title: Design and synthesis of pyridine-substituted itraconazole analogues with improved antifungal activities, water solubility and bioavailability.
abstract: To improve antifungal activities, water solubility and bioavailability, a series of novel analogues of itraconazole-containing pyridine rings were designed and synthesized. Their antifungal activities were evaluated in vitro against six clinically important fungi by measuring the minimal inhibitory concentrations (MICs). Most of the compounds showed more potent antifungal activities than that of itraconazole. In particular, the analogues 30d, 30c, 31c, and 36d exhibited much higher solubility and bioavailability than that of itraconazole. The bioavailability of 36d (42.2%) was five times higher than that of itraconazole (8%) and was negative for genetic toxicology in the Ames test.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Zining
authors.initials: Z
authors.lastname: Liu
authors.forename: Xufeng
authors.initials: X
authors.lastname: Cao
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Huili
authors.initials: H
authors.lastname: He
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D005658:Fungi / Q000187:drug effects*; D017964:Itraconazole / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D011725:Pyridines; D014867:Water; D017964:Itraconazole; C023666:pyridine