Synthesis of new 3-methylthio-5-aryl-4-isothiazolecarbonitriles with broad antiviral spectrum.
The isothiazole derivative 3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile, coded IS-50, which in previous studies had exhibited a broad antipicornavirus spectrum of action, was selected as the model for the synthesis of a new series of 3-methylthio-5-aryl-4-isothiazolecarbonitriles. These compounds were prepared in good yield (from 66 to 82%) by alkylation of 3-methylthio-5-(4-hydroxyphenyl)-4-isothiazolecarbonitrile with suitable bromides in the presence of acetone; only the 4-cyanophenoxy derivatives were obtained in a yield of less than 30%. All the compounds were screened against a panel of 17 representative human rhinovirus (HRV) serotypes belonging to both A and B groups, enteroviruses polio 1, ECHO 9 and Coxsackie B1, cardiovirus EMC, measles virus, and herpes simplex virus type 1 (HSV-1). Our results demonstrate that HRV 86 (group A) and HRVs 39 and 89 (group B) are the rhinovirus serotypes more susceptible to the action of these compounds. Isothiazole derivatives with a longer intermediate alkyl chain exhibited good activity against polio 1 and ECHO 9. The compound bearing a butyl group between the two phenoxy rings showed the lowest IC(50) against Coxsackie B1 and measles viruses. No activity against HSV-1 was detected with any of the compounds screened.
Cutrì
C C C
CC
Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy.
Garozzo
A
A
Siracusa
M A
MA
Castro
A
A
Tempera
G
G
Sarvà
M C
MC
Guerrera
F
F
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects*; D013696:Temperature; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects
C466379:3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile; D000998:Antiviral Agents; D009570:Nitriles; D013844:Thiazoles