In vivo biological activity of antioxidative aminothiazole derivatives.
For the development of novel antioxidants having therapeutic utility, a new series of condensed 4- and 5-aminothiazole derivatives has been synthesized using simple methods. Condensed 4-aminothiazoles were prepared by the reaction of alpha-bromolactams with thioamides in ethanol and 5-aminothiazole derivatives were obtained by the treatment of 3-(acylamino)lactams with a thiating agent such as phosphorous pentasulfide and Lawesson's reagent in pyridine. In vitro assay of the condensed 5-aminothiazole derivatives showed them to be potent inhibitors of lipid peroxidation. In order to evaluate these compounds in an in vivo system, we devised a simple and reproducible method in which the inhibition of characteristic behaviors induced by spinal injection of FeCl2 was expressed numerically. Compounds having strong in vitro activity protected the central nervous system form injury caused by iron-dependent lipid peroxidation. The results suggest that the in vivo assay developed in this study should be useful as a screening method for antioxidants and also that condensed 5-aminothiazole derivatives are promising candidates for the treatment of traumatic and ischemic injury of the central nervous system.
Uchikawa
O
O
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
Fukatsu
K
K
Suno
M
M
Aono
T
T
Doi
T
T
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides; D004353:Drug Evaluation, Preclinical; D005290:Ferric Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D000975:Antioxidants; D002712:Chlorides; D005290:Ferric Compounds; D013844:Thiazoles; C024555:ferric chloride