58905-18-3Relevant academic research and scientific papers
Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the 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
, (2021/03/16)
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.
Novel triazole derivatives containing different ester skeleton: Design, synthesis, biological evaluation and molecular docking
Han, Xiaoyan,Ren, Liwen,Song, Yali,Sun, Xiaoyang,Wang, Jinhua,Wang, Shumin,Xiao, Bin,Zhang, Na
, p. 64 - 69 (2020/02/03)
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.
Use of miconazole and derivatives thereof as TGR5 agonists (by machine translation)
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Paragraph 0031; 0035, (2020/05/02)
The invention belongs to the technical field of medicines, and relates to novel application TGR5 of miconazole and derivatives thereof in treatment, of diseases and conditions of a biological pathologic process involved in treatment, and. The miconazole and the analogues thereof can activate TGR5 active, for use TGR5 in the treatment or prevention of diseases associated with, activity modulation. (by machine translation)
ULK1 micromolecule stimulant and application of stimulant in antitumor drug
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Paragraph 0102; 0103; 0104; 0107, (2017/07/31)
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.
Synthesis and evaluation of novel benzene-ethanol bearing 1,2,4-triazole derivatives as potential antimicrobial agents
Li, Bochao,Zhang, Dawei,Zhang, Yumin,Dan Jiang,Li, Shuang,Lei, Wei,Wang, Huiying,Lin, Feng
, p. 44 - 51 (2017/01/12)
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.
Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo
Zhang, Lan,Fu, Leilei,Zhang, Shouyue,Zhang, Jin,Zhao, Yuqian,Zheng, Yaxin,He, Gu,Yang, Shengyong,Ouyang, Liang,Liu, Bo
, p. 2687 - 2701 (2017/04/06)
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.
Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
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
, p. 284 - 301 (2014/08/05)
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.
Aromatic ethers of 1-aryl 2-(1H-azolyl)ethanol: study of antifungal activity
Wahbi, Y.,Caujolle, R.,Tournaire, C.,Payard, M.,Linas, M. D.,Seguela, J. P.
, p. 955 - 962 (2007/10/03)
Aromatic ethers related to antifungal azole miconazole were synthesized and tested against various strains of Candida.We found that activity is related to the nature of the aromatic ring and the position of substituents on this ring.Activity is more strongly dependent on the substituent in the 2-position of the ethyl chain on the aromatic group linked through the oxygen.Triazoles were always less potent than the corresponding imidazole analogues. - Keywords: imidazole; 1,2,4-triazole; antifungal activity; yeast; structure-activity relationship
Fungicidal novel substituted phenethyl-triazolyl derivatives
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, (2008/06/13)
A fungicidally active substituted phenethyl-triazolyl derivative of the formula STR1 in which X1 and X2 each independently is halogen or halogenoalkyl, and one of them may also be hydrogen, Y is >C=N--O--R or >CH--O--R, R is phenoxyethyl which is optionally substituted in the phenyl part, or an addition product thereof with an acid or salt.
2-Hydroxyarylethyltriazole fungicides
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, (2008/06/13)
This invention relates to 2-hydroxyarylethyl-1,2,4-triazoles, their acid addition salts and metal salt complexes. This invention also relates to the method of preparation and use of these compounds. These compounds and salts thereof are highly active broa
