Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors—implications for early Myasthenia gravis treatment

Komloova, Marketa; Musílek, Kamil; Horova, Anna; Holas, Ondřej; Dohnal, Vlastimil; Gunn‐Moore, Frank; Kuča, Kamil

doi:10.1016/j.bmcl.2011.02.047

Cited by 30 publications

(19 citation statements)

References 32 publications

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“…The results from the docking calculations presented in this study are in general agreement with previous docking studies for non-oxime based, bis-pyridinium-inhibitors of cholinesterases, which predicted similar orientations within active site of AChE [23,24]. The low IC 50 values for compound 13 further suggest a characteristic dual binding site that was elucidated by in silico studies.…”

Section: Resultssupporting

confidence: 90%

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Šepsová

Karasová

Korábečný

et al. 2013

IJMS

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Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

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Section: Resultssupporting

confidence: 90%

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Šepsová

Karasová

Korábečný

et al. 2013

IJMS

Self Cite

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“…During recent years, numerous alternative substances with known anti-cholinesterase activity have been studied to evaluate their prophylactic efficacy in comparison with pyridostigmine bromide (28)(29)(30)(31). Some of them are already in clinical use or have been developed as potential therapeutics for other indications such as Myasthenia gravis (32) or Alzheimerʼs disease (AD) (33)(34).…”

Section: Discussionmentioning

confidence: 99%

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

Kassa

Korábečný

Nepovimová

2017

Acta Med. (Hradec Kralove, Czech Repub.)

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A B ST R AC T Aim: The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. Methods: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD 50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman. Results: 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. Conclusion: These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2. K E Y WO R D S soman; reversible inhibitors of acetylcholinesterase; antidotes; pharmacological pretreatment; mice

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“…In addition to wide-range use of AChE inhibitors towards AD, certain chemical classes of pesticides, such as organophosphates and carbamates, work by interfering or inhibiting irreversibly this enyzme, which is expressed in all invertebrate and vertebrate animals as a key enzyme of the cholinergic system [13,14]. Another treatment approach for utilization of AChE inhibitors has been stated against myasthenia gravis (MG) through inhibition of peripheral AChE [15,16], while AChE inhibitors are also considered as the third line drugs for the treatment of glaucoma, which have been described to be better agents with fewer local and systemic adverse effects [17]. …”

Section: Introductionmentioning

confidence: 99%

Nature: A Substantial Source of Auspicious Substances with Acetylcholinesterase Inhibitory Action

Orhan

2013

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Acetylcholinesterase (AChE) (EC 3.1.1.7) is an important enzyme that breaks down of acetylcholine in synaptic cleft in neuronal junctions. Inhibition of AChE is associated with treatment of several diseases such as Alzheimer’s disease (AD), myasthenia gravis, and glaucoma as well as the mechanisms of insecticide and anthelmintic drugs. Several AChE inhibitors are available in clinical use currently for the treatment of AD; however, none of them has ability, yet, to seize progress of the disease. Consequently, an extensive research has been going on finding new AChE inhibitors. In this sense, natural inhibitors have gained great attention due to their encouraging effects toward AChE. In this review, promising candidate molecules with marked AChE inhibition from both plant and animal sources will be underlined.

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Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors—implications for early Myasthenia gravis treatment

Cited by 30 publications

References 32 publications

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

Nature: A Substantial Source of Auspicious Substances with Acetylcholinesterase Inhibitory Action

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