Prodrugs

Ateş‐Alagöz, Zeynep; Adejare, Adeboye

doi:10.1016/b978-0-12-820007-0.00009-x

Cited by 2 publications

(1 citation statement)

References 117 publications

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“…Such benzoxazine derivatives possess characteristics ( e.g. , cell permeability, oral availability, in vitro stability, and straightforward synthesis) that suggest that they may act as prodrugs in mammals. − Furthermore, all identified hydrolysis products elute from our reversed-phase column prior to their respective parent compounds, suggesting that the products are more polar and therefore likely more mobile than their parent in aqueous systems. Structural similarity to chloroacetamide derivatives may also suggest analogous toxicological effects to those determined for products of chloroacetamide hydrolysis. ,− ,− More work is needed to assess the fate and effects of dichloroacetamide hydrolysis products, especially those of benoxacor that are most likely to form in environmentally relevant systems.…”

Section: Results and Discussionmentioning

confidence: 99%

Acid- and Base-Mediated Hydrolysis of Dichloroacetamide Herbicide Safeners

McFadden

Patterson

Reber

et al. 2021

Environ. Sci. Technol.

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Safeners are used extensively in commercial herbicide formulations. Although safeners are regulated as inert ingredients, some of their transformation products have enhanced biological activity. Here, to fill gaps in our understanding of safener environmental fate, we determined rate constants and transformation products associated with the acid- and base-mediated hydrolysis of dichloroacetamide safeners AD-67, benoxacor, dichlormid, and furilazole. Second-order rate constants for acid- (HCl) and base-mediated (NaOH) dichloroacetamide hydrolysis (2.8 × 10 –3 to 0.46 and 0.3–500 M –1 h –1 , respectively) were, in many cases (5 of 8), greater than those reported for their chloroacetamide herbicide co-formulants. In particular, the rate constant for base-mediated hydrolysis of benoxacor was 2 orders of magnitude greater than that of its active ingredient co-formulant, S -metolachlor. At circumneutral pH, only benoxacor underwent appreciable hydrolysis (5.3 × 10 –4 h –1 ), and under high-pH conditions representative of lime-soda softening, benoxacor’s half-life was 13 h—a timescale consistent with partial transformation during water treatment. Based on Orbitrap LC–MS/MS analysis of dichloroacetamide hydrolysis product mixtures, we propose structures for major products and three distinct mechanistic pathways that depend on the system pH and compound structure. These include base-mediated amide cleavage, acid-mediated amide cleavage, and acid-mediated oxazolidine ring opening. Collectively, this work will help to identify systems in which hydrolysis contributes to the transformation of dichloroacetamides, while also highlighting important differences in the reactivity of dichloroacetamides and their active chloroacetamide co-formulants.

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