title: Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers.
abstract: A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Li
authors: L
authors: Tang
authors: Liying
authors: L
authors: Zhao
authors: Lingjuan
authors: L
authors: Hong
authors: Fenyan
authors: F
authors: Yang
authors: Rong
authors: R
authors: Sheng
authors: Jianzhong
authors: J
authors: Chen
authors: Ying
authors: Y
authors: Shi
authors: Naimin
authors: N
authors: Zhou
authors: Yongzhou
authors: Y
authors: Hu
mesh_terms: D015195:Drug Design; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000737:chemistry; D017385:Sequence Homology; D013329:Structure-Activity Relationship
chemical_list: D016166:Free Radical Scavengers; D006633:Histamine Antagonists; D007211:Indoles; D018100:Receptors, Histamine H3
keywords: Benzyl tertiary amine; Free radical scavengers; H(3) receptor antagonists; Melatonin