Non-alcoholic steatohepatitis (NASH) is emerging as a rapidly growing health concern. Bile acids (BAs) function as endocrine signaling molecules and exhibit therapeutic potential for NASH. To develop safer and more effective BA derivatives for NASH treatment, 25 amino acid-conjugated bile acid derivatives were designed and synthesized based on the pharmacological properties of the leading compound A17. The anti-lipid accumulation, anti-inflammatory and anti-fibrosis activities of these compounds were evaluated, and their structure-activity relationships were elucidated. Notably, compound C04 exhibited superior in vitro activity compared to obeticholic acid and demonstrated enhanced efficacy in improving both NASH and fibrosis in preclinical murine models via oral administration. These findings suggest that C04 is a promising candidate for NASH treatment and warrants further investigation.

2025-07-01·European Journal of Medicinal Chemistry

Heterocycle-fused phenylcyclohexylamines as novel multi-target antagonists of N-methyl-D-aspartate (NMDA) receptor and monoamine transporter for treating depression

Article

作者: Li, Pengcheng ; Aisa, Haji Akber ; Ji, Jing ; Xu, Zhijian ; Zayniddin, Nuriddinov ; Mamateli, Obul ; Zheng, Jiefang ; Hu, Zhengtao ; He, Yang ; Tian, Guanghui ; Zhu, Weiliang ; Chen, Hai ; Gong, Xudong ; Hu, Tianwen ; Wang, Guan ; Shen, Jingshan ; Zheng, Fuqiang ; Abduahadi, Safomuddin ; Hou, Qiongqiong ; Cheng, Jiaxin

Simultaneously modulating the glutamatergic and monoaminergic systems represents a promising strategy for treating depression. In this study, a series of multi-target antagonists targeting both NMDAR and monoamine transporters (SERT, DAT, and NET) was designed and evaluated for their antidepressant potential in vitro and in vivo. Among these heterocycle-fused phenylcyclohexylamine derivatives, compound A16 demonstrated potent and relatively balanced multi-target activity (A16: IC₅₀(NMDAR): IC₅₀(SERT): IC₅₀(DAT): IC₅₀(NET) = 1.8:1.0:1.9:1.3) compared to the lead compound S1. Pharmacokinetic studies revealed that A16 exhibited moderate clearance in microsomes and favorable oral brain exposure in mice. In vivo assessments showed that A16 and its R-isomer A17 exhibited significant antidepressant-like effects in the forced swim test and tail suspension test in mice. Notably, A17 demonstrated significant antidepressant-like effects at doses as low as 1 mg/kg, with no indication of addiction risk at 20 mg/kg. Collectively, these findings identify A17, a heterocycle-fused phenylcyclohexylamine as a promising scaffold for developing non-addictive, rapid-acting antidepressants.

2025-03-01·Bioorganic Chemistry

Design, synthesis, crystal structure, fungicidal activity, and mechanism of action of novel thiazole-based hydrazide derivatives containing the 4-aminoquinazoline moiety

Article

作者: Yang, Lan ; Li, Hong ; Liu, Shengping ; Li, Sha ; Sun, Mingman ; Bao, Xiaoping ; Yi, Mingyan

A family of novel thiazole-based hydrazide derivatives bearing the 4-aminoquinazoline moiety were designed and synthesized by the molecular hybridization strategy, and assessed for their antifungal activities in vitro and in vivo. Among these derivatives, the chemical structure of compound A26 was clearly confirmed via X-ray crystallography. The bioassay results revealed that some of the synthesized compounds exhibited significant inhibition effects against the tested phytopathogenic fungi. For example, in vitro EC₅₀ (half maximal effective concentration) values of compounds A19 and A26 against Rhizoctonia solani, A19 against Verticillium dahliae, A26 against Alternaria solani, and A17 against Colletotrichum gloeosporioides were all less than 3.0 μg/mL. In particular, compound A19 with a 2-fluorophenyl group had an EC₅₀ value as low as 2.87 μg/mL towards R. solani, comparable to that of Chlorothalonil (1.44 μg/mL) and slightly inferior to those of Carbendazim and Boscalid (0.85 and 0.83 μg/mL, respectively). In addition, in vivo assays using this compound displayed the curative and protective efficiencies of 48.4% and 59.6% against R. solani, respectively, at the concentration of 200 μg/mL. Moreover, the mechanistic studies indicated that compound A19 likely exerted its highly antifungal effects by acting as an effective succinate dehydrogenase (SDH) inhibitor with an IC₅₀ value of 29.33 μM, based on SDH enzymatic inhibition assays and molecular docking studies. Meanwhile, the presence of compound A19 adversely impacted the integrity of cell membranes and mycelial morphologies of R. solani.

100 项与 Angstrom-17 相关的药物交易

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