title: Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents.
abstract: Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Xiaokang
authors.initials: X
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ni
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Fulin
authors.initials: F
authors.lastname: Lian
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D066329:Protein Aggregates / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D000110:Acetylcholinesterase; D013890:Thiourea