Structure activity relationships of imido N-alkyl semicarbazones, thiosemicarbazones and acethydrazones as hypolipidemic agents in rodents.
A series of nitrogen substituted N-butan-3-one derivatives of cyclic imides (phthalimide, substituted phthalimide, o-benzosulfimide, 1,8-naphthalimide, 2,3-dihydrophthalazine-1,4-dione and diphenimide) and their semicarbazone, thiosemicarbazone and acethydrazone derivatives were investigated for hypolipidemic activity in rodents. These compounds were generally potent hypolipidemic agents, lowering serum cholesterol levels on an average of 37% and serum triglyceride levels on an average of 29% after 16 days dosing at 20 mg/kg day intraperitoneally (I.P.) in mice. Several analogs, most notably the semicarbazone and acethydrazone derivatives of 1-N-(1,8-naphthalimido)-butan-3-one, demonstrated improved hypocholesterolemic activity relative to their ketone precursors. Similarly, the acethydrazone derivatives generally resulted in improved hypotriglyceridemic activity in each series of 2-(3-oxobutyl)-2,3-dihydrophthalazone-1,4-dione analogs tested. The thiosemicarbazones in mice generally resulted in a loss in hypolipidemic activity. Select compounds, 1-N-3-methylphthalimido butan-3-semicarbazone (Ig) and 1-(4-methoxyphthalazine-1(2H)-one)yl butan-3(N-acetyl)hydrazone (IVg), at 10 mg/kg/day orally administered to rats demonstrated potent hypolipidemic activity after 14 days. These compounds lowered liver, small intestine mucosa and aorta wall tissue lipids, e.g. cholesterol and triglycerides, and raised fecal excretion of cholesterol moderately and of triglyceride significantly. Rat serum lipoprotein fractions after treatment for 14 days showed that the two agents lowered VLDL cholesterol and raised HDL cholesterol content.
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208.
J M
JM
Chapman
P
P
DeLucy
O T
OT
Wong
I H
IH
Hall
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005243:Feces / Q000032:analysis; D006835:Hydrazones / Q000494:pharmacology*; D000960:Hypolipidemic Agents; D007421:Intestine, Small / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D012664:Semicarbazones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000494:pharmacology*
D006835:Hydrazones; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D012664:Semicarbazones; D013882:Thiosemicarbazones