Relationships Between the Chemical Structure and Pharmacological Activity in a Series of Synthetic Quinuclidine Derivatives

Mashkovsky, M. D.; Yakhontov, L. N.

doi:10.1007/978-3-0348-7068-9_6

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…4 BZ is also classed as a glycolate with reference to the chemically substituted glycol component of the molecule. Many structural modifications of glycolates have been made and the structural changes have been correlated with the biological activity of the molecule.…”

Section: Other Literature On Bzmentioning

confidence: 99%

Surviving the impossible: The long March from Srebrenica. An investigation of the possible use of chemical warfare agents

Hay

1998

Medicine, Conflict and Survival

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In July 1995 about 15,000 people attempted to walk from the enclave of Srebrenica to free territory in Bosnia. Two-thirds were captured or killed. Many of the remainder experienced hallucinations on the march, leading them to believe they were the victims of chemical weapons. This paper reports extended structured interviews with 35 survivors, including three doctors, carried out a year later on behalf of Human Right Watch. The literature on the likeliest CW agent, 3-quinuclidinyl benzilate (BZ), and on stress as a cause of hallucinations, is reviewed. While CW exposure cannot be ruled out, it is concluded that the hallucinations can be ascribed to the consequence of multiple stresses--artillery attacks, exhaustion due to lack of sleep, starvation, thirst and the effects of drinking unpurified water.

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Section: Other Literature On Bzmentioning

confidence: 99%

Surviving the impossible: The long March from Srebrenica. An investigation of the possible use of chemical warfare agents

Hay

1998

Medicine, Conflict and Survival

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“…In the creation of new drug molecules, one of the most widely utilized methods is the modification of the structure of known active compounds or the most important mediators of desired biochemical processes [ 11 ]. The group of synthetic quinuclidine derivatives is a very good example of compounds prepared in that way [ 12 ]. Due to its highly symmetrical structure, the heterocyclic system of quinuclidine (1-azabicyclo[2.2.2]-octane) is extremely chemically stable and is present as a structural unit of many natural and synthetic physiologically active substances [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability

Žunec,

Vadlja,

Ramić

et al. 2023

IJMS

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The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system’s activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 − 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1′-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1′-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7–200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12–C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells’ mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds’ scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.

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“…Sequifenadine (1-azabicyclo[2.2.2]oct-3-yl[bis(2-methylphenyl)]-methanol) hydrochloride (Figure ) is a H 1 -receptor antagonist which also inhibits 5-HT 1 receptors of serotonin, thus decreasing the activity of allergy mediators histamine and serotonin. , Sequifenadine is a quinuclidine derivative, which is structurally related to quifenadine . To the best of our knowledge, there are no reports on the existence of polymorphs or solvates of sequifenadine hydrochloride.…”

Section: Introductionmentioning

confidence: 99%

Polymorphs and Hydrates of Sequifenadine Hydrochloride: Crystallographic Explanation of Observed Phase Transitions and Thermodynamic Stability

Kons

Be̅rziņš

Actiņš

2017

Crystal Growth & Design

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In this study, detailed analysis of crystal structures was used to rationalize the observed stability and phase transformations of sequifenadine hydrochloride polymorphs and hydrates, as well as to understand the observed structural diversity. The performed polymorph and hydrate screening revealed the existence of six polymorphs and four hydrates. Crystal structures of these phases were determined either from single crystal or from powder diffraction data. The different possibilities for packing of sequifenadine cations were found to be the main reason for the observed structural diversity of polymorphs. The hydrate structures were found to be structurally similar and related to those of particular polymorphs, which was consistent with the observed easy phase transitions among the related pairs.

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Relationships Between the Chemical Structure and Pharmacological Activity in a Series of Synthetic Quinuclidine Derivatives

Cited by 6 publications

References 52 publications

Surviving the impossible: The long March from Srebrenica. An investigation of the possible use of chemical warfare agents

Surviving the impossible: The long March from Srebrenica. An investigation of the possible use of chemical warfare agents

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability

Polymorphs and Hydrates of Sequifenadine Hydrochloride: Crystallographic Explanation of Observed Phase Transitions and Thermodynamic Stability

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