Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains

IF 2.1 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Ana Carolina Justino de Araújo, Priscilla Ramos Freitas, Isaac Moura Araújo, Gustavo Miguel Siqueira, João Arthur de Oliveira Borges, Daniel Sampaio Alves, Gustavo Marinho Miranda, Igor José dos Santos Nascimento, João Xavier de Araújo-Júnior, Edeildo Ferreira da Silva-Júnior, Thiago Mendonça de Aquino, Francisco Jaime Bezerra Mendonça Junior, Emmanuel Silva Marinho, Helcio Silva dos Santos, Saulo Relison Tintino, Henrique Douglas Melo Coutinho
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引用次数: 0

Abstract

Background

Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic.

Objectives

The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines.

Methods

The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets.

Results

There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action.

Conclusions

Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

合成噻嗪类药物对多重耐药菌株的增强抗生素活性及吸收、分布、代谢、排泄和毒性(ADMET)分析。
背景:噻二嗪是一种结构上含有两个氮原子和一个硫原子的杂环化合物。这些合成分子具有一些相关的药理活性,如抗真菌、抗菌和抗寄生虫。目的:本研究旨在评价噻二嗪类化合物可能的体外和体内相互作用。方法:采用高效液相色谱法对化合物进行初步合成、纯化和确证。采用多重耐药菌株金黄色葡萄球菌10和铜绿假单胞菌24对噻二嗪衍生物的直接和修饰抗生素活性进行了评价。ADMET试验(吸收、分布、代谢、排泄和毒性)评估了化合物对数千种被认为是生物活性靶标的大分子的影响。结果:在化学合成中,在结构的一个芳香环的碳4或碳3中添加了不同的离子,确保了产物的可变性。有可能观察到的结果表明,这些化合物可能通过环加氧酶2机制起作用,除了参与炎症反应外,还通过帮助钠重吸收起作用。噻二嗪类似物中存在的胺基赋予物质亲水性,但由于其他配体的改变和插入,这一主要特性已被改变。类似物的特性通常允许容易的肠道吸收,减少可能的肝毒性作用,并使可能的神经和抗炎作用。抑菌活性试验显示有轻微的直接作用,主要是IJ23类似物的作用。一些化合物能够改变抗生素庆大霉素和诺氟沙星对多重耐药菌株的作用,表明可能存在协同作用。结论:在本研究获得的所有结果中,噻二嗪类似物作为可能的辅助药物在抗菌、抗炎和低毒的神经作用方面的相关性是明确的。不排除需要进一步的研究来验证这些影响在生物体中的作用。
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来源期刊
CiteScore
5.30
自引率
6.90%
发文量
111
审稿时长
6-12 weeks
期刊介绍: Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.
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