New HSV-1 Anti-Viral 1′-Homocarbocyclic Nucleoside Analogs with an Optically Active Substituted Bicyclo[2.2.1]Heptane Fragment as a Glycoside Moiety

Molecules

Ekaterina Sinegubova¹  Alexandrina Volobueva¹  VladimirV. Zarubaev¹  AlexanderV. Slita²  Johan Neyts²  Dirk Jochmans²  ConstantinI. Tănase³  Lucia Pintilie³  Anamaria Hanganu⁴  Maria Maganu⁴  Constantin Drăghici⁴ 

[1] Department of Virology, Pasteur Institute of Epidemiology and Microbiology, 197101 St. Petersburg, Russia;KU Leuven Department of Micobiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, BE-3000 Leuven, Belgium;National Institute for Chemical-Pharmaceutical Research and Development, Department of Bioactive Substances and Pharmaceutical Technologies, 112 Vitan Av., 031299 Bucharest-3, Romania;Organic Chemistry Center “C.D.Nenitescu”, Spectroscopy Laboratory, 202 B Splaiul Independentei, 060023 Bucharest, Romania;

关键词: 1′-homocarbonucleosides;    bicyclo[2.2.1]heptane nucleosides;    6-chloropurine;    6-substituted adenine nucleosides;    antiviral activity;    herpesviruses;    molecular docking;   

DOI  :  10.3390/molecules24132446

来源: DOAJ

【 摘 要 】

New 1′-homocarbanucleoside analogs with an optically active substituted bicyclo[2.2.1]heptane skeleton as sugar moiety were synthesized. The pyrimidine analogs with uracil, 5-fluorouracil, thymine and cytosine and key intermediate with 6-chloropurine (5) as nucleobases were synthesized by a selective Mitsunobu reaction on the primary hydroxymethyl group in the presence of 5-endo-hydroxyl group. Adenine and 6-substituted adenine homonucleosides were obtained by the substitution of the 6-chlorine atom of the key intermediate 5 with ammonia and selected amines, and 6-methoxy- and 6-ethoxy substituted purine homonucleosides by reaction with the corresponding alkoxides. No derivatives appeared active against entero, yellow fever, chikungunya, and adeno type 1viruses. Two compounds (6j and 6d) had lower IC₅₀ (15 ± 2 and 21 ± 4 µM) and compound 6f had an identical value of IC₅₀ (28 ± 4 µM) to that of acyclovir, suggesting that the bicyclo[2.2.1]heptane skeleton could be further studied to find a candidate for sugar moiety of the nucleosides.

【 授权许可】

Unknown