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.
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.