2. Academic Validation
  3. Discovery of C-3 isoxazole substituted thiochromone S,S-dioxide derivatives as potent and selective inhibitors for monoamine oxidase B (MAO-B)

Discovery of C-3 isoxazole substituted thiochromone S,S-dioxide derivatives as potent and selective inhibitors for monoamine oxidase B (MAO-B)

  • Eur J Med Chem. 2024 Jan 5:263:115956. doi: 10.1016/j.ejmech.2023.115956.
Pengbing Mi 1,  Yan Tan 2,  Shiying Ye 2,  Jia-Jia Lang 3,  You Lv 4,  Jinhuan Jiang 2,  Limei Chen 2,  Jianxiong Luo 2,  Yuqing Lin 2,  Zhonghua Yuan 5,  Xing Zheng 6,  Ying-Wu Lin 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address: [email protected].
  • 2 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan 421001, China.
  • 3 School of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan 421001, China.
  • 4 College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an, Shaanxi 710021, China; Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi 710026, China.
  • 5 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan 421001, China. Electronic address: [email protected].
  • 6 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan 421001, China; Department of Pharmacy, Hunan Vocational College of Science and Technology, Changsha, Hunan 410004, China. Electronic address: [email protected].
  • 7 School of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address: [email protected].
PMID: 37992521 DOI: 10.1016/j.ejmech.2023.115956
Abstract

Developing new scaffolds for highly potent and selective inhibitors of human Monoamine Oxidase B (hMAO-B) is a crucial objective in enhancing the efficacy and safety in the clinical treatment of neurodegenerative diseases. In this study, we have identified a series of C-3 isoxazole-substituted thiochromone S,S-dioxide derivatives that exhibit strong inhibitory activity against hMAO-B. The strategy of oxidizing thiochromone to thiochromone S,S-dioxide solves the key defect of extreme insolubility observed for thiochromone analogues. In addition, the sulfone group contributes extra hydrogen(H)-bonding interactions with Tyr435, which significantly increases the activity of thiochromone S,S-dioxide derivatives against hMAO-B. Furthermore, the presence of isoxazole group provides potential H-bonding interaction and electrostatic interaction with the residue of Tyr326, while the rigid aryl ring introduces a potential steric conflict with Phe208 of hMAO-A to improve both potency and selectivity. In our investigations, several compounds (9c, 10c, 10e, 10g, 10l and 10m) demonstrate remarkable single-digit nanomolar potency. These compounds exhibit favorable cytotoxicity profiles in both differentiated SH-SY5Y and HVSMC cells, without apparent cardiotoxic effects. Moreover, compounds 10e and 10h do not lead to an increase in ROS levels in differentiated SH-SY5Y cells, further demonstrating their potential as safe and effective hMAO-B inhibitors. These findings indicate that the C-3 isoxazole substituted thiochromone S,S-dioxide analogues are potential leading compounds for the development of selective inhibitors with high potency.

Keywords

Human monoamine oxidase B inhibitor; Thiochromone; Thiochromone S,S-dioxide.

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