Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives

The preparation of new fourteen thiourea and fourteen product of their condensation with 1,4-dibromobutane, viz. 1,3-thiazepine derivatives, of 10-isopropyl-8-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione and 1-isopropyl-7-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione is described. Elemental analysis, MS and 1H NMR spectra confirmed the identity of the products. The molecular structure of linear disubstituted thiourea derivative and its cyclization product was determined by an X-ray crystal structure analysis. Two of new obtained compounds (6b′ and 7a′) were tested for their pharmacological activity on animal central nervous system (CNS) in behavioral animal tests. With relatively low acute toxicity (LD50 lower than 2000 mg kg−1 i.p.) they exhibited significant influence on spontaneous locomotor activity and body temperature. Additionally, compounds reduced number of the “head twitch” episodes after 5-hydroksytryptophan (5-HTP) administration.New compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA+ viruses Yellow fever virus (YFV) and Bovine viral diarrhea virus (BVDV), both belonging to Flaviridae. Three of new obtained compounds showed a modest activity against HIV-1 wtIIIB, BVDV and YFV.

Graphical abstractThe preparation of new fourteen thiourea and fourteen product of their condensation with 1,4-dibromobutane, viz. 1,3-thiazepine derivatives, of 10-isopropyl-8-methyl-4-aza-tricyclo [5.2.2.02,6]undec-8-ene-3,5-dione and 1-isopropyl-7-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione is described. Elemental analysis, MS and 1H NMR spectra confirmed the identity of the products. The molecular structure of linear disubstituted thiourea derivative and its cyclization product was determined by an X-ray crystal structure analysis. Two of new obtained compounds were tested for their pharmacological activity on animal central nervous system (CNS). They exhibited significant influence on spontaneous locomotor activity, body temperature and “head twitch” response.New compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA+ viruses Yellow fever virus (YFV) and Bovine viral diarrhea virus (BVDV), both belonging to Flaviridae. Three of new obtained compounds showed a modest activity against HIV-1 wtIIIB, BVDV and YFV.Figure optionsDownload full-size imageDownload as PowerPoint slide