title: Design, synthesis, and structure-activity relationship studies of novel fused heterocycles-linked triazoles with good activity and water solubility.
abstract: 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Cao
authors.forename: Zhaoshuan
authors.initials: Z
authors.lastname: Sun
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Cao
authors.forename: Ruilian
authors.initials: R
authors.lastname: Wang
authors.forename: Tongkai
authors.initials: T
authors.lastname: Cai
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chu
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D002175:Candida / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000737:chemistry*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D006571:Heterocyclic Compounds; D014230:Triazoles; D014867:Water