Polycyclic N-benzamido imides with potent activity against vaccinia virus.
The synthesis and antiviral activity of a series of novel polycyclic analogues of the orthopoxvirus egress inhibitor tecovirimat (ST-246) is presented. Several of these compounds display sub-micromolar activity against vaccinia virus, and were more potent than cidofovir (CDV). The more active compounds were about 10-fold more active than CDV, with minimum cytotoxic concentrations above 100 μM. Chemical manipulations of the two carbon-carbon double bonds present in the compounds were carried out to further explore the structure-activity relationships of these new polycyclic imides. Hydrogenation of the two carbon-carbon double bonds decreases antiviral activity, whereas either cyclopropanation or epoxidation of the double bonds fully eliminates the antiviral activity.
Torres
Eva
E
Institute of Biomedicine, Universitat de Barcelona, Spain.
Duque
María D
MD
Camps
Pelayo
P
Naesens
Lieve
L
Calvet
Teresa
T
Font-Bardia
Mercè
M
Vázquez
Santiago
S
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D011083:Polycyclic Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects*; D010797:Phthalimides
D000998:Antiviral Agents; D001549:Benzamides; D007094:Imides; D054833:Isoindoles; D011083:Polycyclic Compounds; C505045:tecovirimat; D010797:Phthalimides