Phenylthioether chalcone derivatives attenuate acute lung injury via suppression of p38 MAPK (MAPK14)-mediated inflammatory signaling
- 1Anhui Province Key Laboratory of Inflammation and Immune Diseases, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province, 230032, PR China
Abstract
Acute lung injury (ALI), characterized by dysregulated inflammation and oxidative stress, remains a major therapeutic challenge due to limited treatment options. Inspired by the anti-inflammatory activity of the in-house synthetic intermediate A1 , we designed and synthesized a series of chalcone derivatives through structural optimization, preserving the phenylthioether moiety while modifying the aromatic ring on one side of the chalcone olefin. Among these, compound B15 emerged as the lead candidate, exhibiting potent nitric oxide (NO) inhibition (IC 50 = 2.6 ± 1.4 μM) in LPS-stimulated RAW264.7 macrophages with minimal cytotoxicity (GI 50 > 100 μM). Mechanistic studies demonstrated that B15 directly binds to p38 MAPK with a K D value of 372.1 nM. It suppressed LPS-induced inflammatory responses in a concentration-dependent manner, downregulating TNF-α and IL-6 transcription, reducing intracellular ROS levels, and inhibiting the activation of multiple inflammatory-related MAPK cascades. In an LPS-induced murine model of ALI, B15 significantly attenuated pathological damage and inflammatory response, including alveolar collapse, interstitial edema, and neutrophil infiltration. Collectively, these finding establish B15 as a promising anti-inflammatory lead for ALI therapy via p38 MAPK inhibition, meriting further pharmacological development.
Related
- Ellagic acid mitigates follicular atresia in laying chickens via GPX4 upregulation to block ferroptosis and p53 suppression to attenuate DNA damage
- Inhibiting MD2 activates AMPK-dependent PPARγ/NOX4 signaling to attenuate mitochondrial oxidative stress and relieve pulmonary hypertension
- HucMSC-EVs attenuate renal fibrosis via miR-874-3p-mediated inhibition of cGAS-STING signaling.
- Alpha-Lipoic Acid and Saxagliptin Attenuate Ferroptosis-Related Ovarian Injury and Modulate FGF21/NOX4–NRF2/HO-1 Signaling in Letrozole-Induced Polycystic Ovary Syndrome
- Panaxadiol derivatives inhibit lung metastasis of breast cancer via DLL4-Notch signaling pathway and palmitoyl carnitine aggregation
BibTeX
@article{yi2026phenylthioether,
title = {{Phenylthioether chalcone derivatives attenuate acute lung injury via suppression of p38 MAPK (MAPK14)-mediated inflammatory signaling}},
author = {Qin-Li Yi and Xue-Jian Zhou and Zhao-Feng Wu and Jia-Xing Jiang and Xin-Hua Liu and Ming-Ming Liu and Jing-Bo Shi},
journal = {Results in Chemistry},
year = {2026},
month = oct,
doi = {10.1016/j.rechem.2026.103976},
url = {https://doi.org/10.1016/j.rechem.2026.103976},
note = {CC BY},
}
RIS
TY - JOUR
TI - Phenylthioether chalcone derivatives attenuate acute lung injury via suppression of p38 MAPK (MAPK14)-mediated inflammatory signaling
AU - Qin-Li Yi
AU - Xue-Jian Zhou
AU - Zhao-Feng Wu
AU - Jia-Xing Jiang
AU - Xin-Hua Liu
AU - Ming-Ming Liu
AU - Jing-Bo Shi
PY - 2026
DA - 2026/10/30
JO - Results in Chemistry
DO - 10.1016/j.rechem.2026.103976
UR - https://doi.org/10.1016/j.rechem.2026.103976
AB - Acute lung injury (ALI), characterized by dysregulated inflammation and oxidative stress, remains a major therapeutic challenge due to limited treatment options. Inspired by the anti-inflammatory activity of the in-house synthetic intermediate A1 , we designed and synthesized a series of chalcone derivatives through structural optimization, preserving the phenylthioether moiety while modifying the aromatic ring on one side of the chalcone olefin. Among these, compound B15 emerged as the lead candidate, exhibiting potent nitric oxide (NO) inhibition (IC 50 = 2.6 ± 1.4 μM) in LPS-stimulated RAW264.7 macrophages with minimal cytotoxicity (GI 50 > 100 μM). Mechanistic studies demonstrated that B15 directly binds to p38 MAPK with a K D value of 372.1 nM. It suppressed LPS-induced inflammatory responses in a concentration-dependent manner, downregulating TNF-α and IL-6 transcription, reducing intracellular ROS levels, and inhibiting the activation of multiple inflammatory-related MAPK cascades. In an LPS-induced murine model of ALI, B15 significantly attenuated pathological damage and inflammatory response, including alveolar collapse, interstitial edema, and neutrophil infiltration. Collectively, these finding establish B15 as a promising anti-inflammatory lead for ALI therapy via p38 MAPK inhibition, meriting further pharmacological development.
SN - 2211-7156
ER -