Towards catch-up therapy: evaluation of nucleophilic active pharmaceutical ingredients for the treatment of percutaneous VX poisoning, in-vial and in-vitro studies

Acetohydroxamic acid salts: mild, simple and effective degradation reagents to counter Novichok nerve agents

“…Recently, following a thorough investigation, we found that a-nucleophiles like hydroxamic acid salts degrade VX effectively on time scale of a few minutes. 30 Moreover, we also demonstrated the therapeutic value and dermal and systemic safety of one of our lead lotions as a "catch-up therapy" against dermal intoxication by VX in live pigs. 31 Decades ago, these types of nucleophiles were already shown to effectively hydrolyze G-agents like sarin.…”

“…This current study commenced by examining the Novichok decontamination activity of four selected hydroxamic acid derivatives, which were previously shown to effectively degrade VX and its simulant. 30 A-232, was chosen as the rst agent to be examined. The hydroxamic acids, i.e., acetohydroxamic, salicylhydroxamic, caprylhydroxamic and bufexamac (Table 1) were converted to the various salts using different inorganic and organic bases.…”

“…Surprisingly, the degradation of A-232 using the AHA Na salt (1a) in a mPEG/H 2 O 9 : 1 mixture, a solution used in the RSDL lotion, proceeded extremely slowly with t 1/2 of more than 300 min, while under the same conditions VX was degraded much faster, with a t 1/2 value of 7.45 min. 30 The more hydrophobic hydroxamic acid salts, Caprylhydroxamate 3a and Bufexamac 4a, were found to have poor solubility in DMSO and its mixtures with water, therefore the reaction of these derivatives with A-232 was performed in a PG/ H 2 O 1 : 1 mixture to show that they are less active than inorganic salts of 1 and 2, degrading A-232 with a t 1/2 of ∼20 min.…”

“…Surprisingly, the degradation of A-232 using the AHA Na salt ( 1a ) in a mPEG/H 2 O 9 : 1 mixture, a solution used in the RSDL lotion, proceeded extremely slowly with t 1/2 of more than 300 min, while under the same conditions VX was degraded much faster, with a t 1/2 value of 7.45 min. 30…”

“…This current study commenced by examining the Novichok decontamination activity of four selected hydroxamic acid derivatives, which were previously shown to effectively degrade VX and its simulant. 30 A-232, was chosen as the first agent to be examined. The hydroxamic acids, i.e.…”