Figueroa-Villar José Daniel, Petronilho Elaine C, Kuca Kamil, Franca Tanos C C
Medicinal Chemistry Group, Department of Chemical Engineering, Military Institute of Engineering, 22270- 090, Rio de Janeiro, Brazil.
Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Králové 50003, Czech Republic.
Curr Med Chem. 2021;28(7):1422-1442. doi: 10.2174/0929867327666200425213215.
Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the Organophosphates (OPs) capable of restricting the enzyme Acetylcholinesterase (AChE), which in turn, controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today, it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relatively long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the Blood-Brain Barrier (BBB). This fact compromises their capacity to reactivating AChE inside the nervous system.
We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds.
Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents' development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs.
To develop these new agents, the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics), organic synthesis, spectroscopic methodologies, biology, biochemical and biophysical information, medicinal chemistry, pharmacology and toxicology, is necessary.
神经毒性化学战剂可被归类为对人类最危险的一些化学物质。其中最有效的制剂是能够抑制乙酰胆碱酯酶（AChE）的有机磷酸酯（OPs），而乙酰胆碱酯酶反过来又控制神经冲动的传递。当AChE被OPs抑制时，其再活化通常可通过阳离子肟来实现。然而，直到如今，尚未开发出一种通用的防御剂，它对被多种现有神经毒性OPs中的任何一种抑制的AChE都具有完全有效的再活化活性。因此，在治疗被OPs中毒的人员之前，有必要确定用于污染的神经毒性化合物，以便选择最有效的肟。不幸的是，这项任务通常需要较长时间，从而增加了死亡的可能性。阳离子肟穿透血脑屏障（BBB）的能力也有限。这一事实损害了它们在神经系统内再活化AChE的能力。
我们对当今科学文献中有关OPs的数据进行了全面搜索，以涵盖在开发针对这些化合物的有效解毒剂的研究中仍然面临的所有主要缺点。
因此，这篇关于神经毒性OPs和AChE再活化的综述为新型药剂的开发提供了见解。最令人期待的防御剂是一种无毒且能有效再活化被所有神经毒性OPs抑制的AChE的分子。
为了开发这些新型药剂，有必要应用不同的科学研究领域，特别是作为计算科学（计算机模拟、对接和动力学）、有机合成、光谱方法、生物学、生化和生物物理信息、药物化学、药理学和毒理学的理论程序。
