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 Научная публикация

Журнал

Molecules
, E-ISSN: 1420-3049

Вых. Данные

Год: 2020, Том: 25, Номер: 23, Номер статьи : 5578;, Страниц : DOI: 10.3390/molecules25235578

Ключевые слова

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

Авторы

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

Организации

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 OpenAlex

Полный текст от издателя

Опубликована online:

27 нояб. 2020 г.

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

БД	Цитирований
Scopus	10
Web of science	9
РИНЦ	10
OpenAlex	9