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首页> 外文期刊>Journal of Tropical Medicine >Chemical Synthesis, Efficacy, and Safety of Antimalarial Hybrid Drug Comprising of Sarcosine and Aniline Pharmacophores as Scaffolds
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Chemical Synthesis, Efficacy, and Safety of Antimalarial Hybrid Drug Comprising of Sarcosine and Aniline Pharmacophores as Scaffolds

机译：化学合成，疗效和抗疟杂化药物的安全性，包括肌肉和苯胺药物作为支架

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Malaria is a disease caused by protozoans transmitted to humans by infected female Anopheles mosquitoes. According to the WHO report of 2015, there were 214 million cases of malaria with 438,000 deaths worldwide. Ninety percent of world’s malaria cases occur in Africa, where the disease is recognized as a serious impediment to economic and social development. Despite advancement in malaria research, the disease continues to be a global problem, especially in developing countries. Currently, there is no effective vaccine for malaria control. In addition, although there are effective drugs for treatment of malaria, this could be lost to the drug resistance in different Plasmodium species. The most lethal form is caused by P. falciparum which has developed resistance to many chemotherapeutic agents and possibly to the current drugs of choice. Reducing the impact of malaria is a key to achieving the sustainable development goals which are geared toward combating the disease. Covalent bitherapy is a rational and logical way of drug design which entails joining a couple of molecules with individual intrinsic action into a unique agent, hence packaging dual activity into one hybrid. This suggests the need to develop new antimalarial drugs that are effective against malaria parasites based on the new mode of action, molecular targets, and chemical structures. In silico studies have shown that sarcosine is able to bind to unique plasmodia proteins (P. falciparum ATCase), whereas aniline can be a ligand to target protein (enoyl acyl carrier protein reductase), hence suppressing the progression of the disease. The main objective of this study was to synthesize and determine the efficacy and safety of antiplasmodial hybrid drug comprising the sarcosine and aniline derivative for management of plasmodial infections. The hybrid drug was synthesized by adding thionyl chloride to sarcosine to form acyl chloride which was then added to aniline to form sarcosine-aniline hybrid molecule. The IC50 of sarcosine-aniline hybrid was 44.80?±?4.70?ng/ml compared with that of aniline derivative which was 22.86?±?1.26?ng/ml. The IC50 of control drugs was 2.63?±?0.38?ng/ml and 5.69?±?0.39?ng/ml for artesunate and chloroquine, respectively. There was a significant difference between IC50 of sarcosine-aniline hybrid and aniline derivative (p0.05). There was also a significant difference between sarcosine-aniline hybrid and standard drugs used to treat malaria including artesunate and chloroquine (p0.05). The ED50 of sarcosine-aniline hybrid drug was 6.49?mg/kg compared with that of aniline derivative which was 3.61?mg/kg. The ED50 of control drugs was 3.56?mg/kg, 2.94?mg/kg, and 1.78?mg/kg for artesunate-aniline hybrid, artesunate, and chloroquine, respectively. There was a significant difference (p0.05) between ED50 of sarcosine-aniline hybrid and both controls such as aniline derivative, artesunate, artesunate-aniline hybrid, and chloroquine. Cytotoxicity results revealed that sarcosine-aniline hybrid was safe to vero cells with a CC50 of 50.18?±?3.53?μg/ml. Sarcosine-aniline hybrid was significantly less toxic compared with artesunate, chloroquine, and doxorubicin. Sarcosine-aniline hybrid was efficacious and safe to mice. Therefore, covalent bitherapy should be used in drug development for drug resistance mitigation.
机译：疟疾是由受感染的女性anopheles蚊子传播给人类的原生动物引起的疾病。据世界卫生组织2015年报告称，全球有21400万例疟疾病例，全球438,000人死亡。在非洲出现九十百分之九十的疟疾病例，该疾病被认为是对经济和社会发展的严重障碍。尽管疟疾研究进展，但疾病仍然是全球性问题，特别是在发展中国家。目前，疟疾控制没有有效的疫苗。此外，虽然有有效的药物治疗疟疾，但这可能会损失不同疟原虫物种的耐药性。最致命的形式是由P. Falciparum引起的，这对许多化学治疗剂产生了抗性并且可能是目前的选择性药物。减少疟疾的影响是实现旨在实现疾病的可持续发展目标的关键。共价斑穴是药物设计的理性和逻辑方式，需要将几个分子与个体内在作用加入一个独特的药剂，因此将双重活性包装成一个杂种。这表明需要开发新的抗疟药药物，该药物基于新的作用方式，分子靶标和化学结构的新模式有效地对抗疟疾寄生虫。在硅研究中表明，肌氨酸能够与独特的疟原虫蛋白质（P. falciparumatascatian）结合，而苯胺可以是靶蛋白（Enoyl酰基载体蛋白质还原酶）的配体，因此抑制了疾病的进展。本研究的主要目的是合成并确定抗血液杂交药物的疗效和安全性，所述抗血液杂交药物包含肌肉氨酸和苯胺衍生物，用于治疗疟原虫感染。通过将亚硫酰氯加入Sarcosine以形成酰氯来合成杂种药物，然后将其加入到苯胺中以形成嗜酸盐 - 苯胺杂交分子。与苯胺衍生物相比，Sarcosine-苯胺杂交物的IC50为44.80？±4.70≤Ng/ ml，其为22.86Ω·α≤1.26≤1.26≤1.26μg/ ml。对照药的IC50分别为2.63°+0.38Ω·ng / ml和5.69？±0.39？ng / ml，分别用于青蒿琥酯和氯喹。 Sarcosine-苯胺杂交和苯胺衍生物的IC50有显着差异（P <0.05）。 Sarcosine-苯胺杂交和标准药物之间的含有显着差异，用于治疗疟疾，包括蒿属和氯喹（P <0.05）。与苯胺衍生物的苯胺 - 苯胺杂交药的ED50为6.49μm≤mg/ kg，苯胺衍生物为3.61Ω·mg / kg。对照药物的ED50分别为3.56Ω·mg / kg，2.94×mg / kg和1.78×mg / kg，分别用于青蒿琥酯 - 苯胺杂交，artesunate和氯喹。 Sarcosine-苯胺杂交的ED50和苯胺衍生物，艺术品，艺术品，芳烯酸酯 - 苯胺杂交和氯喹等对照之间存在显着差异（P <0.05）。细胞毒性结果表明，Sarcosine-苯胺杂交体对Vero细胞的安全性，CC50为50.18〜±3.53Ω·μg/ ml。与青蒿酸盐，氯喹和多柔比星相比，Sarcosine-苯胺杂交毒性显着较小。 Sarcosine-苯胺杂交对小鼠有效和安全。因此，应在药物发育中用于耐药性缓解的。

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