Background: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- buněčné linie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- HeLa buňky MeSH
- knihovny malých molekul chemie farmakologie MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- nervová bojová látka škodlivé účinky MeSH
- soman škodlivé účinky MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The reactivating and therapeutic efficacy of two newly developed oximes (K305, K307) was compared with the oxime K203 and trimedoxime using in vivo methods The study determining percentage of reactivation of tabun-inhibited acetylcholinesterase in the peripheral as well as central nervous system (diaphragm, brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed oximes is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While the ability of the oxime K305 to reduce acute toxicity of tabun in mice is approaching to the therapeutic efficacy of trimedoxime, the ability of another novel bispyridinium oxime K307 to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and the oxime K203. Thus, the reactivating and therapeutic efficacy of both examined newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
- MeSH
- acetylcholinesterasa účinky léků MeSH
- antidota aplikace a dávkování farmakologie toxicita MeSH
- atropin aplikace a dávkování farmakologie toxicita MeSH
- bránice enzymologie MeSH
- modely u zvířat MeSH
- mozek enzymologie účinky léků MeSH
- mutantní kmeny myší MeSH
- nervová bojová látka farmakologie chemie toxicita MeSH
- organofosfáty farmakologie toxicita MeSH
- oximy * farmakologie chemie klasifikace MeSH
- potkani Wistar MeSH
- reaktivátory cholinesterázy aplikace a dávkování farmakologie toxicita MeSH
- trimedoxim farmakologie chemie klasifikace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.
- MeSH
- acetylcholinesterasa chemie MeSH
- amyloidní beta-protein antagonisté a inhibitory chemie MeSH
- aniliny chemická syntéza chemie MeSH
- cholinesterasové inhibitory chemická syntéza chemie MeSH
- kinetika MeSH
- látky ovlivňující centrální nervový systém chemická syntéza chemie MeSH
- lidé MeSH
- rekombinantní proteiny chemie MeSH
- simulace molekulového dockingu MeSH
- takrin analogy a deriváty MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.
- MeSH
- acetylcholinesterasa chemie MeSH
- antioxidancia chemická syntéza farmakologie toxicita MeSH
- cholinesterasové inhibitory chemická syntéza farmakologie toxicita MeSH
- chromany (dihydrobenzopyrany) chemie farmakologie toxicita MeSH
- hematoencefalická bariéra MeSH
- hepatocyty účinky léků MeSH
- injekce intramuskulární MeSH
- jaterní mikrozomy účinky léků metabolismus MeSH
- katalýza MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- potkani Wistar MeSH
- racionální návrh léčiv MeSH
- scavengery volných radikálů chemická syntéza farmakologie MeSH
- takrin chemie farmakologie toxicita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.
- MeSH
- antidota terapeutické užití MeSH
- atropin farmakologie MeSH
- chemické bojové látky toxicita MeSH
- cholinesterasové inhibitory toxicita MeSH
- injekce intramuskulární MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- myši MeSH
- organofosfáty toxicita MeSH
- oximy terapeutické užití MeSH
- parasympatolytika farmakologie MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny terapeutické užití MeSH
- reaktivátory cholinesterázy terapeutické užití MeSH
- trimedoxim terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.
- MeSH
- acetylcholinesterasa krev chemie metabolismus MeSH
- antagonisté muskarinových receptorů terapeutické užití MeSH
- antidota terapeutické užití MeSH
- atropin terapeutické užití MeSH
- bránice účinky léků enzymologie MeSH
- cholinesterasové inhibitory aplikace a dávkování chemie toxicita MeSH
- kombinovaná farmakoterapie MeSH
- mozek účinky léků enzymologie MeSH
- myši MeSH
- neurony účinky léků enzymologie MeSH
- neurotoxické syndromy krev farmakoterapie etiologie metabolismus MeSH
- obidoxim chlorid terapeutické užití MeSH
- outbrední kmeny zvířat MeSH
- oximy terapeutické užití MeSH
- potkani Wistar MeSH
- proteiny nervové tkáně agonisté antagonisté a inhibitory metabolismus MeSH
- pyridinové sloučeniny terapeutické užití MeSH
- reaktivátory cholinesterázy terapeutické užití MeSH
- sarin aplikace a dávkování antagonisté a inhibitory toxicita MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The potency of two novel oximes (K920, K923) to reactivate tabun-inhibited acetylcholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited peripheral acetylcholinesterase (diaphragm) and central acetylcholinesterase (brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed oximes is lower than the reactivating potency of the oxime K203 and trimedoxime. The therapeutic efficacy of both newly developed oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun in mice was lower compared to the oxime K203 and trimedoxime. All differences in reactivating efficacy of oximes and different protective ratios were found for selected doses of oximes used in this study. Based on the results obtained, we can conclude that the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning. The conclusion is only relevant for the experimental animals used in this study because of remarkable species differences in reactivating properties of oximes.
- MeSH
- atropin aplikace a dávkování MeSH
- chemické bojové látky otrava MeSH
- cholinesterasové inhibitory terapeutické užití MeSH
- hodnocení léčiv MeSH
- kombinovaná terapie MeSH
- krysa rodu rattus MeSH
- myši MeSH
- organofosfáty toxicita MeSH
- otrava organofosfáty farmakoterapie MeSH
- oximy terapeutické užití MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny terapeutické užití MeSH
- reaktivátory cholinesterázy terapeutické užití MeSH
- terapeutická ekvivalence MeSH
- trimedoxim terapeutické užití MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
This paper describes preparation and in vitro evaluation of 19 compounds related to the selective experimental cholinesterase inhibitor BW284c51. The novel compounds were prepared as fragments of parent molecule BW284c51 and evaluated on the model of human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase. The IC₅₀ values of the prepared compounds were compared to the parent molecule BW284c51. None of the compounds was superior to the parent drug, but two BW284c51 fragments showed promising hAChE inhibition in µM scale and improved selectivity. These two fragments were further subjected to the molecular modelling study and their enzyme interactions were rationalized. The structure-activity relationship of the prepared series was stated.
- MeSH
- acetylcholinesterasa chemie MeSH
- benzenaminium, 4,4'-(3-oxo-1,5-pentandiyl)bis(N,N-dimethyl-N-2-propenyl-), dibromid chemie MeSH
- butyrylcholinesterasa chemie MeSH
- cholinesterasové inhibitory chemická syntéza chemie MeSH
- katalytická doména MeSH
- kvartérní amoniové sloučeniny chemická syntéza chemie MeSH
- lidé MeSH
- rekombinantní proteiny chemie MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
