Development and Evaluation of Novichokolysis-1: A Novel Synthetic Antidote for Rapid Neutralization and Neuroprotection against Novichok Nerve Agents

A newly designed molecule, tentatively named Novichokolysis-1, incorporates an advanced scaffold featuring a substituted macrocyclic structure appended with hydroxamic acid residues. This compound demonstrates the ability to neutralize Novichok-class nerve agents in aqueous buffer with half-lives as short as 2 minutes under physiological conditions (37°C, pH 7.4). The detoxification efficacy arises from the micromolar affinity of the macrocyclic moiety for the positively charged Novichok intermediates, coupled with an optimally positioned hydroxamic acid group. The reaction proceeds through phosphonylation of the hydroxamic acid, followed by an intramolecular rearrangement akin to a modified Lossen reaction, resulting in stoichiometric neutralization rather than catalytic turnover. Despite this limitation, Novichokophane-1 sets a new benchmark as a low-molecular-weight neutralizer for Novichok agents under mild physiological conditions, providing a promising lead structure for antidote development against these exceptionally toxic nerve agents.