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1.
Eur J Med Chem ; 258: 115593, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37390508

RESUMO

17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is a multifunctional mitochondrial enzyme and putative drug target for the treatment of various pathologies including Alzheimer's disease or some types of hormone-dependent cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physico-chemical properties. This led to the identification of several submicromolar inhibitors (IC50 ∼0.3 µM), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17ß-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren't found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Relação Estrutura-Atividade , 17-Hidroxiesteroide Desidrogenases , Encéfalo/metabolismo , Inibidores Enzimáticos/química
2.
Acta Medica (Hradec Kralove) ; 64(3): 145-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34779379

RESUMO

AIM: The comparison of neuroprotective and central reactivating effects of the oxime K870 in combination with atropine with the efficacy of standard antidotal treatment in tabun-poisoned rats. METHODS: The neuroprotective effects of antidotal treatment were determined in rats poisoned with tabun at a sublethal dose using a functional observational battery 2 h and 24 h after tabun administration, the tabun-induced brain damage was investigated by the histopathological evaluation and central reactivating effects of oximes was evaluated by the determination of acetylcholinesterase activity in the brain using a standard spectrophotometric method. RESULTS: The central reactivating efficacy of a newly developed oxime K870 roughly corresponds to the central reactivating efficacy of pralidoxime while the ability of the oxime HI-6 to reactivate tabun-inhibited acetylcholinesterase in the brain was negligible. The ability of the oxime K870 to decrease tabun-induced acute neurotoxicity was slightly higher than that of pralidoxime and similar to the oxime HI-6. These results roughly correspond to the histopathological evaluation of tabun-induced brain damage. CONCLUSION: The newly synthesized oxime K870 is not a suitable replacement for commonly used oximes in the antidotal treatment of acute tabun poisonings because its neuroprotective efficacy is only slightly higher or similar compared to studied currently used oximes.


Assuntos
Substâncias para a Guerra Química , Reativadores da Colinesterase , Organofosfatos , Oximas , Venenos , Compostos de Piridínio , Acetilcolinesterase , Animais , Antídotos/farmacologia , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/farmacologia , Oximas/farmacologia , Compostos de Pralidoxima , Compostos de Piridínio/farmacologia , Ratos , Ratos Wistar
3.
Molecules ; 22(7)2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28696367

RESUMO

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.


Assuntos
Substâncias para a Guerra Química/intoxicação , Reativadores da Colinesterase/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Intoxicação por Organofosfatos/tratamento farmacológico , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Atropina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Humanos , Masculino , Síndromes Neurotóxicas/tratamento farmacológico , Ratos Wistar , Trimedoxima/uso terapêutico
4.
Toxicol Mech Methods ; 27(3): 236-243, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28043192

RESUMO

The ability of two newly developed bispyridinium oximes (K920, K923) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the oxime K203 and trimedoxime using a functional observational battery (FOB). The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (130 µg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by FOB at 2 h after tabun administration. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment while one non-treated tabun-poisoned rat died within 2 h. Both newly developed oximes (K920, K923) combined with atropine were able to markedly decrease tabun-induced neurotoxicity in the case of sublethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity did not prevail the neuroprotective efficacy of trimedoxime and the oxime K203. Therefore, the newly developed oximes are not suitable for the replacement of currently available oximes (especially trimedoxime) in the treatment of acute tabun poisonings.


Assuntos
Reativadores da Colinesterase/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Trimedoxima/uso terapêutico , Animais , Reativadores da Colinesterase/química , Masculino , Estrutura Molecular , Fármacos Neuroprotetores/química , Síndromes Neurotóxicas/etiologia , Oximas/química , Compostos de Piridínio/química , Ratos Wistar , Trimedoxima/química
5.
Acta Medica (Hradec Kralove) ; 58(4): 135-43, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26960827

RESUMO

AIM: The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. METHODS: The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 µg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. RESULTS: All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. CONCLUSION: The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.


Assuntos
Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Sistema Nervoso/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Organofosfatos/toxicidade , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Trimedoxima/farmacologia , Animais , Atropina/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Intoxicação por Organofosfatos/tratamento farmacológico , Intoxicação por Organofosfatos/etiologia , Ratos , Ratos Wistar
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