Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings
Kamil Kuca,1,2 Jana Zdarova Karasova,2,3 Ondrej Soukup,2 Jiri Kassa,3 Eva Novotna,2 Vendula Sepsova,2,3 Anna Horova,2 Jaroslav Pejchal,3 Martina Hrabinova,2,3 Eva Vodakova,2 Daniel Jun,2,3 Eugenie Nepovimova,1,2 Martin Valis,4 Kamil Musilek1,2 1Department of Chemistry, Faculty of Science, Universit...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2018-03-01
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| Series: | Drug Design, Development and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/development-of-small-bisquaternary-cholinesterase-inhibitors-as-drugs--peer-reviewed-article-DDDT |
| _version_ | 1819225316413931520 |
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| author | Kuca K Karasova JZ Soukup O Kassa J Novotna E Sepsova V Horova A Pejchal J Hrabinova M Vodakova E Jun D Nepovimova E Valis M Musilek K |
| author_facet | Kuca K Karasova JZ Soukup O Kassa J Novotna E Sepsova V Horova A Pejchal J Hrabinova M Vodakova E Jun D Nepovimova E Valis M Musilek K |
| author_sort | Kuca K |
| collection | DOAJ |
| description | Kamil Kuca,1,2 Jana Zdarova Karasova,2,3 Ondrej Soukup,2 Jiri Kassa,3 Eva Novotna,2 Vendula Sepsova,2,3 Anna Horova,2 Jaroslav Pejchal,3 Martina Hrabinova,2,3 Eva Vodakova,2 Daniel Jun,2,3 Eugenie Nepovimova,1,2 Martin Valis,4 Kamil Musilek1,2 1Department of Chemistry, Faculty of Science, University of Hradec Kralove, 2Biomedical Research Center, University Hospital Hradec Kralove, 3Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, 4Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic 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. Keywords: AChE inhibitors, prophylaxis, pre-treatment, nerve agents, toxicity, soman |
| first_indexed | 2024-12-23T10:07:40Z |
| format | Article |
| id | doaj.art-b4208817c3c949e5a1ae1fa74faea45a |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-23T10:07:40Z |
| publishDate | 2018-03-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-b4208817c3c949e5a1ae1fa74faea45a2022-12-21T17:51:03ZengDove Medical PressDrug Design, Development and Therapy1177-88812018-03-01Volume 1250551237140Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisoningsKuca KKarasova JZSoukup OKassa JNovotna ESepsova VHorova APejchal JHrabinova MVodakova EJun DNepovimova EValis MMusilek KKamil Kuca,1,2 Jana Zdarova Karasova,2,3 Ondrej Soukup,2 Jiri Kassa,3 Eva Novotna,2 Vendula Sepsova,2,3 Anna Horova,2 Jaroslav Pejchal,3 Martina Hrabinova,2,3 Eva Vodakova,2 Daniel Jun,2,3 Eugenie Nepovimova,1,2 Martin Valis,4 Kamil Musilek1,2 1Department of Chemistry, Faculty of Science, University of Hradec Kralove, 2Biomedical Research Center, University Hospital Hradec Kralove, 3Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, 4Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic 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. Keywords: AChE inhibitors, prophylaxis, pre-treatment, nerve agents, toxicity, somanhttps://www.dovepress.com/development-of-small-bisquaternary-cholinesterase-inhibitors-as-drugs--peer-reviewed-article-DDDTAChE inhibitorsprophylaxispre-treatmentnerve agentstoxicitysoman |
| spellingShingle | Kuca K Karasova JZ Soukup O Kassa J Novotna E Sepsova V Horova A Pejchal J Hrabinova M Vodakova E Jun D Nepovimova E Valis M Musilek K Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings Drug Design, Development and Therapy AChE inhibitors prophylaxis pre-treatment nerve agents toxicity soman |
| title | Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings |
| title_full | Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings |
| title_fullStr | Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings |
| title_full_unstemmed | Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings |
| title_short | Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings |
| title_sort | development of small bisquaternary cholinesterase inhibitors as drugs for pre treatment of nerve agent poisonings |
| topic | AChE inhibitors prophylaxis pre-treatment nerve agents toxicity soman |
| url | https://www.dovepress.com/development-of-small-bisquaternary-cholinesterase-inhibitors-as-drugs--peer-reviewed-article-DDDT |
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