A HTS Assay for the Detection of Organophosphorus Nerve Agent Scavengers

Abstract

A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

“…Oximes are well-known antidotes for the treatment of OP poisonings. Their mode of action involves reactivation of the OP-inhibited acetylcholinesterase [29], yet previous work has also indicated that certain oximes are able to cleave OPs directly [30]. We show that some of our cyclodextrin derivatives efficiently reduce GF concentrations in solution under physiological conditions within seconds, thus preventing the OP from inhibiting AChE.…”

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

“…Since their introduction in 1981, [11][12][13][14][15][16][17] self-immolative spacers found applications in prodrugs, [4,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] sensors for chemicals or enzymes, [33][34][35][36][37][38][39][40][41] and for drug delivery. [26-28, 30-32, 42-46] Self-immolative spacers are also increasingly used in materials science, [47][48][49][50][51] where their unique feature of kinetically programmable auto-destruction provides unprecedented opportunities for sustainable matter management( i.e.…”

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

“…73 It is able to cleave the P-S bond of OP thereby yielding to the corresponding isoxazole analogue and non-toxic phosphonic adduct, thus through this preventing recapture phenomena. 74 The two uncharged oximes (35 and 36) as shown in Fig. 16, had a superior or similar in vitro ability to reactivate AChE inhibited by VX and tabun as compared to HI-6, obidoxime, TMB-4 and HLö À7.…”

“…45 Salicylaldoximes are known to be able to quickly cleave the P-S bond of organophosphates and avoid the re-inhibition phenomenon in their reactivation process, but salicylaldoximes lack reactivation ability due to their poor affinity for. 74 By using the dual binding site strategy, several PSLs were conjugated with salicylaldoximes as shown in Fig. 26 in order to increase their affinity.…”