Jump to main content
Jump to site search

Issue 16, 2019
Previous Article Next Article

Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers

Author affiliations

Abstract

Despite their unique benefits imparted by their structure and reactivity, certain α-nucleophile molecules remain underexplored as chemical inactivators for the topical decontamination of reactive organophosphates (OPs). Here, we present a library of thirty α-nucleophile scaffolds, each designed with either a pyridinium aldoxime (PAM) or hydroxamic acid (HA) α-nucleophile core tethered to a polar or charged scaffold for optimized physicochemical properties and reactivity. These library compounds were screened for their abilities to catalyze the hydrolysis of a model OP, paraoxon (POX), in kinetic assays. These screening experiments led to the identification of multiple lead compounds with the ability to inactivate POX two- to four-times more rapidly than Dekon 139—the active ingredient currently used for skin decontamination of OPs. Our mechanistic studies, performed under variable pH and temperature conditions suggested that the differences in the reactivity and activation energy of these compounds are fundamentally attributable to the core nucleophilicity and pKa. Following their screening and mechanistic studies, select lead compounds were further evaluated and demonstrated greater efficacy than Dekon 139 in the topical decontamination of POX in an ex vivo porcine skin model. In addition to OP reactivity, several compounds in the PAM class displayed a dual mode of activity, as they retained the ability to reactivate POX-inhibited acetylcholine esterase (AChE). In summary, this report describes a rationale for the hydrophilic scaffold design of α-nucleophiles, and it offers advanced insights into their chemical reactivity, mechanism, and practical utility as OP decontaminants.

Graphical abstract: Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers

Back to tab navigation

Supplementary files

Publication details

The article was received on 28 Feb 2019, accepted on 26 Mar 2019 and first published on 26 Mar 2019


Article type: Paper
DOI: 10.1039/C9OB00503J
Citation: Org. Biomol. Chem., 2019,17, 3951-3963

  •   Request permissions

    Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers

    P. T. Wong, S. Bhattacharjee, J. Cannon, S. Tang, K. Yang, S. Bowden, V. Varnau, J. J. O'Konek and S. K. Choi, Org. Biomol. Chem., 2019, 17, 3951
    DOI: 10.1039/C9OB00503J

Search articles by author

Spotlight

Advertisements