Toxicity Assessment of a Derivative Designed by Using the Privileged Structure Dihydropyridine: LQFM310, a Nifedipine Analog.

IF 2.7 4区 医学 Q3 TOXICOLOGY
Amanda C Silva, Michele R Machado, Gerlon A R Oliveira, Gessyca G Costa, Gisele A R Oliveira, Luciano M Lião, Eric S Gil, Ricardo Menegatti, Gloria N S Silva
{"title":"Toxicity Assessment of a Derivative Designed by Using the Privileged Structure Dihydropyridine: LQFM310, a Nifedipine Analog.","authors":"Amanda C Silva, Michele R Machado, Gerlon A R Oliveira, Gessyca G Costa, Gisele A R Oliveira, Luciano M Lião, Eric S Gil, Ricardo Menegatti, Gloria N S Silva","doi":"10.1002/jat.4829","DOIUrl":null,"url":null,"abstract":"<p><p>The privileged structures, such as dihydropyridine, are present in bioactive compounds exhibiting biological activities by interacting with multiple pharmacological targets. The dihydropyridine-containing compounds are usually related to the calcium channel-blocking abilities in the treatment of cardiovascular diseases, such as nifedipine. Other pharmaceutical applications have been described for these compounds, being a starting point for the obtaining of new drug candidates. The privileged structures are usually related to nontoxic effects; however, other chemical groups of dihydropyridine-containing compounds may result in impairment of the safety profile, such as nifedipine, described as teratogenic and embryotoxic in vivo. Here, we designed LQFM310 through the molecular hybridization strategy by incorporating the dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate scaffold from nifedipine and butyl hydroxytoluene (BHT). As the phenolic hydroxyl from BHT is capable of conferring antioxidant activity, the electrochemical analysis was performed. In addition, the toxicological profile of LQFM310 was investigated by using the embryo-larval stage of zebrafish (Danio rerio) and compared to nifedipine. As a result, LQFM310 demonstrated the antioxidant potential and did not induce significant lethal or sublethal effects in the toxicological assay. However, nifedipine induced 100% mortality in embryos and larvae from 25 μM for 96 h post fertilization (hpf) and sublethal effects at 10 μM. Therefore, LQFM310 demonstrated a safer profile than nifedipine in the zebrafish-based toxicity model, identifying that the nitroaromatic scaffold may be responsible for the toxicity effect of nifedipine. Considering the presence of privileged structures as dihydropyridine, LQFM310 is a promising compound for investigation in pharmacology assays of several diseases.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Applied Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/jat.4829","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The privileged structures, such as dihydropyridine, are present in bioactive compounds exhibiting biological activities by interacting with multiple pharmacological targets. The dihydropyridine-containing compounds are usually related to the calcium channel-blocking abilities in the treatment of cardiovascular diseases, such as nifedipine. Other pharmaceutical applications have been described for these compounds, being a starting point for the obtaining of new drug candidates. The privileged structures are usually related to nontoxic effects; however, other chemical groups of dihydropyridine-containing compounds may result in impairment of the safety profile, such as nifedipine, described as teratogenic and embryotoxic in vivo. Here, we designed LQFM310 through the molecular hybridization strategy by incorporating the dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate scaffold from nifedipine and butyl hydroxytoluene (BHT). As the phenolic hydroxyl from BHT is capable of conferring antioxidant activity, the electrochemical analysis was performed. In addition, the toxicological profile of LQFM310 was investigated by using the embryo-larval stage of zebrafish (Danio rerio) and compared to nifedipine. As a result, LQFM310 demonstrated the antioxidant potential and did not induce significant lethal or sublethal effects in the toxicological assay. However, nifedipine induced 100% mortality in embryos and larvae from 25 μM for 96 h post fertilization (hpf) and sublethal effects at 10 μM. Therefore, LQFM310 demonstrated a safer profile than nifedipine in the zebrafish-based toxicity model, identifying that the nitroaromatic scaffold may be responsible for the toxicity effect of nifedipine. Considering the presence of privileged structures as dihydropyridine, LQFM310 is a promising compound for investigation in pharmacology assays of several diseases.

硝苯地平类似物二氢吡啶衍生物LQFM310的毒性评价。
特殊结构,如二氢吡啶,存在于生物活性化合物中,通过与多种药理靶点相互作用表现出生物活性。在心血管疾病的治疗中,含二氢吡啶的化合物通常与钙通道阻断能力有关,如硝苯地平。这些化合物的其他药物应用已经被描述,作为获得新的候选药物的起点。特权结构通常与无毒作用有关;然而,含二氢吡啶化合物的其他化学基团可能导致安全性受损,例如硝苯地平,在体内被描述为致畸和胚胎毒性。本研究采用硝苯地平和丁羟基甲苯(BHT)合成的二甲基2,6-二甲基-1,4-二氢吡啶-3,5-二羧酸酯骨架,通过分子杂交策略设计了LQFM310。由于BHT的酚羟基具有抗氧化活性,因此进行了电化学分析。此外,通过斑马鱼胚胎-幼虫期研究了LQFM310的毒理学特征,并与硝苯地平进行了比较。结果表明,LQFM310显示出抗氧化潜力,并且在毒理学试验中没有引起显著的致死或亚致死效应。然而,硝苯地平在25 μM条件下对96 h的胚胎和幼虫有100%的死亡率,在10 μM条件下有亚致死作用。因此,LQFM310在斑马鱼毒性模型中表现出比硝苯地平更安全的特征,表明硝苯地平的毒性作用可能与硝苯地平的硝苯地平的毒性作用有关。LQFM310具有与二氢吡啶类似的特殊结构,因此在多种疾病的药理学研究中具有广阔的应用前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
7.00
自引率
6.10%
发文量
145
审稿时长
1 months
期刊介绍: Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信