Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine–1,5-Benzodiazepine Hybrids

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine–1,5-Benzodiazepine Hybrids Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2023, Volume: 28, Number: 10, Article number : 4234, Pages count : 20 DOI: 10.3390/molecules28104234

Authors

Cheremnykh Kirill P. ¹ , Bryzgalov Arkadiy O. ¹ , Baev Dmitry S. ¹ , Borisov Sergey A. ¹ , Sotnikova Yulia S. ¹ , Savelyev Victor A. ¹ , Tolstikova Tatyana G. ¹ , Sagdullaev Shamansur S. ² , Shults Elvira E. ¹

Affiliations

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences
2	S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan

Funding (1)

Российский Научный Фонд

23-73-00077

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 50 -alkynone-lappaconitines in situ by acyl Sonogashira coupling of 50 -ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Cheremnykh K.P. , Bryzgalov A.O. , Baev D.S. , Borisov S.A. , Sotnikova Y.S. , Savelyev V.A. , Tolstikova T.G. , Sagdullaev S.S. , Shults E.E.
Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine–1,5-Benzodiazepine Hybrids
Molecules. 2023. Т.28. №10. 4234 :1-20. DOI: 10.3390/molecules28104234 WOS РИНЦ OpenAlex

Published online:

May 22, 2023

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