A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning

Abstract

Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier to reach the centrally inhibited enzymes. Many strategies have been evaluated over the years to overcome this weakness. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their in vitro reactivation efficacy on organophosphorus inhibited human acetylcholinesterase and the crystal structure of two compounds in complex with the enzyme. We also determined their protective index on intoxicated mice as well as their pharmacokinetics. In order to gain a fine understanding of our compounds trafficking through the blood-brain barrier, we evaluated the endothelial 2 permeability coefficients of our molecules with a human in vitro model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the active glucose transporter located at the blood-brain barrier.

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes

“…Such a disadvantage is associated with the hydrophilicity of the oxime and its permanent positive charge [10]. There are several main directions for improving oxime therapy: an active search for new, more effective reactivators [13][14][15][16] and the development of oxime formulations (including nanocarriers) that ensure their passage through biological barriers, i.e., BBB [17,18]. The second strategy has been widely studied and described in a previous review [19].…”

Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model

“…The BBB model used in this study consists in cultivating human primary endothelial cells derived from hematopoietic stem cells expressing CD34+ with human brain pericytes for 6 days. Endothelial cells acquire major BBB properties such as low paracellular permeability, expression of receptors and transporters, among others, and can be used to predict brain distribution of drugs or assess BBB physiology and neuroinflammation [ 54 , 55 , 56 ]. Under these conditions, endothelial cells are renamed brain-like endothelial cells (BLECs).…”

Novel uncharged triazole salicylaldoxime derivatives as potential acetylcholinesterase reactivators: comprehensive computational study, synthesis and in vitro evaluation

“…10,11 Furthermore, numerous uncharged oximes which have less potent in compared with the pralidoxime, obidoxime, and HI-6 were presented recent years. [12][13][14][15][16] In this work, considering the importance of the issue, several uncharged aldoximes were designed based on the parameters affecting the reactivating property and the ability to cross the BBB (Fig. 2).…”