Design, Synthesis, and Structure-Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility
文献类型：期刊论文
| 作者 | Cao, Xufeng1; Sun, Zhaoshuan2; Cao, Yongbing3; Wang, Ruilian3; Cai, Tongkai3; Chu, Wenjing1; Hu, Wenhao2; Yang, Yushe1
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2014-05-08 |
| 卷号 | 57期号:9页码:3687-3706 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm4016284 |
| 文献子类 | Article |
| 英文摘要 | Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]-triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles. |
| WOS关键词 | AZOLE ANTIFUNGAL AGENTS ; AUTOMATED PATCH-CLAMP ; IN-VITRO EVALUATION ; LANOSTEROL 14-ALPHA-DEMETHYLASE ; MOLECULAR DOCKING ; BIOLOGICAL EVALUATION ; METABOLIC STABILITY ; CANDIDA-ALBICANS ; DERIVATIVES ; VALIDATION |
| 资助项目 | Key New Drug Creation and Manufacturing Program, China[2009ZX09301-001] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000335879100007 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277079]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物安全性评价中心 |
| 通讯作者 | Hu, Wenhao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.E China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai 200062, Peoples R China; 3.Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cao, Xufeng,Sun, Zhaoshuan,Cao, Yongbing,et al. Design, Synthesis, and Structure-Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility[J]. JOURNAL OF MEDICINAL CHEMISTRY,2014,57(9):3687-3706. |
| APA | Cao, Xufeng.,Sun, Zhaoshuan.,Cao, Yongbing.,Wang, Ruilian.,Cai, Tongkai.,...&Yang, Yushe.(2014).Design, Synthesis, and Structure-Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility.JOURNAL OF MEDICINAL CHEMISTRY,57(9),3687-3706. |
| MLA | Cao, Xufeng,et al."Design, Synthesis, and Structure-Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility".JOURNAL OF MEDICINAL CHEMISTRY 57.9(2014):3687-3706. |
入库方式： OAI收割
来源：上海药物研究所
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