2. Academic Validation
  3. Synthesis and biological evaluation of novel naphthoquinone [2,3-d] thiazole derivatives as potent 17β-HSD10 inhibitor

Synthesis and biological evaluation of novel naphthoquinone [2,3-d] thiazole derivatives as potent 17β-HSD10 inhibitor

  • Bioorg Chem. 2026 Jun 5:173:109669. doi: 10.1016/j.bioorg.2026.109669.
Erfeng Liu 1,  Shiyun Dao 1,  Chao Cui 1,  Wanqing He 1,  Lijun Zhang 2,  Huang Tang 3
Affiliations

Affiliations

  • 1 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, University Engineering Research Center for Chemistry of Characteristic Medicinal Resources (Guangxi), Guangxi Normal University, Guilin City, Guangxi 541004, China.
  • 2 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, University Engineering Research Center for Chemistry of Characteristic Medicinal Resources (Guangxi), Guangxi Normal University, Guilin City, Guangxi 541004, China. Electronic address: ajun840618@mailbox.gxnu.edu.cn.
  • 3 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, University Engineering Research Center for Chemistry of Characteristic Medicinal Resources (Guangxi), Guangxi Normal University, Guilin City, Guangxi 541004, China. Electronic address: hyhth@163.com.
PMID: 41747361 DOI: 10.1016/j.bioorg.2026.109669
Abstract

A series of novel naphthoquinone[2,3-d] thiazole derivatives were designed as 17β-HSD10 inhibitors. Compound 14 emerged as the lead candidate, demonstrating potent 17β-HSD10 inhibition (IC50 = 6.33 μM) and favorable blood-brain barrier permeability. Molecular docking confirmed key interactions between its core scaffold and the 17β-HSD10 catalytic triad. In APP/PS1 mice, compound 14 significantly improved cognitive function without affecting 17β-HSD10 protein levels. It functionally inhibited 17β-HSD10, leading to rescued mitochondrial function (24% reduction in ROS, 76% increase in ATP, suppressed cytochrome c release), attenuated CDK5/p25 activation and Tau hyperphosphorylation, restored BDNF levels (58% increase in cortex), and reduced Aβ plaque load by approximately two-thirds. These results establish compound 14 as a multi-target neuroprotective agent for AD, concurrently ameliorating mitochondrial impairment, Tau pathology, and Aβ deposition through functional inhibition of 17β-HSD10.

Keywords

17β-HSD10; Microtubule-associated protein tau; Mitochondrial function; Naphthoquinone[2,3-d] thiazole derivative; Neuroprotection.

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