Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

Carlos A. Valdez; Doris Lam; Victoria Lao; Alagu Subramanian; Heather A. Enright; Michael A. Malfatti; Nicholas A. Be; Mark L. Dreyer

doi:10.1016/j.tet.2023.133598

Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

Carlos A. Valdez^*, Doris Lam, Victoria Lao, Alagu Subramanian, Heather A. Enright, Michael A. Malfatti, Nicholas A. Be, Mark L. Dreyer

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

An improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated form of the hydroxyiminoacetic acid with yields ranging between 84 and 90% for primary amines, 65–75% for α-substituted and cyclic amines, while producing decent 41–48% yields for the sterically hindered α,α-substituted amines, that can not be obtained using the previously established method.

Original language	English
Article number	133598
Journal	Tetrahedron
Volume	144
DOIs	https://doi.org/10.1016/j.tet.2023.133598
State	Published - 7 Sep 2023
Externally published	Yes

Keywords

Amide-coupling
Blood brain barrier
Nerve agent
Oximes
Reactivators

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10.1016/j.tet.2023.133598

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title = "Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure",

abstract = "An improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated form of the hydroxyiminoacetic acid with yields ranging between 84 and 90% for primary amines, 65–75% for α-substituted and cyclic amines, while producing decent 41–48% yields for the sterically hindered α,α-substituted amines, that can not be obtained using the previously established method.",

keywords = "Amide-coupling, Blood brain barrier, Nerve agent, Oximes, Reactivators",

author = "Valdez, {Carlos A.} and Doris Lam and Victoria Lao and Alagu Subramanian and Enright, {Heather A.} and Malfatti, {Michael A.} and Be, {Nicholas A.} and Dreyer, {Mark L.}",

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year = "2023",

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doi = "10.1016/j.tet.2023.133598",

language = "English",

volume = "144",

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TY - JOUR

T1 - Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

AU - Valdez, Carlos A.

AU - Lam, Doris

AU - Lao, Victoria

AU - Subramanian, Alagu

AU - Enright, Heather A.

AU - Malfatti, Michael A.

AU - Be, Nicholas A.

AU - Dreyer, Mark L.

PY - 2023/9/7

Y1 - 2023/9/7

N2 - An improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated form of the hydroxyiminoacetic acid with yields ranging between 84 and 90% for primary amines, 65–75% for α-substituted and cyclic amines, while producing decent 41–48% yields for the sterically hindered α,α-substituted amines, that can not be obtained using the previously established method.

AB - An improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated form of the hydroxyiminoacetic acid with yields ranging between 84 and 90% for primary amines, 65–75% for α-substituted and cyclic amines, while producing decent 41–48% yields for the sterically hindered α,α-substituted amines, that can not be obtained using the previously established method.

KW - Amide-coupling

KW - Blood brain barrier

KW - Nerve agent

KW - Oximes

KW - Reactivators

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U2 - 10.1016/j.tet.2023.133598

DO - 10.1016/j.tet.2023.133598

M3 - Article

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SN - 0040-4020

VL - 144

JO - Tetrahedron

JF - Tetrahedron

M1 - 133598

ER -

Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

Abstract

Keywords

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