Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer’s disease

Wenhai Huang; Dan Lv; Haiping Yu; Rong Sheng; Sun Chol Kim; Peng Wu; Kedi Luo; Jia Li; Yongzhou Hu

doi:10.1016/j.bmc.2010.06.042

Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer’s disease

Wenhai Huang, Dan Lv, Haiping Yu, Rong Sheng, Sun Chol Kim, Peng Wu, Kedi Luo, Jia Li, Yongzhou Hu

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a–d, 9a–g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85±2.46μmol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.

Original language	English
Journal	Bioorganic & Medicinal Chemistry
Volume	18
Issue number	15
Pages (from-to)	5610-5615
ISSN	0968-0896
DOIs	https://doi.org/10.1016/j.bmc.2010.06.042
Publication status	Published - 2010
Externally published	Yes

Keywords

Alzheimer’s disease
BACE 1 inhibitor
Metal chelators
Dual-target-directed ligands

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10.1016/j.bmc.2010.06.042

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title = "Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer{\textquoteright}s disease",

abstract = "Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a–d, 9a–g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85±2.46μmol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.",

keywords = "Alzheimer{\textquoteright}s disease, BACE 1 inhibitor, Metal chelators, Dual-target-directed ligands",

author = "Wenhai Huang and Dan Lv and Haiping Yu and Rong Sheng and Kim, {Sun Chol} and Peng Wu and Kedi Luo and Jia Li and Yongzhou Hu",

year = "2010",

doi = "10.1016/j.bmc.2010.06.042",

language = "English",

volume = "18",

pages = "5610--5615",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Pergamon Press",

number = "15",

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TY - JOUR

T1 - Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer’s disease

AU - Huang, Wenhai

AU - Lv, Dan

AU - Yu, Haiping

AU - Sheng, Rong

AU - Kim, Sun Chol

AU - Wu, Peng

AU - Luo, Kedi

AU - Li, Jia

AU - Hu, Yongzhou

PY - 2010

Y1 - 2010

N2 - Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a–d, 9a–g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85±2.46μmol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.

AB - Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a–d, 9a–g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85±2.46μmol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.

KW - Alzheimer’s disease

KW - BACE 1 inhibitor

KW - Metal chelators

KW - Dual-target-directed ligands

U2 - 10.1016/j.bmc.2010.06.042

DO - 10.1016/j.bmc.2010.06.042

M3 - Journal article

C2 - 20620068

SN - 0968-0896

VL - 18

SP - 5610

EP - 5615

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 15

ER -

Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer’s disease

Abstract

Keywords

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