Synthesis and anti-picornaviridae in vitro activity of a new class of helicase inhibitors the N,N'-bis[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl] alkyldicarboxamides

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 3; no. 6; p. 520
• Main Authors: Carta, A, Loriga, M, Piras, S, Paglietti, G, Ferrone, M, Fermeglia, M, Pricl, S, La Colla, P, Collu, G, Sanna, T, Loddo, R
• Format: Journal Article
• Language: English
• Published: Netherlands 01.11.2007
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cell Line; Cell Survival - drug effects; Enterovirus - drug effects; Enterovirus - enzymology; Flaviviridae - drug effects; Flaviviridae - enzymology; Humans; Picornaviridae - drug effects; Picornaviridae - enzymology; RNA Helicases - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 1573-4064; 1875-6638
• DOI: 10.2174/157340607782360308

A series N,N'-bis[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkyldicarboxamides (3a-f and 5a-j) were prepared starting from their already known (1a-d) and (4a-c) or new (4d) amine parents. Because of the antiviral activity of several N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides previously reported, title compounds were evaluated in vitro for cytotoxicity and antiviral activity against viruses representative of Picornaviridae, [i.e. Enterovirus Coxsackie B2 (CVB-2) and Polio (Sb-1)] and of two of the three genera of the Flaviviridae [Bovine Viral Diarrhea Virus (BVDV) and Yellow Fever Virus (YFV)]. Furthermore, because of the in silico activity against the RNA-dependent RNA-helicase of Polio 1 previously reported, title compounds were evaluated against the 3D model of the Sb-1 helicase and against the 2D model of the CVB-2 helicase. As a reference we used the antiviral and in silico activities of an imidazo counterpart of the title compounds, N,N'-bis[4-(2-benzimidazolyl)phenyl]alkyldicarboxamides (III) that other authors reported to be able to inhibit the corresponding enzyme of Hepatitis C Virus (HCV). In cell-based antiviral assays, N,N'-bis[4-(1H-benzotriazol-1-yl)phenyl]alkyldicarboxamides (3a-f) resulted completely inactive whereas the bis-5,6-dimethyl-benzotriazol-2-yl derivatives (5d-f) exhibited good activity against the Enteroviruses, (EC(50)s ranged between 7 and 11 microM against CVB-2 and 19-52 against Sb-1). Interestingly, bis-5,6-dichloro-benzotriazol-2-yl derivatives (5h-j) showed very selective activity against CVB-2 (EC(50)s = 4-11 microM) whereas they resulted completely inactive against all the other viruses screened. In general, all title compounds showed a good cytotoxicity profile in MT-4 cells. Molecular modeling investigations showed that active compounds may interact with the binding site of the Sb-1 helicase and that their free binding energy values are in agreement with their EC(50)s values.