; 0060; 0061
(2020/06/20)
-
- Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans
-
Abstract: Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals. Graphic abstract: [Figure not available: see fulltext.]
- Franz, Katherine J.,Hunsaker, Elizabeth W.,McAuliffe, Katherine J.
-
-
- Synthesis, optimization, antifungal activity, selectivity, and cyp51 binding of new 2-aryl-3-azolyl-1-indolyl-propan-2-ols
-
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
-
-
- Antifungal activity, mode of action variability, and subcellular distribution of coumarin-based antifungal azoles
-
Azole antifungals inhibit the biosynthesis of ergosterol, the fungal equivalent of cholesterol in mammalian cells. Here we report an investigation of the activity of coumarin-substituted azole antifungals. Screening against a panel of Candida pathogens, including a mutant lacking CYP51, the target of antifungal azoles, revealed that this enzyme is inhibited by triazole-based antifungals, whereas imidazole-based derivatives have more than one mode of action. The imidazole-bearing antifungals more effectively reduced trailing growth associated with persistence and/or recurrence of fungal infections than triazole-based derivatives. The imidazole derivatives were more toxic to mammalian cells and more potently inhibited the activity of CYP3A4, which is one of the main causes of azole toxicity. Using live cell imaging, we showed that regardless of the type of azole ring fluorescent 7-diethylaminocoumarin-based azoles localized to the endoplasmic reticulum, the organelle that harbors CYP51. This study suggests that the coumarin is a promising scaffold for development of novel azole-based antifungals that effectively localize to the fungal cell endoplasmic reticulum.
- Elias, Rebecca,Benhamou, Raphael I.,Jaber, Qais Z.,Dorot, Orly,Zada, Sivan Louzoun,Oved,Pichinuk, Edward,Fridman
-
supporting information
p. 779 - 790
(2019/07/10)
-
- New potent antifungal triazole alcohols containing N-benzylpiperazine carbodithioate moiety: Synthesis, in vitro evaluation and in silico study
-
A number of 1H-1,2,4-triazole alcohols containing N-(halobenzyl)piperazine carbodithioate moiety have been designed and synthesized as potent antifungal agents. In vitro bioassays against different Candida species including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis revealed that the N-(4-chlorobenzyl) derivative (6b) with MIC values of 0.063–0.5 μg/mL had the best profile of activity, being 4–32 times more potent than fluconazole. Docking simulation studies confirmed the better fitting of compound 6b in the active site of lanosterol 14α-demethylase (CYP51) enzyme, the main target of azole antifungals. Particularly, the potential of compound 6b against fluconazole-resistant isolates along with its minimal toxicity against human erythrocytes and HepG2 cells make this prototype compound as a good lead for discovery of potent and safe antifungal agents.
- Mahmoudi, Yaser,Badali, Hamid,Hashemi, Seyedeh Mahdieh,Ansari, Mahsa,Fakhim, Hamed,Fallah, Marjan,Shokrzadeh, Mohammad,Emami, Saeed
-
-
- Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents
-
The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.
- Thamban Chandrika, Nishad,Shrestha, Sanjib K.,Ngo, Huy X.,Tsodikov, Oleg V.,Howard, Kaitlind C.,Garneau-Tsodikova, Sylvie
-
p. 158 - 173
(2018/02/10)
-
- Novel fluconazole derivatives with promising antifungal activity
-
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.
- Thamban Chandrika, Nishad,Shrestha, Sanjib K.,Ngo, Huy X.,Howard, Kaitlind C.,Garneau-Tsodikova, Sylvie
-
supporting information
p. 573 - 580
(2018/01/04)
-
- Antifungal Compounds
-
Compounds and compositions having antifungal activity, and methods of using the antifungal compounds and compositions, are described for use in treating fungal infections.
- -
-
Paragraph 0098; 0099
(2018/07/30)
-
- Novel carbazole-triazole conjugates as DNA-targeting membrane active potentiators against clinical isolated fungi
-
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
-
p. 579 - 589
(2018/06/20)
-
- ORGANOMETALLIC FLUCONAZOLE DERIVATES AND THEIR USE AS ANTIMYCOTICS
-
The invention relates to compounds characterized by a general formula (1), wherein OM is an organometallic compound. OM is independently selected from the group of an unsubstituted or substituted metal sandwich compound, an unsubstituted or substituted ha
- -
-
Paragraph 0076; 0080; 0086; 0087
(2018/04/20)
-
- Design, synthesis, & biological activity of new triazole & nitro-triazole derivatives as antifungal agents
-
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
-
-
- Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design, synthesis and bioactive evaluation
-
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)
-
- Design and synthesis of new fluconazole analogues
-
We have synthesized new fluconazole analogues containing two different 1,2,3-triazole units in the side chain. The synthesis of new amide analogues using a variety of acids is also described. All the compounds showed very good antifungal activity. A hemol
- Pore, Vandana S.,Agalave, Sandip G.,Singh, Pratiksha,Shukla, Praveen K.,Kumar, Vikash,Siddiqi, Mohammad I.
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p. 6551 - 6561
(2015/06/16)
-
- 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
-
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)
-
- Asymmetric synthesis, antifungal activity and molecular modeling of iodiconazole isomers
-
Iodiconazole is a novel antifungal agent that was developed in its racemic form. In order to investigate the effects of the chiral center on the antifungal activity, R- and S-isomers of iodiconazole were prepared on the basis of the asymmetric Sharpless epoxidation. (S)-Iodiconazole was proved to have better antifungal activity than the (R)-isomer. The binding modes of the two isomers with lanosterol 14α-demethylase were clarified by molecular docking. Two isomers of iodiconazole, a novel antifungal agent, were prepared by asymmetric synthesis. Their antifungal activity and binding modes were investigated. Copyright
- Zhang, Yongqiang,Wang, Shengzheng,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian,Sheng, Chunquan
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p. 1139 - 1143
(2013/10/21)
-
- Synthesis and antifungal activity of the novel triazole derivatives containing 1,2,3-triazole fragment
-
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
-
p. 1215 - 1222
(2013/11/06)
-
- Synthesis and antifungal activity of the novel triazole compounds
-
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
-
p. 704 - 708
(2013/06/05)
-
- Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents
-
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
-
experimental part
p. 5363 - 5366
(2012/09/22)
-
- Design, synthesis, and biological evaluation of novel 1, 2, 4-triazole derivatives as antifungal agent
-
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
-
p. 1895 - 1901
(2013/04/24)
-
- Synthesis and Biological Evaluation of Triazole Derivatives as Potential Antifungal Agent
-
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
-
scheme or table
p. 382 - 387
(2012/09/08)
-
- Synthesis and antifungal activity of novel triazole derivatives
-
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
-
experimental part
p. 1649 - 1656
(2012/03/26)
-
- Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities
-
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
-
supporting information; experimental part
p. 4391 - 4402
(2011/11/06)
-
- 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
-
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.
-
supporting information; experimental part
p. 722 - 725
(2010/06/12)
-
- THIOPHENE CONTAINING ANALOGUES OF FLUCONAZOLE AS ANTIFUNGAL AGENTS AND PROCESS THEREOF
-
The present invention discloses novel compounds of the Formula (1), containing thiophene moieties and pharmaceutically acceptable salts thereof, methods for preparing these compounds, the use of these compounds in prevention and treatment of fungal infections, and pharmaceutical preparations containing these novel compounds.
- -
-
Page/Page column 16
(2010/05/13)
-
- ANTIFUNGAL COMPOUNDS CONTAINING BENZOTHIAZINONE, BENZOXAZINONE OR BENZOXAZOLINONE AND PROCESS THEREOF
-
The present invention discloses novel compounds of the Formula (1), comprising benzothiazinone, benzoxazinone or benzoxazolinone moieties having antifungal activity, method for preparing these compounds and the use of these compounds as antifungal agents
- -
-
Page/Page column 11
(2010/05/13)
-
- Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues
-
Fluconazole based novel mimics containing 1,2,3-triazole were designed and synthesized as antifungal agents. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 12, 15, and 16 were found to be more potent against Candida fungal pathogens than control drugs fluconazole and amphotericin B. The studies presented here provide structural modification of fluconazole to give 1,2,3-trazole containing molecules. Furthermore, these molecules were evaluated in vivo against Candida albicans intravenous challenge in Swiss mice and antiproliferative activities were tested against human hepatocellular carcinoma Hep3B and human epithelial carcinoma A431. It was found that compound 12 resulted in 97.4% reduction in fungal load in mice and did not show any profound proliferative effect at lower dose (0.001 mg/ml).
- Aher, Nilkanth G.,Pore, Vandana S.,Mishra, Nripendra N.,Kumar, Awanit,Shukla, Praveen K.,Sharma, Aanchal,Bhat, Manoj K.
-
scheme or table
p. 759 - 763
(2009/12/03)
-
- A short synthesis of 3,6-disubstituted N-2-thienyl/aryl-indoles
-
A short synthetic strategy for 3,6-disubstituted-N-2-thienyl/aryl-indoles, involving reaction of substituted 2,4-difluoro/dichloro-styrene epoxide with substituted 2-formylaminothiophenes or substituted N-formylanilines in the presence of a base followed by treatment with an acid, has been developed. The method was applied for the synthesis of a number of indoles with a variety of substituents at 1, 3, and 6 positions of the indole moiety.
- Borate, Hanumant B.,Sawargave, Sangmeshwer P.,Maujan, Suleman R.
-
supporting information; experimental part
p. 6562 - 6566
(2011/03/17)
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- Synthesis and crystallographic characterization of 1-((2-(2,4- Difluorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole: A crucial intermediate for the synthesis of azole antifungal drugs
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Preparation of oxirane 3 was accomplished in two steps. 1H-1,2,4-triazole was reacted with 2,4-difluoro-α-chloroacetophenone 1 in presence of K 2CO3 in refluxing toluene to provide compound 2. Compound 2 was treated with trimethylsul
- Patel, Pallav D.,Talele, Tanaji T.,Fronczek, Frank R.
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experimental part
p. 923 - 926
(2010/06/19)
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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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- 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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experimental part
p. 1913 - 1920
(2009/09/30)
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- Efficient microwave-assisted synthesis of 1-(1H-indol-1-yl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents
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New conazole antifungals, in the series of triazole alcohols 23a-d and 24a-e incorporating an indole moiety substituted at 5-position by halogens, a cyano or 4-methoxyphenyl group, have been synthesized by ring opening of corresponding oxiranes 15 and 16. These dihalogeno intermediates and their congeneers could be prepared in high yields by Corey-Chaykovsky reaction under microwave irradiation.
- Lebouvier, Nicolas,Giraud, Francis,Corbin, Typhanie,Na, Young Min,Le Baut, Guillaume,Marchand, Pascal,Le Borgne, Marc
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p. 6479 - 6483
(2007/10/03)
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- Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking
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In a continuing effort to develop highly potent azole antifungal agents, the three-dimensional quantitative structure-activity relationship methods, CoMFA and CoMSIA, were applied using a set of novel azole antifungal compounds. The binding mode of the compounds at the active site of lanosterol 14α-demethylase was further explored using the flexible docking method. Various hydrophobic, van der Waals, π-π stacking, and hydrogen bonding interactions were observed between the azoles and the enzyme. Based on results from the molecular modeling, a receptor-based pharmacophore model was established to guide the rational optimization of the azole antifungal agents. Thus, a total of 57 novel azoles were designed and synthesized by a three-step optimization process. In vitro antifungal assay revealed that the antifungal activities of these novel azoles were greatly improved, which confirmed the reliability of the model from molecular modeling.
- Sheng, Chunquan,Zhang, Wannian,Ji, Haitao,Zhang, Min,Song, Yunlong,Xu, Hui,Zhu, Jie,Miao, Zhenyuan,Jiang, Qingfen,Yao, Jianzhong,Zhou, Youjun,Zhu, Jü,Lü, Jiaguo
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p. 2512 - 2525
(2007/10/03)
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- CRYSTALLINE 1-[2-(2,4-DIFLUOROPHENYL)-OXIRANYL METHYL]-1H-1,2,4-TRIAZOLE
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A crystalline form of the compound 1-[2-(2,4-difluorophenyl)-oxiranyl methyl]-1H-1,2,4-triazole and a process for preparing the form. The crystalline form can be used for preparing fluconazole.
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Page/Page column 3
(2008/06/13)
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- ANTIFUNGAL AZOLE DERIVATIVES HAVING A FLUOROVINYL MOIETY AND PROCESS FOR THE PREPARATION THEREOF
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An azole derivative of formula (I) having a fluorovinyl moiety or a pharmaceutically acceptable salt thereof is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi, and has advantageously low toxicity.
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Page/Page column 21-22
(2010/02/10)
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- Synthesis and in vitro and in vivo structure-activity relationships of novel antifungal triazoles for dermatology
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In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in
- Meerpoel, Lieven,Backx, Leo J. J.,Van Der Veken, Louis J. E.,Heeres, Jan,Corens, David,De Grout, Alex,Odds, Frank C.,Van Gerven, Frans,Woestenborghs, Filip A. A.,Van Breda, Andre,Oris, Michel,Van Dorsselaer, Pascal,Willemsens, Gustaaf H. M.,Vermuyten, Karen J. P.,Marichal, Patrick J. M. G.,Vanden Bossche, Hugo F.,Ausma, Jannie,Borgers, Marcel
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p. 2184 - 2193
(2007/10/03)
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- Synthesis of some new propanol derivatives analogous to fluconazole
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A series of 2-(2,4-difluorophenyl)-1-(1H-1,2,4 triazol-1-yl-methyl)-3- (substituted heterocycl)-propan-2-ol, which are analogous to fluconazole, were synthesized via the reaction of 2-(2,4-difluorophenyl)-2-[1-(1,2,4- triazolmethide)]oxiran with various heterocyclic systems.
- Heravi, Majid M.,Motamedi, Radineh
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p. 2329 - 2334
(2007/10/03)
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- Synthesis of novel substituted tetrazoles having antifungal activity
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In an effort to find potent antifungal agents, a variety of triazole derivatives with a 5-substituted tetrazole structure 6, 7, 12 and 14 were prepared and evaluated for antifungal activity against Candida spp., Cryptococcus neoformans, and Aspergillus spp. in vitro. The location of the methyl group at the C-3 of compounds 12 and 14 has been demonstrated to be a key structural element of antifungal potency.
- Upadhayaya, Ram Shankar,Jain, Sanjay,Sinha, Neelima,Kishore, Nawal,Chandra, Ramesh,Arora, Sudershan K.
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p. 579 - 592
(2007/10/03)
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- Novel azole or triazole derivatives, method for preparing the same and use thereof as antifungal medicaments
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The invention concerns novel azole or triazole derivatives of formula (I), wherein: X, Ar1, Ar3, A, R1, R5, R6, R7 and B are such as defined in the description, their preparation method and their use as antifungal medicines.
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- Synthesis of 1-triazolyl-4-trimethylsilyl-2-butanol and 1-triazolyl-5-trimethylsilyl-2-pentanol derivatives and an investigation of their fungicidal activities
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A new series of azole derivatives of 1-triazolyl-4-trimethylsilyl-2-butanol and 1-triazolyl-5-trimethylsilyl-2-pentanol were synthesized and evaluated for fungicidal activities against rice blast, sheath blight, and powdery mildew on barley. The derivatives of 2,4-difluorobenzene exhibited high antifungal activities when applied by spray, but exhibited no fungicidal activity by submerged application.
- Itoh, Hiroyuki,Yoneda, Rieko,Tobitsuka, Junzo,Ohta, Hiroshi,Takahi, Yukiyoshi,Tsuda, Mikio,Takeshiba, Hideo
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p. 1113 - 1116
(2007/10/03)
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- Azole compounds as therapeutic agents for fungal infections
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The present invention relates to the derivatives of specially substituted azole compounds which have improved antifungal activity as compared to known compounds such as fluconazole and itraconazole and the processes for the preparation thereof. This invention also relates to pharmaceutical compositions containing the compounds of the present invention and their use in treating and/or preventing fungal infections in mammals, preferably humans.
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Page column 31
(2010/02/05)
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- Azole compounds designed by molecular modelling show antifungal activity as predicted
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Rational approaches involving drug discovery technologies such as computational and combinatorial chemistry and high throughput screening have been useful tools to design and discover new drugs more efficiently. The interplay among structure-activity relationships, computer modelling, chemical synthesis and pharmacological testing can lead to better products for a particular therapeutic purpose. The work presented in this paper reports an example of successful application of computer-aided drug design method to find new azole antifungal agents. The designed compounds have been synthesized in the laboratory and tested for antifungal activity against Candida albicans ATCC 24433 in vitro. Two compounds exhibit good activity in vitro, which can be optimized for better activity.
- Karki, Rajeshri G.,Gokhale, Vijay M.,Kharkar, Prashant S.,Kulkarni, Vithal M.
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p. 372 - 381
(2007/10/03)
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- PPL-catalyzed enzymatic asymmetrization of a 2-substituted prochiral 1,3-diol with remote chiral functionality: Improvements toward synthesis of the eutomers of SCH 45012
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Porcine pancreatic lipase (PPL) catalysis has been used to establish both stereocenters of the cis-(tetrahydrofuranylmethyl) tosylate 4. In addition to the enzymatic differentiation of the hydroxyl groups of the pro-chiral 1,3-diol segment of 2, successful enzymatic resolution of the racemic diol 10 provided an alternate route to the important precursor 1.
- Lovey, Raymond G.,Saksena, Anil K.,Girijavallabhan, Viyyoor M.
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p. 6047 - 6050
(2007/10/02)
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- Triazole Derivatives
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A triazole derivative having antifungal activity is disclosed. The compounds are represented by the following formula: wherein Ar represents a phenyl group or a phenyl group substituted with one or two groups selected from the group consisting of halogen
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