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1.
Int J Mol Sci ; 25(1)2023 Dec 21.
Article in English | MEDLINE | ID: mdl-38203326

ABSTRACT

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.


Subject(s)
Butyrylcholinesterase , Cholinesterase Inhibitors , Humans , Cholinesterase Inhibitors/pharmacology , Acetylcholinesterase , Bromides , Cell Survival , Acetylcholine , Pain , Quinuclidines/pharmacology
2.
Pharmaceuticals (Basel) ; 15(10)2022 Sep 30.
Article in English | MEDLINE | ID: mdl-36297327

ABSTRACT

A series of 46 Cinchona alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants (Ki) ranged from 3.9-80 µM, and 0.075-19 µM for BChE. The most potent AChE inhibitor was N-(para-fluorobenzyl)cinchoninium bromide, while N-(meta-fluorobenzyl)cinchonidinium bromide was the most potent BChE inhibitor with Ki constant in the nanomolar range. Generally, compounds were non-selective or BChE selective cholinesterase inhibitors, where N-(meta-fluorobenzyl)cinchonidinium bromide was the most selective showing 533 times higher preference for BChE. In silico study revealed that twenty-six compounds should be able to cross the blood-brain barrier by passive transport. An extensive machine learning procedure was utilized for the creation of multivariate linear regression models of AChE and BChE inhibition. The best possible models with predicted R2 (CD-derivatives) of 0.9932 and R2(CN-derivatives) of 0.9879 were calculated and cross-validated. From these data, a smart guided search for new potential leads can be performed. These results pointed out that quaternary Cinchona alkaloids are the promising structural base for further development as selective BChE inhibitors which can be used in the central nervous system.

3.
Antibiotics (Basel) ; 10(6)2021 May 31.
Article in English | MEDLINE | ID: mdl-34073082

ABSTRACT

Bacterial infections that do not respond to current treatments are increasing, thus there is a need for the development of new antibiotics. Series of 20 N-substituted quaternary salts of cinchonidine (CD) and their quasi-enantiomer cinchonine (CN) were prepared and their antimicrobial activity was assessed against a diverse panel of Gram-positive and Gram-negative bacteria. All tested compounds showed good antimicrobial potential (minimum inhibitory concentration (MIC) values 1.56 to 125.00 µg/mL), proved to be nontoxic to different human cell lines, and did not influence the production of reactive oxygen species (ROS). Seven compounds showed very strong bioactivity against some of the tested Gram-negative bacteria (MIC for E. coli and K. pneumoniae 6.25 µg/mL; MIC for P. aeruginosa 1.56 µg/mL). To establish a connection between antimicrobial data and potential energy surfaces (PES) of the compounds, activity/PES models using principal components of the disc diffusion assay and MIC and data towards PES data were built. An extensive machine learning procedure for the generation and cross-validation of multivariate linear regression models with a linear combination of original variables as well as their higher-order polynomial terms was performed. The best possible models with predicted R2(CD derivatives) = 0.9979 and R2(CN derivatives) = 0.9873 were established and presented. This activity/PES model can be used for accurate prediction of activities for new compounds based solely on their potential energy surfaces, which will enable wider screening and guided search for new potential leads. Based on the obtained results, N-quaternary derivatives of Cinchona alkaloids proved to be an excellent scaffold for further optimization of novel antibiotic species.

4.
PLoS One ; 13(10): e0205193, 2018.
Article in English | MEDLINE | ID: mdl-30289893

ABSTRACT

This paper describes the synthesis and anticholinesterase potency of Cinchona-based alkaloids; ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. The quaternization of quinuclidine moiety of each compound was carried out with groups diverse in their size: methyl, benzyl and differently meta- and para-substituted benzyl groups. All of the prepared compounds reversibly inhibited human butyrylcholinesterase and acetylcholinesterase with Ki constants within nanomolar to micromolar range. Five cinchonidine derivatives displayed 95-510 times higher inhibition selectivity to butyrylcholinesterase over acetylcholinesterase and four were potent butyrylcholinesterase inhibitors with Ki constants up to 100 nM, of which N-para-bromobenzyl cinchonidinium bromide can be considered a lead for further modifications and optimizations for possible use in the treatment of neurodegenerative diseases.


Subject(s)
Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/pharmacology , Cinchona Alkaloids/chemistry , Drug Design , Neurodegenerative Diseases/drug therapy , Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/therapeutic use , Cinchona/chemistry , Enzyme Assays , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
5.
Molecules ; 23(5)2018 May 18.
Article in English | MEDLINE | ID: mdl-29783685

ABSTRACT

In the search for a new class of potential antimicrobial agents, five novel N-substituted imidazole 2-aldoximes and their six quaternary salts were evaluated. The antimicrobial activity was assessed against a panel of representative Gram-positive and Gram-negative bacteria, including multidrug resistant bacteria. All compounds demonstrated potent in vitro activity against the tested microorganisms, with MIC values ranging from 6.25 to 50.0 µg/mL. Among the tested compounds, two quaternary compounds (N-but-3-enyl- and meta- (10) or para- N-chlorobenzyl (11) imidazolium 2-aldoximes) displayed the most potent and broad-spectrum activity against both Gram-positive and Gram-negative bacterial strains. The broth microdilution assay was also used to investigate the antiresistance efficacy of the both most active compounds against a set of Enterobacteriaceae isolates carried a multiple extended-spectrum ß-lactamases (ESBLs) in comparison to eight clinically relevant antibiotics. N-but-3-enyl-N-meta-chlorobenzyl imidazolium 2-aldoxime was found to possess promising antiresistance efficacy against a wide range of ß-lactamases producing strains (MIC 2.0 to 16.0 µg/mL). Best results for that compound were obtained against Escherichia coli and Enterobacter cloacae producing multiple ß-lactamases form A and C molecular classes, which were 32- and 128-fold more potent than ceftazidime and cefotaxime, respectively. To visualize the results, principal component analysis was used as an additional classification tool. The mixture of ceftazidime and compound 10 (3 µg:2 µg) showed a strong activity and lower the necessary amount (up to 40-fold) of 10 against five of ESBL-producing isolates (MIC ≤ 1 µg/mL).


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Gram-Negative Bacteria/drug effects , Imidazoles/chemistry , Oximes/chemistry , Anti-Bacterial Agents/pharmacology , Cefotaxime/pharmacology , Ceftazidime/pharmacology , Drug Resistance, Multiple, Bacterial , Enterobacter cloacae/drug effects , Escherichia coli/drug effects , Imidazoles/pharmacology , Microbial Sensitivity Tests , Oximes/pharmacology , beta-Lactamases/metabolism
6.
Molecules ; 22(7)2017 Jul 22.
Article in English | MEDLINE | ID: mdl-28737687

ABSTRACT

For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3), derivatives of the 9-oxocinchonidine, were synthesized and investigated in reactivation of various OP-inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease). Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range.


Subject(s)
Acetylcholinesterase/metabolism , Alkaloids/chemistry , Butyrylcholinesterase/metabolism , Organophosphorus Compounds/pharmacology , Oximes/chemistry , Enzyme Activation/drug effects , Structure-Activity Relationship
7.
Molecules ; 17(1): 786-95, 2012 Jan 16.
Article in English | MEDLINE | ID: mdl-22249408

ABSTRACT

Since the optically active quinuclidin-3-ol is an important intermediate in the preparation of physiologically or pharmacologically active compounds, a new biocatalytic method for the production of chiral quinuclidin-3-ols was examined. Butyrylcholinesterase (BChE; EC 3.1.1.8) was chosen as a biocatalyst in a preparative kinetic resolution of enantiomers. A series of racemic, (R)- and (S)-esters of quinuclidin-3-ol and acetic, benzoic, phthalic and isonicotinic acids were synthesized, as well as their racemic quaternary N-benzyl, meta- and para-N-bromo and N-methylbenzyl derivatives. After the resolution, all N-benzyl protected groups were successfully removed by catalytic transfer hydrogenation with ammonium formate (10% Pd-C). Hydrolyses studies with BChE confirmed that (R)-enantiomers of the prepared esters are much better substrates for the enzyme than (S)-enantiomers. Introduction of bromine atom or methyl group in the meta or para position of the benzyl moiety resulted in a considerable improvement of the stereoselectivity compared to the non-substituted compounds. Optically pure quinuclidin-3-ols were prepared in high yields and enantiopurity by the usage of various N-benzyl protected groups and BChE as a biocatalyst.


Subject(s)
Butyrylcholinesterase/chemistry , Esters/chemical synthesis , Quinuclidines/chemical synthesis , Biocatalysis , Esters/chemistry , Esters/isolation & purification , Formates/chemistry , Hydrogenation , Hydrolysis , Quinuclidines/chemistry , Quinuclidines/isolation & purification , Stereoisomerism
8.
J Trauma Stress ; 15(5): 377-87, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12392225

ABSTRACT

This study examined the relative contribution of 2 exile-related variables--social isolation and daily activity level--and war experiences of violence and loss, to levels of PTSD and depressive symptomatology in 2 groups of Bosnian refugees, 1 clinical group (N = 59) and the other a nonclinical community (N = 40) group. As hypothesized, exposure to war-related violence was highly predictive of PTSD symptoms in both groups; in addition, social isolation was significantly related to PTSD symptomatology in the community group. In contrast, depressive symptomatology was accounted for primarily by the exile-related stressors. For the clinical group, depressive symptoms were also accounted for by experiences of war-related loss. The implications of these findings for mental health interventions with refugees are considered.


Subject(s)
Refugees/psychology , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/psychology , Warfare , Activities of Daily Living , Adult , Bosnia and Herzegovina/ethnology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Social Isolation , Stress Disorders, Post-Traumatic/diagnosis , Surveys and Questionnaires , United States/epidemiology
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