Toxic effect prediction of cefatirizine amidine sodium and its impurities by structure-toxicity relationship of cephalosporins

Qian, Jianqin; Han, Ying; Li, Jin; Zhang, Jingpu; Hu, Chang‐Qin

doi:10.1016/j.tiv.2017.09.021

Cited by 17 publications

(14 citation statements)

References 13 publications

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“…Furthermore, triazoles are weakly acidic and weakly basic and are more sensitive to reducing agents. Moreover, the 1,2,3-triazole-based compound, carboxyamidotriazole, has been successfully clinically evaluated for cancer treatment (Figure 7) [54][55][56]. Furthermore, the strong dipole properties of the triazole unit increased its importance in the field of medicinal chemistry, as it binds to the biological target with high affinity.…”

Section: 23-triazolesmentioning

confidence: 99%

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications

et al. 2020

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The analogs of nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. More than 75% of drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties. In the forthcoming decade, a much greater share of new nitrogen-based pharmaceuticals is anticipated. Many new nitrogen-based heterocycles have been designed. The number of novel N-heterocyclic moieties with significant physiological properties and promising applications in medicinal chemistry is ever-growing. In this review, we consolidate the recent advances on novel nitrogen-containing heterocycles and their distinct biological activities, reported over the past one year (2019 to early 2020). This review highlights the trends in the use of nitrogen-based moieties in drug design and the development of different potent and competent candidates against various diseases.

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Section: 23-triazolesmentioning

confidence: 99%

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications

et al. 2020

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“…However, only a few reports have described the structure–toxicity relationship of cephalosporins in detail, especially the toxicity of their impurities. In order to study structure–toxicity relationship of drugs, control the quality and safety of drugs, and speed up the drug development processes, we previously established the zebrafish embryo toxicity models ( Zhang et al, 2015 ; Han et al, 2017 ; Qian et al, 2017 ), cardiac toxicity models ( Han et al, 2015 ), and neurotoxicity models ( Chen et al, 2017 ) for the evaluation of drug toxicity, containing the active pharmaceutical ingredients and impurities’ toxicity assessment. Our previous studies on zebrafish embryo toxicity testing also suggested that both the C-7 and C-3 substituents of cephalosporins are toxic functional groups ( Zhang et al, 2013 ; Han et al, 2017 ), and the C-3 side chain of cefoperazone may induce bleeding ( Han et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral Effects of Cephalosporins: Assessment of Locomotors Activity, Motor and Sensory Development in Zebrafish

et al. 2018

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Most third- and fourth-generation cephalosporins, such as cefotaxime, cefmenoxime, cefepime, and cefpirome, contain an aminothiazoyl ring at the C-7 position. Drug impurity, which may be produced either during synthesis or upon degradation, can induce adverse effects. Various reports have indicated that neurotoxicity is a side effect of cephalosporin. In this study, we developed methods for assessing the free-swimming activities and behaviors in zebrafish larvae in response to continuous darkness and stimulation of light-to-dark photoperiod transition by chemical treatments. We also performed transcriptome analysis to identify differentially expressed genes (DEGs). Gene ontology analysis revealed that various processes related to nervous system development were significantly enriched by DEGs. We integrated 16 DEGs with protein–protein interaction networks and identified that neuroactive ligand–receptor interaction [e.g., λ-aminobutyric acid and glutamate receptor, metabotropic 1a (GRM1A)] pathway was regulated by the compounds. Our findings suggested that neurobehavioral effects mainly depend on the mother nucleus structure 7-aminocephalosporanic acid and the substitution at the C-3 position. In addition, gad2, or111-4, or126-3, grm1a, opn8c, or111-5, or113-2, and or118-3 may potentially be utilized as novel biomarkers for this class of cephalosporins, which causes neurotoxicity. This study provides neurological behavior, transcriptome, and docking information that could be used in further investigations of the structures and developmental neurotoxicity relationship of chemicals.

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“…Rule 5: For the structure characteristics, two common types of the cephalosporins, one is the C-7 side chain with an aminothiazoyl ring, while the other is the C-3 side chain with a methylthiotetrazole (MTT) group. Compared with other structures at the C-7 or C-3 side chains, the acute toxicity based on the structure of aminothixime or MTT is weak (Zhang et al, 2013; Qian et al, 2018).…”

Section: Resultsmentioning

confidence: 97%

“…We have recently systematically discussed the structure-toxicity relationship of cephalosporins via the zebrafish embryo toxicity test combined with computational chemistry and molecular docking techniques. This showed that the C-3 and C-7 side chains of cephalosporins are the main toxic functional groups leading to embryo toxicity, neurotoxicity, and cardiotoxicity of cephalosporins and impurities (Zhang et al, 2013; Han et al, 2017, Han B. et al, 2018, Han et al, 2018a; Qian et al, 2018). Therefore, the aim of this study was to systematically summarize the structure-toxicity relationships of cephalosporins and use software to predict the toxicity of ceftazidime impurities listed in Europium pharmacopeia (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities

et al. 2019

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To improve the quality control of drugs, we predicted the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of ceftazidime (CAZ) and its impurities via in silico methods. We used three types of quantitative structure-activity relationship and docking software for precise prediction: Discovery Studio 4.0, OECD QSAR Toolbox 4.1, Toxtree, and the pkCSM approach. The pharmacokinetics and toxicity of ceftazidime and impurity A (Δ-2-CAZ) are similar. The biological properties of impurity B (CAZ E -isomer) are different from CAZ. Therefore, we focused on drug stability to analyze impurity B. Impurities D and I have strong lipophilicity, good intestinal absorption, and poor excretion in the body. Impurity D is particularly neurotoxic and genotoxic. It is important to control the content of impurity D. The toxicity of impurity F is low, but the toxicity is enhanced when it becomes the C-3 side chain of CAZ and forms a quaternary amine group. We conclude that the beta-lactam ring of nucleus, the quaternary amine group at the C-3 side chain, and the acetates at the C-7 side chain of CAZ are the main toxic functional groups. Impurities B and D may be the genetic impurity in CAZ and may also have neurotoxicity. This in silico approach can predict the toxicity of other cephalosporins and impurities.

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Toxic effect prediction of cefatirizine amidine sodium and its impurities by structure-toxicity relationship of cephalosporins

Cited by 17 publications

References 13 publications

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications

Neurobehavioral Effects of Cephalosporins: Assessment of Locomotors Activity, Motor and Sensory Development in Zebrafish

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities

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