Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS

doi:10.1016/j.ejmech.2023.115412

兰州大学机构库

	Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS
	Akhtar, Maryam; Niu, Jiabin; Zhu, Yujie; Luo, Zhaoyi; Tian, Ting; Dong, Yuanliang; Wang, Yuan; Fareed, Muhammad Subaan; Lin, Li
	2023-08-05
Online publication date	2023-05
Source Publication	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Impact Factor & Quartile
ISSN	0223-5234
Volume	256
page numbers	11
Abstract	Isoquinoline alkaloids are a rich source of multimodal agents with distinctive structural specificity and various pharmacological activities. In the present report, we propose a combination of design, synthesis, computational study, primary in-vitro screening using the lipopolysaccharide (LPS)-induced RAW 264.7 cell line, and in-vivo evaluation in mice models as a novel approach to speed up anti-inflammatory drugs discovery. The nitric oxide (NO) inhibitory effect of new compounds revealed that all of them displayed the potent NO inhibitory ability in a dose-dependent manner with no obvious cytotoxicity. A series of the model compounds 7a, 7b, 7d, 7f, and 7g have been identified as the most promising, with IC50 values of 47.76 mu M, 33.8 mu M, 20.76 mu M, 26.74 mu M, and 47.8 mu M respectively in LPS-induced RAW 264.7 cell line. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. Western blotting data of 7d identified that our synthesized compounds can down-regulate and suppress the expression of the key inflammatory enzyme, inducible nitric oxide synthase (iNOS). These results suggested that synthesized compounds may be potent anti-inflammatory agents, inhibiting the NO-release, in turn, iNOS inflammatory pathways. Furthermore, in-vivo anti-inflammatory detection via xylene-induced ear edema in mice revealed that these compounds could also inhibit swelling in mice, with model compound 7h showing an inhibition activity (64.4%) at a concentration of 10 mg/kg comparable to the reference drug celecoxib. Molecular docking results showed that shortlisted compounds (7b, 7c, 7d, 7e, and 7h) had a potential binding affinity for iNOS with low energies, with S-Score to be-7.57,-8.22,-7.35,-8.95,-9.94 kcal/mol, respectively. All results demonstrated that the newly synthesized chiral pyrazolo isoquinoline derivatives are highly potential anti-inflammatory agents.
Keyword	Anti-inflammatory Pyrazolo isoquinoline Nitric oxide inhibition Inducible nitric oxide synthase Celecoxib
Publisher	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI	10.1016/j.ejmech.2023.115412
Indexed By	SCIE ; IC
Language	英语
WOS Research Area	Pharmacology & Pharmacy
WOS Subject	Chemistry, Medicinal
WOS ID	WOS:000998889000001
Original Document Type	Article
PMID	37146344
Citation statistics
Document Type	期刊论文
Identifier	https://ir.lzu.edu.cn/handle/262010/529860
Collection	兰州大学
Corresponding Author	Lin, Li
Affiliation	Chinese Acad Med Sci, Lanzhou Univ,2019RU066, Inst Biochem & Mol Biol,Res Unit Peptide Sci, Sch Basic Med Sci,Key Lab Preclin Study New Drugs, 2019RU066, Lanzhou 730000, Peoples R China
Recommended Citation GB/T 7714	Akhtar, Maryam,Niu, Jiabin,Zhu, Yujie,et al. Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,256.
APA	Akhtar, Maryam.,Niu, Jiabin.,Zhu, Yujie.,Luo, Zhaoyi.,Tian, Ting.,...&Lin, Li.(2023).Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,256.
MLA	Akhtar, Maryam,et al."Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 256(2023).

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