Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2020, Volume: 25, Number: 23, Article number : 5578;, Pages count : DOI: 10.3390/molecules25235578

Tags

alkaloids; analgesic activity; cross-coupling reaction; lappaconitine; multi-component synthesis; pyrimidine

Authors

Cheremnykh Kirill P. ¹ , Savelyev Victor A. ¹ , Borisov Sergey A. ¹ , Ivanov Igor D. ² , Baev Dmitry S. ¹ , Tolstikova Tatyana G. ¹ , Vavilin Valentin A. ² , Shults Elvira E. ¹

Affiliations

1	Novosibirsk Institute of Organic Chemistry, Russian Academy of Sciences, Siberian BranchLavrentjev Avenue 9, Novosibirsk, 630090, Russian Federation
2	Federal Research Center Insitute of Molecular Biology and Biophysics, Timakov St., Novosibirsk, 630117, Russian Federation

Convenient and efficient routes to construct hybrid molecules containing diterpene alkaloid lappaconitine and pyrimidine fragments are reported. One route takes place via first converting of lappaconitine to 1-ethynyl-lappaconitine, followed by the Sonogashira cross-coupling-cyclocondensation sequences. The other involves the palladium-catalyzed carbonylative Sonogashira reaction of 5'-iodolappaconitine with aryl acetylene and Mo (CO)6 as the CO source in acetonitrile and subsequent cyclocondensation reaction of the generated alkynone with amidines. The reaction proceeded cleanly in the presence of the PdCl2-(1-Ad)2PBn∙HBr catalytic system. The protocol provides mild reaction conditions, high yields, and high atom and step-economy. Pharmacological screening of lappaconitine-pyrimidine hybrids for antinociceptive activity in vivo revealed that these compounds possessed high activity in experimental pain models, which was dependent on the nature of the substituent in the 2 and 6 positions of the pyrimidine nucleus. Docking studies were undertaken to gain insight into the possible binding mode of these compounds with the voltage-gated sodium channel 1.7. The moderate toxicity of the leading compound 12 (50% lethal dose (LD50) value was more than 600 mg/kg in vivo) and cytotoxicity to cancer cell lines in vitro encouraged the further design of therapeutically relevant analogues based on this novel type of lappaconitine-pyrimidine hybrids.

Cheremnykh K.P. , Savelyev V.A. , Borisov S.A. , Ivanov I.D. , Baev D.S. , Tolstikova T.G. , Vavilin V.A. , Shults E.E.
Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

Molecules. 2020. V.25. N23. 5578; . DOI: 10.3390/molecules25235578 WOS Scopus РИНЦ

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Published online:

Nov 27, 2020

Web of science	WOS:000597468800001
Scopus	2-s2.0-85097036868
Elibrary	45109643
OpenAlex	W3109906232