title: Design, synthesis, and cytoprotective effect of 2-aminothiazole analogues as potent poly(ADP-ribose) polymerase-1 inhibitors.
abstract: A series of novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors were designed within 2-aminothiazole analogues (4-10) based on a constructed three-dimensional pharmacophore model. After synthesis, the inhibitory effect on PARP-1 activity and the cytoprotective action of these compounds were tested and evaluated. Among them, compounds 4-6 and 10 appeared to be potent PARP-1 inhibitors with IC(50) values less than 1 microM, which had been perfectly predicted by pharmacophore model. These compounds proved to be highly potent against cell injury induced by H(2)O(2) and oxygen-glucose deprivation (OGD) in PC12 cells. These novel 2-aminothiazole analogues are potentially applicable as neuroprotective agents for the treatment of neurological diseases.
authors.affiliation: Department of Medicinal Chemistry and Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Zhang
authors.forename: Jin-Lan
authors.initials: JL
authors.lastname: Ruan
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wu
authors.forename: Feng-Chao
authors.initials: FC
authors.lastname: Jiang
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.forename: Xiang-Long
authors.initials: XL
authors.lastname: Chen
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Bao-Shuai
authors.initials: BS
authors.lastname: Cao
authors.forename: Gang-Ying
authors.initials: GY
authors.lastname: Chen
authors.forename: Yi-Jing
authors.initials: YJ
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016716:PC12 Cells; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013844:Thiazoles; D006861:Hydrogen Peroxide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1