Activity of Mannich bases of 7-hydroxycoumarin against Flaviviridae

• Published in: Bioorganic & medicinal chemistry 2008-03, Vol.16 (5), p.2591-2605
• Main Authors: Mazzei, Mauro, Nieddu, Erika, Miele, Mariangela, Balbi, Alessandro, Ferrone, Marco, Fermeglia, Maurizio, Mazzei, Marco T., Pricl, Sabrina, La Colla, Paolo, Marongiu, Fabio, Ibba, Cristina, Loddo, Roberta
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Coumarin derivatives; Cricetinae; Dogs; Flaviviridae; Flaviviridae - chemistry; Flaviviridae - drug effects; Flaviviridae - metabolism; HCV; Humans; Mannich bases; Mannich Bases - chemistry; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Umbelliferones - chemical synthesis; Umbelliferones - chemistry; Umbelliferones - pharmacology; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.11.045

Some Mannich bases of 7-hydroxycoumarin were prepared and tested against viruses containing single-stranded, positive-sense RNA genomes (ssRNA +). When position 7 was propylated, the resulting 7-propyloxy derivatives were in some cases endowed with an interesting activity against BVDV. Therefore, 7-propyloxy derivatives were submitted to a molecular modeling study using DNA polymerase of HCV as a target. The good correlation between calculated molecular modeling IC 50 and experimental EC 50 is reasonable proof that DNA polymerase is potentially involved in the inhibition of surrogate HCV viruses. Some Mannich bases of 7-hydroxycoumarin ( 2) and their simple derivatives ( 3 and 4) were prepared and tested against viruses containing single-stranded, positive-sense RNA genomes (ssRNA +). This study was directed toward Flaviviridae and, in particular, HCV surrogate viruses (BVDV, YFV). The 7-hydroxy derivatives 2 were generally devoid of activity, but when position 7 was propylated, the resulting 7-propyloxy derivatives 3 were in some cases endowed with an interesting activity against BVDV. The formation of 7-benzoyl derivatives 4 gave compounds generally lacking in activity against Flaviviridae, whereas the appearance of activity against RSV has been observed. Also some unsymmetrical methylene derivatives 5– 7 (namely coumarins bridged to chromones or indoles) were found moderately active in antiviral tests. Derivatives 3 were submitted to a molecular modeling study using DNA polymerase of HCV as a target. The good correlation between calculated molecular modeling IC 50 and experimental EC 50 indicates that DNA polymerase is potentially involved in the inhibition of surrogate HCV viruses.