Novel cholinesterase reactivators

Musílek, Kamil; Maliňák, Dávid; Nepovimová, Eugenie; Andrýs, Rudolf; Skarka, Adam; Kuča, Kamil

doi:10.1016/b978-0-12-819090-6.00069-6

Cited by 6 publications

(5 citation statements)

References 76 publications

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“…Acetylcholinesterase (AChE) is a serine hydrolase enzyme involved in the termination of nerve impulses by rapid hydrolysis of acetylcholine (neurotransmitter) [ 49 ]. However, present study demonstrated that the application of phytol or spores alone or in different proportions elicited concentration-dependent activities of AChE.…”

Section: Discussionmentioning

confidence: 99%

Toxin-Pathogen Synergy Reshaping Detoxification and Antioxidant Defense Mechanism of Oligonychus afrasiaticus (McGregor)

2018

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Current study reveals the likelihood to use pathogen and toxin mutually as an effective and eco-friendly strategy for Oligonychus afrasiaticus (McGregor) management, which could reduce toxicant dose and host killing time. Therefore, phytol and Beauveria bassiana in different proportions were evaluated to determine their effectiveness. Prior to ascertaining host mortality and defense mechanisms, we have recorded in vitro action of phytol using different concentrations (0.70, 1.40, 2.10, 2.80, and 3.50 mg/mL) against B. bassiana suspension. In vitro compatibility assays revealed that growth parameters (vegetative growth, sporulation, and viability) of B. bassiana were least affected by the action of phytol at all tested concentrations. Biological Index of B. bassiana exhibited compatibility with phytol allowed us to conduct Joint toxicity bioassays in which phytol and spores mixed in different proportions in order to attain maximum treatment effect in terms of high mortality at low concentration under short time. Results revealed that joint-application exhibited both synergistic (treatments with higher proportions of phytol), and antagonistic interaction (treatments with higher proportions of spores) interactions. Biochemical mechanisms involved in host antioxidant and detoxification response were explored by quantifying their respective enzymatic activities. Lethality of different treatments induced different patterns of detoxification enzymes including glutathione S-transferase (GST) and acetylcholinesterase (AchE). Overall, the least potent treatments (20% phytol:80% spores, and 40% phytol:60% spores) established in the current study induced relatively higher GST and AchE activities. On the other hand, the most potent treatment (80% phytol:20% spores) at its maximum concentration exhibited negligible relative GST and AchE activities. Antioxidant enzyme activities of CAT and SOD measured in the current study showed moderate to complex interaction might because of toxin-pathogen remarkable synergy. This study suggested that joint application of phytol with B. bassiana spores have shown tremendous acaricidal potential and found to be promising new strategy for controlling old world date mites.

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Section: Discussionmentioning

confidence: 99%

Toxin-Pathogen Synergy Reshaping Detoxification and Antioxidant Defense Mechanism of Oligonychus afrasiaticus (McGregor)

2018

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“…Acetylcholinesterase is a serine hydrolase [ 37 ]. Its principal biological function is to terminate the impulse transmissions at cholinergic synapses within the nervous system by rapidly hydrolyzing the neurotransmitter acetylcholine [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Phytochemical Properties and In Vitro Biological Activities of Phenolic Compounds from Flower of Clitoria ternatea L.

Tang

Chen

et al. 2022

Molecules

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Phenolic compounds from the flower of Clitoria ternatea L. (PCFCTL) were extracted using a high-speed shearing extraction technique and purified by AB-8 macroporous resins, and the phytochemical composition of the purified phenolic compounds from the flower of Clitoria ternatea L. (PPCFCTL) was then analyzed. Subsequently, its bioactivities including antioxidant properties, enzyme inhibitory activities, and antiproliferative activities against several tumor cell lines were evaluated. Results indicated that the contents of total phenolics, flavonoids, flavonols, flavanols, and phenolic acids in PPCFCTL were increased by 3.29, 4.11, 2.74, 2.43, and 2.96-fold, respectively, compared with those before being purified by AB-8 macroporous resins. The results showed PPCFCTL have significant antioxidant ability (measured by reducing power, RP, and ferric reducing antioxidant power method, FRAP) and good DPPH, ABTS+, and superoxide anion radical scavenging activities. They can also significantly inhibit lipase, α-amylase, and α-glucosidase. In addition, morphological changes of HeLa, HepG2, and NCI-H460 tumor cells demonstrated the superior antitumor performance of PPCFCTL. However, the acetylcholinesterase inhibitory activity was relatively weak. These findings suggest that PPCFCTL have important potential as natural antioxidant, antilipidemic, anti-glycemic and antineoplastic agents in health-promoting foods.

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“…Following the previously synthesized uncharged thienostilbene oximes as potential cholinesterase reactivators [17], a number of new oximes 1-21 were synthesized starting from the prepared phosphonium salts and corresponding aldehydes. The new oximes 1-3 (Figure 2) have the oxime group directly attached to the triazole ring and without the presence of the central double bond in the skeleton, while the other derivatives belong to heterostilbenes with an oxime group on the thiophene (4, 5, 7, 8, 18-21) or furan (6,(9)(10)(11)(12)(13)(14)(15)(16)(17) ring (Figure 3). Triazole oximes 1-3 were obtained (in 8-50% of isolated yields) from the triazole nitro aldehyde 24 (Scheme 1) either by direct conversion into an oxime (compound 3) or by conversion of nitro aldehyde in a reaction with amine into new substituted triazole aldehydes 22 and 23, and then by their conversion into an oxime (compounds 1 and 2).…”

Section: Synthesis Of New Uncharged Oximes 1-21mentioning

confidence: 99%

“…Consequently, most oximes developed to restore the activity of OP-AChE conjugates have been shown to be nearly ineffective in restoring OP-BChE activity. Moreover, although all of the reactivators tested so far showed a somewhat successful recovery of AChE catalytic activity inhibited by individual OP compounds [9,10], no oxime was an universal reactivator of various OP-AChE conjugates.…”

Section: Introductionmentioning

confidence: 97%

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Preprint

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New furan, thiophene and triazole oximes were synthesized through several-step reaction paths to investigate their potential for development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Acute OP poisoning is still a challenge in treating patients despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, are blocked by the OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to cholinergic crisis. Oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper we described the synthesis of 63 heterostilbene derivatives out of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents – sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in micromolar range, we identified several oximes as BChE or AChE selective inhibitors with a potential for drug development. Moreover, even oximes were poor reactivators of AChE, four heterocyclic derivatives reactivated the cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had comparable reactivation efficacy to the standard oxime HI-6. In silico analysis and molecular docking studies connected the kinetic data to the structural features of these oximes, and confirmed their productive interactions with the active site of the cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases like Alzheimer’s and Parkinson’s.

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Novel cholinesterase reactivators

Cited by 6 publications

References 76 publications

Toxin-Pathogen Synergy Reshaping Detoxification and Antioxidant Defense Mechanism of Oligonychus afrasiaticus (McGregor)

Toxin-Pathogen Synergy Reshaping Detoxification and Antioxidant Defense Mechanism of Oligonychus afrasiaticus (McGregor)

Phytochemical Properties and In Vitro Biological Activities of Phenolic Compounds from Flower of Clitoria ternatea L.

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

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