Benzodioxane Carboxamide Derivatives As Novel Monoamine Oxidase B Inhibitors with Antineuroinflammatory Activity

Demeng Sun; Bo Wang; Yanmei Jiang; Zuo Kong; Mengxue Mu; Changhuan Yang; Jingbo Tan; Yun Hu

doi:10.1021/acsmedchemlett.3c00532

Benzodioxane Carboxamide Derivatives As Novel Monoamine Oxidase B Inhibitors with Antineuroinflammatory Activity

ACS Med Chem Lett. 2024 May 20;15(6):798-805. doi: 10.1021/acsmedchemlett.3c00532. eCollection 2024 Jun 13.

Authors

Demeng Sun¹, Bo Wang¹, Yanmei Jiang¹, Zuo Kong¹, Mengxue Mu¹, Changhuan Yang¹, Jingbo Tan¹, Yun Hu¹

Affiliation

¹ School of Bioengineering, Zhuhai Campus, Zunyi Medical University, Zhuhai 519041, China.

PMID: 38894921
PMCID: PMC11181489 (available on 2025-06-13)
DOI: 10.1021/acsmedchemlett.3c00532

Abstract

In this study, a series of N-phenyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (hMAO-B). The structure-activity relationship (SAR) was investigated and summarized. Compound 1l (N-(3,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC₅₀ value of 0.0083 μM and the selectivity index (IC₅₀ (hMAO-A)/IC₅₀ (hMAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound 1l acted as a competitive and reversible inhibitor of hMAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions, and the rationale was provided. Additionally, compound 1l could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ_1-42-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ_1-42. Since compound 1l exhibited low neurotoxicity, we believe that the hit compound with dual activities of inhibiting MAO-B and antineuroinflammation could be further investigated as a novel potential lead for future studies in vivo.