One-pot synthesis and pharmacological evaluation of new quinoline/pyrimido-diazepines as pulmonary antifibrotic agents.

IF 3.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Future medicinal chemistry Pub Date : 2024-09-18 DOI:10.1080/17568919.2024.2394018

Michael Atef Fawzy,Karim Hagag Ibrahim,Ashraf A Aly,Asmaa H Mohamed,Sara Mohamed Naguib Abdel Hafez,Walaa Yehia Abdelzaher,Eslam B Elkaeed,Aisha A Alsfouk,El-Shimaa Mn Abdelhafez

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引用次数: 0

Abstract

Aim: Pulmonary fibrosis is a life threating disease which requires an immediate treatment and due to the limited medications, this study focused on synthesizing a series of quinoline-based pyrimidodiazepines 4a-f as a novel antifibrotic hit.Materials & methods: The target compounds were synthesized via a one-pot reaction then investigated in a rat model of lung fibrosis induced by bleomycin (BLM).Results: Results revealed significant attenuation of the tested pro-inflammatory cytokines, fibrotic genes and apoptotic markers; however, Bcl-2 was upregulated, indicating a protective effect against fibrosis. Moreover, the molecular docking studies highlighted promising interactions between compounds 4b and 4c and specific amino acids within the protein pockets of caspase-3 (ARG341 and THR177), malondialdehyde (LYS195, LYS118 and ARG188) and TNF-α (SER99 and NME102).Conclusion: Compounds 4b and 4c emerge as promising candidates for further preclinical investigation as pulmonary antifibrotic agents.

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作为肺部抗纤维化药物的新型喹啉/嘧啶二氮杂卓的单锅合成和药理学评价。

目的：肺纤维化是一种威胁生命的疾病，需要立即治疗，由于药物有限，本研究重点合成了一系列喹啉基嘧啶二氮杂卓 4a-f 作为新型抗纤维化药物：通过一锅反应合成目标化合物，然后在博莱霉素（BLM）诱导的大鼠肺纤维化模型中进行研究：结果表明，受试的促炎细胞因子、纤维化基因和细胞凋亡标志物均明显减少；然而，Bcl-2上调，表明其具有抗纤维化的保护作用。此外，分子对接研究强调了化合物 4b 和 4c 与 Caspase-3（ARG341 和 THR177）、丙二醛（LYS195、LYS118 和 ARG188）和 TNF-α（SER99 和 NME102）蛋白质口袋中的特定氨基酸之间有希望的相互作用：结论：化合物 4b 和 4c 很有希望作为肺部抗纤维化制剂接受进一步的临床前研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.