RESUMO
A series of bis-pyridinium oximes connected by xylene linkers were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by nerve agent sarin and the data were compared with 2-PAM and obidoxime. Among the synthesized compounds, N,N'-p-xylene-bis-[(2,2'-hydroxyiminomethyl)pyridinium] dibromide (3c) was found to be the most potent reactivator for hAChE inhibited by sarin. The oxime 3c exhibited 45% regeneration of inhibited hAChE, in comparison to 34% and 24% regeneration by 2-PAM and obidoxime, respectively, at a concentration of 10(-3) M within 10 min. The higher reactivation efficacies of these oximes were attributed to their acid dissociation constants (pKa). The pKa values of all the oximes were determined spectrophotometrically and correlated with their observed reactivation potential. This method involving the in vitro reactivation of inhibited hAChE may be useful for the screening of new oximes as reactivators.
Assuntos
Inibidores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Sarina/antagonistas & inibidores , Acetilcolinesterase/metabolismo , Adulto , Algoritmos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/química , Reagentes de Ligações Cruzadas/química , Avaliação Pré-Clínica de Medicamentos/métodos , Membrana Eritrocítica/enzimologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Cinética , Masculino , Oximas/química , Compostos de Piridínio/química , Sarina/toxicidade , Xilenos/química , Xilenos/farmacologiaRESUMO
A series of bis-pyridinium oximes connected by methoxy alkane linkers were synthesized and their in vitro reactivation efficacy was evaluated against sarin-inhibited human AChE, and data were compared with 2-PAM and obidoxime. Among the synthesized compounds, 1,2-dimethoxy ethylene bis-[4,4'-(hydroxyiminomethyl) pyridinium] dichloride (4P-2) and 1,2-dimethoxy ethylene bis-[3,3'-(hydroxyiminomethyl) pyridinium] dichloride (3P-2) were found to be the most potent reactivators of human AChE inhibited by nerve agent sarin. The oximes 4P-2 and 3P-2 exhibited 41% and 36% regeneration of sarin-inhibited AChE, respectively, whereas 2-PAM showed 32% regeneration. The higher reactivation efficacy of the oximes was attributed to their acid dissociation constants (pK(a)). The pK(a) values of all the oximes were determined by UV-vis spectrophotometric method and correlated with their observed reactivation potential. Overall, the study reveals that the oxime 4P-2 may have therapeutic potential in the reactivation of human AChE inhibited by sarin.
Assuntos
Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Cloreto de Obidoxima/farmacologia , Compostos de Pralidoxima/farmacologia , Sarina/toxicidade , Adulto , Membrana Eritrocítica/enzimologia , Humanos , Técnicas In Vitro , MasculinoRESUMO
A series of novel bis-pyridinium oximes connected by bis-methoxymethyl benzene, 1,4-bis-methoxymethyl (cis)-but-2-ene and 1,4-bis-methoxymethyl but-2-yne linkers were synthesized and their in vitro reactivation efficacy was evaluated against diisopropyl phosphorofluoridate (DFP) inhibited acetylcholinesterase (AChE) and compared with the established antidote 2-PAM and obidoxime. However, the best reactivation was observed with the standard oxime 2-PAM. The reactivation efficacy of 1,3-dimethoxymethyl benzene bis-[4,4'-(hydroxyiminomethyl) pyridinium] dichloride (3d) and 1,4-dimethoxy but-2-ene bis-[4,4'-(hydroxyiminomethyl) pyridinium] dichloride (3g) was comparable with that of obidoxime, another standard antidote.
