N-Imidazolyl-4-chromanones, N-imidazolyl-1-tetralones, and their alcohols as hypolipemic agents raising high-density lipoproteins

Abstract

A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.

Antihyperlipidemic Effect of Flavonoids from Pterocarpus marsupium

“…Detection of phytochemicals in EtOAc extract.-Resolution of EtOAc extract over thin layer chromatoplates (Si02) with different developing solvents revealed the presence of seven compounds, six of which were identified as marsupsin [1], pterosupin [2], liquiritigenin [3], pterostilbene, isoliquiritigenin, and 3-(/>-hydroxyphenyl)-lactic acid by co-chromatography with authentic samples previously isolated from this source (11). The seventh compound was characterized as pterocarpol, a sesquiterpene alcohol not previously reported from this species, by its isolation and spectral comparison with reported data (14).…”

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Serum lipid levels in rats with hyperlipidemia induced by diet as well as by Triton were determined after oral administration of EtOAc extract of Pterocarpus marsupium heartwood and its flavonoid constituents, marsupsin [1], pterosupin £2], and liquiritigenin [3]. Administration of EtOAc extract for 14 consecutive days produced a significant reduction of serum triglyceride, total cholesterol, and LDLand VLDL-cholesterol levels without any significant effect on the level of HDL-cholesterol.

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“…The search for new drugs with the ability to reduce and/or regulate serum cholesterol and triglyceride concentrations has gained momentum over the years, resulting in a plethora of publications reporting significant activity of a variety of natural (1,2) and synthetic (3)(4)(5) agents. Molecular modification of naturally occurring lead compounds has also given rise to potent agents like pravastatin and simvastatin; the former prepared by replacement of the methyl group of the naturally occurring lovastatin by a hydroxyl group and the latter a methylated derivative of compactin (6).…”

Mlicrosomal Enzyme Induction, Lipoproteins and Atherosclerosis

“…Both in clinical (Luoma et al 1985b) and experimental studies (Cozzi et al 1986) the increase has been associated with elevated HDL-C levels and HDL-C/LDL-C ratios. Relationships between serum and liver lipids, proteins and apopro teins.…”

“…Microsomal enzyme inducers may increase liver size, which has been regarded as a marker of microsomal induction. Both in clinical (Luoma et al 1985b) and experimental studies (Cozzi et al 1986) the increase has been associated with elevated HDL-C levels and HDL-C/LDL-C ratios.…”