Bioorganic and Medicinal Chemistry, volume 91, pages 117413

Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase

Yitian Zhao ^{1, 2}

Min Zhang ¹

Xudong Hou ¹

Jiaxin Han ²

Xiaoya Qin ¹

Yun Yang ^{1, 2}

Yunqing Song ¹

Zhikai Liu ^{1, 2}

Yong Zhang ^{2, 3}

Zhijian Xu ^{2, 3}

Qi Jia ¹

Yiming Li ¹

KAIXIAN CHEN ^{1, 2, 3}

Bo Li ^{2, 3}

Weiliang Zhu ^{1, 2, 3}

Guangbo Ge ¹

Hide authors affiliations Show authors affiliations: 3 affiliations

Shanghai University of Traditional Chinese medicine, Shanghai 201203, China |

State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China |

School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China |

Publication type: Journal Article

Publication date: 2023-08-01

Elsevier

Journal: Bioorganic and Medicinal Chemistry

Quartile SCImago

Quartile WOS

Impact factor: 3.5

ISSN: 09680896, 14643391

DOI: 10.1016/j.bmc.2023.117413

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Organic Chemistry

Drug Discovery

Biochemistry

Molecular Biology

Pharmaceutical Science

Clinical Biochemistry

Molecular Medicine

Abstract

Obesity is a growing global health problem and is associated with increased prevalence of many metabolic disorders, including diabetes, hypertension and cardiovascular disease. Pancreatic lipase (PL) has been validated as a key target for developing anti-obesity agents, owing to its crucial role in lipid digestion and absorption. In the past few decades, porcine PL (pPL) is always used as the enzyme source for screening PL inhibitors, which generate numerous pPL inhibitors but the potent inhibitors against human PL (hPL) are rarely reported. Herein, a series of salicylanilide derivatives were designed and synthesized, while their anti-hPL effects were assayed by a fluorescence-based biochemical approach. To investigate the structure-activity relationships of salicylanilide derivatives as hPL inhibitors in detail, structural modifications on three rings (A, B and C) of the salicylanilide skeleton were performed. Among all tested compounds, 2t and 2u were found possessing the most potent anti-PL activity, showing IC50 values of 1.86 μM and 1.63 μM, respectively. Inhibition kinetic analyses suggested that both 2t and 2u could effectively inhibit hPL in a non-competitive manner, with the ki value of 1.67 μM and 1.70 μM, respectively. Fluorescence quenching assays suggested that two inhibitors could quench the fluorescence of hPL via a static quenching procedure. Molecular docking simulations suggested that 2t and 2u could tightly bind on an allosteric site of hPL. Collectively, the structure-activity relationships of salicylanilide derivatives as hPL inhibitors were carefully investigated, while two newly identified reversible hPL inhibitors (2t and 2u) could be used as promising lead compounds to develop novel anti-obesity drugs.

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GOST Copy

Zhao Y. et al. Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase // Bioorganic and Medicinal Chemistry. 2023. Vol. 91. p. 117413.

GOST all authors (up to 50) Copy

Zhao Y., Zhang M., Hou X., Han J., Qin X., Yang Y., Song Y., Liu Z., Zhang Y., Xu Z., Jia Q., Li Y., CHEN K., Li B., Zhu W., Ge G. Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase // Bioorganic and Medicinal Chemistry. 2023. Vol. 91. p. 117413.

RIS |

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RIS Copy

TY - JOUR

DO - 10.1016/j.bmc.2023.117413

UR - https://doi.org/10.1016/j.bmc.2023.117413

TI - Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase

T2 - Bioorganic and Medicinal Chemistry

AU - Zhao, Yitian

AU - Zhang, Min

AU - Hou, Xudong

AU - Han, Jiaxin

AU - Qin, Xiaoya

AU - Yang, Yun

AU - Song, Yunqing

AU - Liu, Zhikai

AU - Zhang, Yong

AU - Xu, Zhijian

AU - Jia, Qi

AU - Li, Yiming

AU - CHEN, KAIXIAN

AU - Li, Bo

AU - Zhu, Weiliang

AU - Ge, Guangbo

PY - 2023

DA - 2023/08/01 00:00:00

PB - Elsevier

SP - 117413

VL - 91

SN - 0968-0896

SN - 1464-3391

ER -

BibTex

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BibTex Copy

@article{2023_Zhao,

author = {Yitian Zhao and Min Zhang and Xudong Hou and Jiaxin Han and Xiaoya Qin and Yun Yang and Yunqing Song and Zhikai Liu and Yong Zhang and Zhijian Xu and Qi Jia and Yiming Li and KAIXIAN CHEN and Bo Li and Weiliang Zhu and Guangbo Ge},

title = {Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase},

journal = {Bioorganic and Medicinal Chemistry},

year = {2023},

volume = {91},

publisher = {Elsevier},

month = {aug},

url = {https://doi.org/10.1016/j.bmc.2023.117413},

pages = {117413},

doi = {10.1016/j.bmc.2023.117413}

}

Found error?

Publisher

Elsevier

Journal

Bioorganic and Medicinal Chemistry

Quartile SCImago

Quartile WOS

Impact factor

3.5

ISSN

09680896 (Print)
14643391 (Electronic)