title: Synthesis and pharmacological properties of benzisothiazole/benzimidazole derivatives with acidic groups.
abstract: The synthesis and the pharmacological evaluation of benzisothiazole and benzimidazole tetrazolyl- and carboxyl- derivatives 1-6 are described. Structural modification was aimed at investigating the influence of two isosteric substituents (tetrazolyl- and carboxyl-) on the title benzofused heterocycles. The antiphlogistic, antipyretic and analgesic activities have been investigated in in vivo experimental models. Additional investigations have been performed in vitro to study the antiplatelet and spasmolytic activity of the compounds synthetized. All the compounds produced peripheral analgesic effects, but were less effective in hot plate test. The tetrazole and the carboxylic benzisothiazole derivatives 2 and 3 proved to be the most effective drugs within the series, exhibiting maximal inhibition of writhes with a potency 3-fold higher than that of acetaminophen. Only compound 5 provided indication for a central analgesic activity since it was active in hot plate test although with a low potency. The findings obtained in these in vivo and in vitro studies indicate that these compounds do not share the same mechanism of action of acetaminophen. All of the compounds under study present lower acute toxicity than acetaminophen when orally administered in mice.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi Parma, Italy. pvicini@ipruniv.cce.unipr.it
authors.forename: Paola
authors.initials: P
authors.lastname: Vicini
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.forename: Loredana
authors.initials: L
authors.lastname: Amoretti
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D019342:Acetic Acid / Q000009:adverse effects; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000737:chemistry; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced; D010147:Pain Measurement / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; D008070:Lipopolysaccharides; D010276:Parasympatholytics; D010975:Platelet Aggregation Inhibitors; D013844:Thiazoles; C466948:benzisothiazole; D000082:Acetaminophen; D019342:Acetic Acid