Design, Synthesis, and Structure-Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility

doi:10.1021/jm4016284

	Design, Synthesis, and Structure-Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility
	Cao, Xufeng 1; Sun, Zhaoshuan 2; Cao, Yongbing 3; Wang, Ruilian 3; Cai, Tongkai 3; Chu, Wenjing 1; Hu, Wenhao 2; Yang, Yushe1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	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.
资助项目	Key New Drug Creation and Manufacturing Program, China[2009ZX09301-001]
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
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000335879100007
内容类型	期刊论文
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.