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Structure activity relationships of imidoN-alkyl semicarbazones, thiosemicarbazones and acethydrazones as hypolipidemic agents in rodents

  • Published:
Lipids

Abstract

A series of nitrogen substitutedN-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 percursors. 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.

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Abbreviations

HDL:

high density lipoprotein

I.P.:

intraperitoneally

LDL:

low density lipoprotein

SAR:

structure activity relationship

VLDL:

very low density lipoprotein

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Authors and Affiliations

  1. Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, 29208, Columbia, SC

    James M. Chapman Jr. & Pierre DeLucy

  2. Division of Medicinal Chemistry & Natural Products, School of Pharmacy, University of North Carolina, 27599, Chapel Hill, NC

    Oi T. Wong & Iris H. Hall

Authors
  1. James M. Chapman Jr.
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  2. Pierre DeLucy
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  3. Oi T. Wong
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  4. Iris H. Hall
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Chapman, J.M., DeLucy, P., Wong, O.T. et al. Structure activity relationships of imidoN-alkyl semicarbazones, thiosemicarbazones and acethydrazones as hypolipidemic agents in rodents. Lipids 25, 391–397 (1990). https://doi.org/10.1007/BF02537982

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  • DOI: https://doi.org/10.1007/BF02537982

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