The synthesis and antiviral activity of 1-(4-сhlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2а,4a-diazacyclopenta[cd]-azulene-2-carboxylic acid derivatives

Authors

  • S. A. Demchenko Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, Ukraine
  • Yu. A. Fedchenkova Nizhyn Mykola Gogol State University, Ukraine https://orcid.org/0000-0003-1240-3053
  • V. V. Sukhoveev Nizhyn Mykola Gogol State University, Ukraine
  • O. S. Bagreeva Nizhyn Mykola Gogol State University, Ukraine
  • A. M. Demchenko Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, Ukraine

DOI:

https://doi.org/10.24959/ophcj.19.182036

Keywords:

1-(4-chlorophenyl)-4-(para-tolyl)-5, 6, 7, 8-tetrahydro-2a, 4a-diazacyclopenta[cd]azulene-2-carboxylic acid substituted (thio)amides, Ribavirin, Amizone, antiviral activity, Flu A H1N1 California/07/2009 virus

Abstract

Aim. To synthesize, prove the structural framework and study the antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid derivatives.
Results and discussion. The antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4adiazacyclopenta[cd]azulene-2-carboxylic acid (4-methoxyphenyl)amide was determined in the Southern Research Institute (SRI, Birmingham, Alabama). The efficacy of this compound was expressed by EC50, IC50 and SI values determined in vitro within a range of concentrations of 0.1 – 100 μg/mL. The antiviral drug Ribavirin (Sigma) and the active substance of Amizon – 4-(N-benzyl)aminocarbonyl-1-methylpyridinium iodide were used as the reference drugs.
Experimental part. Condensation of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with α-amino-4-methylacetophenone hydrochloride led to 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine. By boiling the latter with α-bromo-4-chloroacetophenone in ethyl acetate 1-[2-(4-chlorophenyl)-2-oxoethyl]-3-(para-tolyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-1-ium bromide was isolated, which in aqueous alkali solution was converted into 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2а,4a-diazacyclopenta[cd]azulene. The latter while reacting with the corresponding aryliso(thio)cyanates in a dry benzene gave 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (thio)amides. 1H NMR-spectra for the compounds synthesized were recorded on a Bruker VXR-300 spectrometer (Germany) with the operating frequency of 299.945 MHz, and also on a Bruker DRX300 (Germany) spectrometer with the operating frequency of 500.13 MHz, in DMSO-d6 using tetramethylsilane (TMS) as an internal standard. The melting points were measured using a RNMK 05 apparatus (VEB Analytik, Dresden).
Conclusions. The series of new 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (thio)amides has been synthesized. The antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (4-methoxyphenyl)amide has been studied in the Southern American Research Institute (SRI, Birmingham, Alabama), and the high level of the antiviral activity has been found against Flu A H1N1 California/07/2009 virus.

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Published

2019-11-14

How to Cite

(1)
Demchenko, S. A.; Fedchenkova, Y. A.; Sukhoveev, V. V.; Bagreeva, O. S.; Demchenko, A. M. The Synthesis and Antiviral Activity of 1-(4-сhlorophenyl)-4-(para-Tolyl)-5,6,7,8-Tetrahydro-2а,4a-diazacyclopenta[cd]-Azulene-2-Carboxylic Acid Derivatives. J. Org. Pharm. Chem. 2019, 17, 37-43.

Issue

Vol. 17 No. 4(68) (2019)

Section

Original Researches

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