RSC Advances View Article Online REVIEW View Journal | View Issue Recent developments on oximes to improve the blood brain barrier penetration for the treatment of Cite this: RSC Adv., 2020, 10, 4465 organophosphorus poisoning: a review Mohd Nor Faiz Norrrahim,a Mas Amira Idayu Abdul Razak,b Noor Aisyah Ahmad Shah,c Herdawati Kasim,c Wan Yusmawati Wan Yusoff,c Norhana Abdul Halim,c Siti Aminah Mohd Nor,c Siti Hasnawati Jamal,c Keat Khim Ong,ac Wan Md Zin Wan Yunus,d Victor Feizal Knight a and Noor Azilah Mohd Kasim *ac Organophosphorus (OP) compounds are highly toxic synthetic compounds which have been used as pesticides and developed as warfare nerve agents. They represent a threat to both military and civilian populations. OP pesticides affect the nervous system and are thought to have caused at least 5 million deaths since their discovery in the 1930s. At present the treatment of OP nerve agent poisoning commonly involves the use of parenteral oximes. However, the blood brain barrier (BBB) remains Creative Commons Attribution-NonCommercial 3.0 Unported Licence. a challenge in the delivery of oximes to the central nervous system (CNS). This is because almost all macromolecule drugs (including oximes) fail to pass through the BBB to reach the CNS structures. The presence of a permanent cationic charge in oximes has made these compounds inefficient in crossing the BBB. Thus, oximes are unable to reactivate acetylcholinesterase (AChE) in the CNS. Using current structural and mechanistic understanding of the BBB under both physiological and pathological conditions, it becomes possible to design delivery systems for oximes and other drugs that are able to Received 21st October 2019 cross the BBB effectively. This review summarises the recent strategies in the development of oximes Accepted 16th December 2019 which are capable of crossing the BBB to treat OP poisoning. Several new developments using oximes DOI: 10.1039/c9ra08599h are reviewed along with their advantages and disadvantages. This review could be beneficial for future This article is licensed under a rsc.li/rsc-advances directions in the development of oxime and other drug delivery systems into the CNS. Open Access Article. Published on 27 January 2020. Downloaded 10/1/2021 2:18:24 PM. aResearch Centre for Chemical Defence, Universiti Pertahanan Nasional Malaysia, cDepartment of Chemistry and Biology, Centre for Defence Foundation Studies, Kem Perdana Sungai Besi, 57000 Kuala Lumpur, Malaysia. E-mail: azilah@upnm. Universiti Pertahanan Nasional Malaysia, Kem Perdana Sungai Besi, 57000 Kuala edu.my; Fax: +603-90514291; Tel: +6013-3906789 Lumpur, Malaysia bDepartment of Defence Science, Faculty of Defence Science and Technology, dResearch Centre for Tropicalisation, Universiti Pertahanan Nasional Malaysia, Kem Universiti Pertahanan Nasional Malaysia, Kem Perdana Sungai Besi, 57000 Kuala Perdana Sungai Besi, 57000 Kuala Lumpur, Malaysia Lumpur, Malaysia Mohd Nor Faiz Norrrahim has Wan Md Zin Wan Yunus is a PhD in Nanotechnology. He is working as a Professor at the working as a post-doctoral National Defence University of fellow at the Research Center for Malaysia. His research interests Chemical Defence, National are materials, chemical Defence University of Malaysia. synthesis, nanomaterials, poly- His research interests are nano- mers, advanced materials, and technology, organic chemistry, biocomposites. materials science, biopolymers and biotechnology. This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,4465–4489 | 4465 View Article Online RSC Advances Review Introduction on efficacy testing of experimental oximes claimed that the oximes have difficulty in reactivating the AChE located in the 7,9 Organophosphorus (OP) compounds were rst developed as CNS. In addition to this potential lethality of this over- insecticides in the 1930s before being later developed as stimulation, of great concern also is the fact that AChE inhibi- a weapon of war. OP poisoning has been a frequent cause of tion by OPs in the CNS can lead to seizures occurring from an admission of people to hospitals and Intensive Care Units (ICU) excess of ACh-mediated activation of the excitotoxic gluta- in developing countries.1 OP poisoning causes about 3 000 000 matergic pathways which can prolong seizures and thus lead to 17,18 acute intoxications annually, 300 000 of which lead to fatali- brain damage. It has also been suggested that exposure to ties.2 OPs that were developed as chemical warfare nerve agents sub-lethal doses of OP can dramatically impact CNS mediated (CWAs) are all highly toxic and dangerous.3–5 OP nerve agents behavioural attributes such as decreased ability to perform 12 have been used and are most likely to be used in the future by tasks. All the currently available oxime reactivators are terrorists and dictators around the world because of their rela- quaternary oximes. Quaternary pyridinium aldoximes have tively easy synthesis and availability of suitable delivery relatively contained permanent positive charges which provides ff systems.6 Warfare and terrorist use of CWAs include the Aum little or no protection against the neurological e ects of OP Shinrikyo terrorist attack in the Tokyo subway in 1995, the exposure in the CNS due to their poor blood brain barrier (BBB) 19,20 1980–1988 Iraq–Iran war where Iraq reportedly used nerve penetration. agents against Iranian troops and later on Kurd civilians and The BBB is a highly selective permeable membrane system the murder of a family member of the North Korea Leader, Kim responsible for maintaining homeostasis by regulating the Jong Nam on February 2017 in Kuala Lumpur.7–9 Despite chemical environment, immune cell transport, and the entry of 21,22 international efforts aimed at regulating and lessening the use toxins into the CNS. The success rate of BBB penetration for 23–25 of these environmentally toxic compounds, more than 100 drugs such as oximes is very low. There are several limita- different OP compounds are still being used intensively as tions imposed by the BBB which includes molecule size, ffl Creative Commons Attribution-NonCommercial 3.0 Unported Licence. pesticides, with only unreliable or sporadic monitoring of the hydrophilicity, polarity, substrate speci city, and active e ux 26–29 environment and workers involved in their use. mechanisms. These properties however, are lacking in most ff OP poisonings involve the inhibition of enzyme acetylcho- oxime structures. Therefore, the development of e ective linesterase (AChE) that physiologically plays an important role measures to counteract the problem of BBB penetration by in neurotransmission.10–12 This will result in the over- oximes in order to treat OP poisoning remains a challenging stimulation of cholinergic receptors by acetylcholine (ACh) issue. Investigations to develop oximes that can penetrate which will occur in the peripheral nervous system, central through the BBB has been reported as one of the current areas 30 nervous system (CNS) and at neuromuscular junctions causing of research interest in the treatment of OP poisonings. To the cholinergic crises, seizures, respiratory arrest, bronchorrhea best of our knowledge, there is lack of papers that discuss on the This article is licensed under a and ultimately lead to fatal consequences.13,14 Current treat- approaches formulated towards BBB penetration of oximes for ment of OP poisonings consists of the administration of OP poisoning treatment. a muscarinic receptor antagonist (e.g. atropine), which coun- Open Access Article. Published on 27 January 2020. Downloaded 10/1/2021 2:18:24 PM. teracts the excessive muscarinic stimulation, and also the Organophosphorus nerve agents administration of an AChE reactivator (pyridinium oximes), which reactivates the physiological function of AChE.3,15,16 The G-series and V-series are the two major classes of OP nerve Successful reactivation of AChE can terminate over- agents.31 Tabun was the rst of the G-series OP nerve agents stimulation of the muscarinic and nicotinic receptors by ACh developed in 1936 by a German scientist named Gerhard and thus prevent further neurotoxicity. However, several reports Schroeder.32 This compound was developed as a pesticide for the chemical manufacturer IG Farbenindustrie. Its lethal Victor Feizal Knight is working Noor Azilah Mohd Kasim is as a Professor at the National working as an Associate Defence University of Malaysia. Professor at the Department of He is also the director of the Defence Science, National Research Center for Chemical Defence University of Malaysia. Defence. His expertise is military Her research interests are medicine and health, and organic chemistry, chemistry, biomedical and chemical materials science and sensors defence. development. 4466 | RSC Adv.,2020,10,4465–4489 This journal is © The Royal Society of Chemistry 2020 View Article Online Review RSC Advances properties lead to its use as a weapon against humans as well as hydrolysis of ACh into choline and acetic acid. However, inhi- for the development of other weaponised OPs. These were the bition of AChE function leads to excessive amount of ACh, G-series nerve agents and the letter ‘G’ referred to agents accumulating at the neuron synapse. This increased amount of developed by the Germans. Later on, by the end of World War II, ACh causes several signs and symptoms of poisoning as German scientists had developed several other OP nerve agents described in the introduction section. The mechanism of such as tabun (GA), soman (GD), sarin (GB) and cyclosarin (GF) toxicity is identical to the one observed in OP exposure.35 which were synthesised in certain quantities that could be used The mechanism of inhibition of AChE by OP nerve agents is as weapons of war. Aer World War II, the V-series of OP nerve shown in Fig. 2(B). This inhibition action involves successive agents, with the initial agent being known as VX was discovered chemical events. The rst is phosphorylation of the active site by Dr Ranajit Ghosh in 1949, a chemist working in England.