Synthesis and antiviral properties derivatives of 1-(para-tolyl)-4-aryl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulene-3-carbothioic acid arylamides
Abstract
Nowadays, H1N1 – strain of so called «swine» or «mexican» subspecie A virus, which is still not studied, and which spreads through aerosol and contact is known to many world countries. Significant number of lethal cases during influenza pandemic season in Ukraine was observed. It should be noted, that patients went to the hospitals in very severe cases, which is why registered daily lethality is in 31,6% of cases.
Everything listed above had made it necessary to conduct preventive measures on global and national levels. One of such measures is creation of new direct action medicinal agents.
The goal of this work was the synthesis of compounds with potential antiviral properties in variety of 5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid derivatives.
We have chosen derivatives of 5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid (6 a–e and 7 a–h), which were synthesized by boiling of 1-(para-tolyl)-4-aryl-5,6,7,8-tetrahydro-2,2a,4a-triazacyclopenta[cd]azulenes (5a or 5b) with corresponding arylisothiocyanates in dry benzene.
Antiviral activity of phenylamid 1-(para-tolyl)-4-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid against Flu A H1N1 California/07/2009 was researched in Southern Research Institute – SRI, Birmingham, Alabama).
Variety of new derivatives of 5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid. Composition and structure of all synthesized compounds are proven by data of element analysis and 1Н NMR spectroscopy.
In conducted researches of antiviral activity of phenylamide 1-(para-tolyl)-4-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid against Flu A H1N1 California/07/2009, it was found out, that synthesized compound shows pronounced antiviral activity, compared to reference medicinal agents Ribavirin and Amizon.
Therefore, conducted researches confirm perspective of development of a new domestic medicinal agent with antiviral activity, based on derivatives of 5,6,7,8,-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-3-carbotionic acid.
References
2. Bartlett J. G. 2009 H1N1 Influenza – Just the Facts: What’s New and What to Expect // Published: 23. 09. 2009. − Available at https://www.medscape.com/viewarticle/709540_2
3. Emergence of novel swine –origin influenza A (H1N1) virus in human. Novel swine–origin influenza A (H1N1) virus investigation team // The New England J. Med − 2009. – V. 360, N 25. − P. 2605–2615. https://doi.org/10.1056/NEJMoa0903810
4. MMWR Morb Mortal Wkly Rep. Update: drug susceptibility of swine–origin influenza A (H1N1) viruses, April 2009. Centers for Disease Control and Prevention (CDC). − 2009. − N 58. − P. 433–435.
5. H1N1. [Elektronnyi resurs]. – Rezhym dostupu: https://uk.wikipedia.org/wiki/H1N1
6. The 2009 H1N1 Pandemic: Summary Highlights, April 2009–April 2010. [Elektronnyi resurs]. – Rezhym dostupu: https://www.cdc.gov/H1N1FLU/cdcresponse.htm
7. Myers K. P. Olsen C. W., Setterquist S. F. et al. Are swine workers in the United States at increased risk of infection with zoonotic influenza virus? // Clin. Infect Dis. − 2006. − N 42. − P. 14–20. https://doi.org/10.1086/498977
8. Shope R. E. Swine influenza. III. Filtration experiments and etiology // J. Exp. Med. − 1931 − N 54. − P. 373–385. https://doi.org/10.1084/jem.54.3.373
9. V Ukraini chekaiut shchonaimenshe try shtamy hryppu [Elektronnyi resurs]. – Rezhym dostupu: https://www.unian.ua/society/409702-v-ukrajini-chekayut-schonaymenshe-tri-shtami-gripu.html
10. Holubka O. S., Onyshchenko O. V., Mironenko A. P. Otsinka naslidkiv tiazhkykh form hrypu ta letalnosti sered osib hrup ryzyku v pandemichnomu sezoni 2009 - 2010 rokiv v Ukraini // Profilaktychna medytsyna.– 2013. – № 3–4 (21). – S. 55–58.
11. Viktorov O. P., Shyrobokov V. P., Matvieieva O. V. ta in. Protyvirusni likarski zasoby pry likuvanni hrypu: efektyvnist ta bezpeka // Ukr. med. chasopys. – 2010. – № 2 (76). – S. 7–12. Rezhym dostupu: https://www.umj.com.ua/article/3006/protivirusni-likarski-zasobi-pri-likuvanni-gripu-efektivnist-ta-bezpeka
12. Moskaliuk V. D., Sydorchuk A. S. Diahnostyka ta likuvannia hrypu: suchasni kliniko-patohenetychni aspekty // Infektsiini khvoroby. – 2016. − № 2 (84).– S. 5–14. https://doi.org/10.11603/1681-2727.2016.2.6513
13. Trinus F. P., Danylenko V. P., Bukhtiarova T. A. ta in. 4-(n-Benzyl)aminokarbonil-1-metylpirydynii yodyd − zneboliuiuchyi zasib z interferonohennymy, protyzapalnymy ta zharoznyzhuiuchymy vlastyvostiamy. Pat. № UA 6752 Ukrainy na vynakhid. Opubl. 29. 12. 1994, Biul. № 8-1.
14. Amizon [Elektronnyi resurs]. – Rezhym dostupu: http://www.ift.org.ua/uk/node/91
15. Effektivnost' Amizona v lechenii i profilaktike virusnyh infekcij (k 10-letiyu primeneniya preparata v klinicheskoj praktike) [Elektronnyi resurs]. – Rezhym dostupu: http://farmak.ua/publication/effektivnost-_amizona_v_lechenii_i_profilaktike_ virousnyh_infektsiy_-k_10-etiyu_primeneniya_preparata_v_klinicheskoy_praktike
16. Normatyvno-dyrektyvni dokumenty MOZ Ukrainy. Amizon. [Elektronnyi resurs]. – Rezhym dostupu: http://mozdocs.kiev.ua/likiview.php?id=20298
17. Ribavirin – oficial'naya instrukciya po primeneniyu [Elektronnyi resurs]. – Rezhym dostupu: https://medi.ru/instrukciya/ribavirin_1672/
18. Demchenko S. A., Fedchenkova Yu. A., Sukhovieiev V. V., Demchenko A. M. Fenilamid (1-para-tolyl)-4-phenyl-5,6,7,8-tetrahidro-2,2a,4a-triazacyklopenta[cd]azulen-2-karbothionovoi kysloty, shcho proiavliaie antyvirusnu aktyvnist po vidnoshenniu do virusu Flu A H1N1 California/07/2009. Pat. № 135687 Ukrainy na korysnu model. № u 2019 01415. Zaiavl. 12. 02. 2019; Opubl. 10. 07. 2019, Biul. № 13/2019.
19. Granik V. G., ZHidkova A. M., Kuryatov N. S. i dr. Acetali laktamov. VII. Issledovanie alkilirovaniya N-metillaktamov i laktimnyh efirov dimetilsul'fatom // HGS. − 1973. − № 11. − S. 1532−1535.
20. Petersen S., Tietze E. Reaktionen cyclischer lactimäther mit acylierten hydrazinderivaten // Chem. Ber. – 1957. – V. 90, Is. 6. – P. 909–921. https://doi.org/10.1002/cber.19570900609
21. Demchenko A. M. Proizvodnye 1,4-diaril-5,6,7,8-tetragidro-2,2a,8a-triazaciklopenta [cd]azulena // HGS. – 2000. – № 8. – S. 1123–1127.
This work is licensed under a Creative Commons Attribution 4.0 International License.
