title: Synthesis of novel 4,5-diphenylthiazole derivatives as potential acyl-CoA:cholesterol O-acyltransferase inhibitors.
abstract: Several novel N-(4,5-diphenylthiazol-2-yl)-N'-aryl or alkyl (thio)ureas and N-(4,5-diphenylthiazol-2-yl)alkanamides were prepared as potential acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitors. Synthesis was accomplished by reaction of 2-amino-4,5-diphenylthiazole with the suitable isocyanate, isothiocyanate or acyl chloride. Some analogues without the 5-phenyl substituent or both the phenyl groups in 4 and 5 position of the thiazole ring were also prepared. Moreover, some bioisosters of the title compounds in which the thiazole ring was replaced by an imidazole were synthesized starting from the 2-amino-4,5-diphenyl-1H-imidazole. The ability of synthesized compounds to inhibit ACAT was evaluated in vitro by measuring the formation of cholesteryl[14C]oleate from cholesterol and [1-14C]oleoyl-CoA in rat liver microsomes. Among the tested compounds, only some thiazole ureas were able to inhibit ACAT in a reasonable degree. N-(4,5-diphenylthiazol-2-yl)- N'-[2,6-bis(2-methylethyl)phenyl] urea (11) and N-(4,5-diphenylthiazol-2-yl)-N'-n-butyl urea (16) were the most active compounds in the series showing IC50 values in the low micromolar range.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: L
authors.initials: L
authors.lastname: Salerno
authors.forename: P
authors.initials: P
authors.lastname: Milla
authors.forename: M
authors.initials: M
authors.lastname: Siracusa
authors.forename: L
authors.initials: L
authors.lastname: Cattel
authors.forename: F
authors.initials: F
authors.lastname: Russo
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology