title: Synthesis and antiviral/antitumor evaluation of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes and related compounds as a new class of diarylsulfones.
abstract: Based on general SARs previously described for anti-HIV-1 diarylsulfone derivatives, a series of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes has been prepared and evaluated as potential antiviral and antitumor agents. In cell culture, some of the 2-aminothiophenes exhibited moderate and selective activity against HIV-1, with 2-amino-3-(2-nitrophenylsulfonyl)thiophene (7e) being most attractive (EC(50)=3.8 microg/mL, CC(50)=>100 microg/mL). In broad-spectrum antiviral assays, the 3-arylsulfonyl-2-(trifluoroacetamido)thiophenes (8c-g) and 2-acetamido-3-arylsulfonyl-5-nitrothiophenes (9f-g) proved considerably active (IC(50)=0.1-10 microg/mL) against human cytomegalovirus (CMV) and/or varicella zoster virus (VZV). Based on the activity of the trifluoroacetamides, ring-modified furan, N-(substituted)pyrrole, phenyl, and 3,4-thiophene analogues were prepared, and these compounds were also active against CMV and/or VZV, with the notable exception of the 3,4-thiophene derivative. In contrast to other amines, the 2-aminopyrrole precursors (13a-d) also exhibited potent activity against CMV. Unfortunately, most of these compounds displayed significant cytotoxicity against human fibroblasts, the cells supporting CMV and VZV replication, and thus selectivity indices were low. The most notable exception to this was the naphthyl-substituted aminopyrrole 13d, which exhibited both potent (IC(50)=0.3 microg/mL) and selective (CC(50)=>50 microg/mL) activity against CMV. Finally, thiophene aryl amides 8i-k displayed moderate in vitro activity against certain leukemia, breast, and colon cancer cell lines.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Stephens
authors.forename: T M
authors.initials: TM
authors.lastname: Felder
authors.forename: J W
authors.initials: JW
authors.lastname: Sowell
authors.forename: G
authors.initials: G
authors.lastname: Andrei
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: R
authors.initials: R
authors.lastname: Snoeck
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017739:Arylsulfonic Acids / Q000138:chemical synthesis; D001943:Breast Neoplasms / Q000188:drug therapy; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy; D003587:Cytomegalovirus / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy; D018139:Simplexvirus / Q000187:drug effects; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D017739:Arylsulfonic Acids; D013876:Thiophenes