In vitro anti-trypanosomal activity of synthetic nitrofurantoin-triazole hybrids against Trypanosoma species causing human African trypanosomosis

IF 2.1 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Anna Seetsi, David D. N'da, Nthatisi Molefe-Nyembe, Keisuke Suganuma, Tsepo Ramatla, Oriel Thekisoe
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引用次数: 0

Abstract

Human African trypanosomosis (HAT) which is also known as sleeping sickness is caused by Trypanosoma brucei gambiense that is endemic in western and central Africa and T. b. rhodesiense that is endemic in eastern and southern Africa. Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time-consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti-trypanosomal activity of nitrofurantoin-triazole hybrids against T. b. gambiense and T. b. rhodesiense parasites in vitro. This study screened 19 synthesized nitrofurantoin-triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin-Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n-alkyl hybrids influenced the increase in anti-trypanosomal activity against T. b. gambiense and T. b. rhodesiense. The short-chain n-alkyl hybrids showed decreased activity compared to the long-chain n-alkyl hybrids, with increased activity against both T. b. gambiense and T. b. rhodesiense. Incorporation of additional electron-donating substituents in some NFT hybrids showed increased anti-trypanosomal activity than to electron-withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti-trypanosomal activity against T. b. gambiense than T. b. rhodesiense. The NFT hybrid no. 16 was among the best performing hybrids against both T. b. gambiense (0.08 ± 0.04 μM) and T. b.rhodesiense (0.11 ± 0.06 μM), and its activity might be influenced by the introduction of fluorine in the para-position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10–100 times fold selective in their anti-trypanosomal activity. The synthesized NFT hybrids showed strong selectivity >10 to T. b. gambiense and T. b. rhodesiense, which indicates that they qualify from the initial selection criteria for potential hit drugs.

合成的硝基呋喃妥因-三唑混合物对引起人类非洲锥虫病的锥虫的体外抗锥虫活性。
人类非洲锥虫病(HAT)又称昏睡病,由流行于非洲西部和中部的布氏锥虫和流行于非洲东部和南部的罗得西亚锥虫引起。用于治疗 HAT 第一阶段的药物效果有限,第二阶段的药物据报道毒性大、价格昂贵、用药耗时,而且寄生虫对这些药物产生了抗药性。本研究的目的是评估硝基呋喃妥因-三唑混合物在体外对冈比亚锥虫和罗得西亚锥虫的抗锥虫活性。本研究筛选了 19 种合成的硝基呋喃妥因-三唑(NFT)混合物对两株人类锥虫的作用,并评估了它们对马丁达比牛肾细胞(MDBK)的细胞毒性。研究结果表明,一些正烷基杂交化合物链长和碳原子数的增加会影响其对冈比亚锥虫和罗得西亚锥虫抗锥虫活性的提高。与长链正烷基杂交体相比,短链正烷基杂交体的活性降低,而对冈比亚锥虫和罗得西亚锥虫的活性提高。在一些 NFT 杂交化合物中加入额外的电子供能取代基后,其抗锥虫活性比 NFT 杂交化合物中的电子吸收取代基更强。测试的 19 种 NFT 杂交种对冈比亚锥虫的抗锥虫活性均优于对罗得西亚锥虫的抗锥虫活性。第 16 号 NFT 杂交种对 T. b. gambiense(0.08 ± 0.04 μM)和 T. b. rhodesiense(0.11 ± 0.06 μM)的抗锥虫活性都是最好的,其活性可能受到在苄基环的对位上引入氟的影响。值得注意的是,本研究中的 NFT 杂交化合物对 MDBK 细胞显示出弱至中等的细胞毒性。本研究中的所有 NFT 杂交化合物的选择性指数值从 18 到大于 915 不等,这意味着它们在抗锥虫活性方面的选择性高达 10-100 倍。合成的NFT杂交种对冈比亚锥虫和罗得西亚锥虫的选择性大于10,这表明它们符合潜在靶向药物的初步筛选标准。
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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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