Elsevier

Bioorganic & Medicinal Chemistry

Volume 15, Issue 24, 15 December 2007, Pages 7809-7829
Bioorganic & Medicinal Chemistry

Synthesis and HMG CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents

https://doi.org/10.1016/j.bmc.2007.08.044Get rights and content

Abstract

A series of novel 4-thiophenyl quinoline-based mevalonolactone derivatives were synthesized from ethyl 6,7,8-trisubstituted-4-chloro-quinoline-3-carboxylates by several reactions and evaluated for their ability to inhibit the rat HMG CoA reductase in vitro. It was found that substitution with a variety of thiophenyl groups at position 4 in quinoline resulted in retention or enhancement of the inhibition and the preferable groups were 4-isopropyl-thiophenyl and 3-methoxy-thiophenyl. (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-isopropylthiophenyl-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A16) and (4R, 6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A23) were approximately three times more potent than rosuvastatin or pitavastatin in inhibiting HMG CoA reductase and selected as the hypocholesterolemic candidates for further evaluation.

Graphical abstract

Novel 4-thiophenyl quinoline-based HMG CoA reductase inhibitors were synthesized. Some compounds showed great potency in vitro.

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Introduction

Hypercholesterolemia is well recognized as a primary risk factor in atherosclerotic diseases and coronary heart disease. Clinical studies with lipid-lowering agents have demonstrated that decreasing elevated serum cholesterol levels reduces the incidence of cardiovascular mortality.1 The class of drugs called statins are currently potent hepocholesterolemic agents for reducing low-density lipoprotein (LDL) particle concentration in the bloodstream by competitive inhibiting 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), a major rate-limiting enzyme in cholesterol biosynthesis.2 Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin.

The structure of statins is characterized by desmethylmevalonic acid or the lactone, the pharmacophore which is connected to a lipophilic ring, such as hexahydronaphthalene, indole, pyrrole, pyrimidine, or quinoline, by a linking element (a two-carbon spacer).3 Numerous attempts to find new potent compounds and systematical QSAR study on heteroaromatic motifs have been undertaken.4, 5 Sliskovic6 and Suzuki3 et al. found that some quinoline derivatives had potent inhibition on HMG CoA reductase. They disclosed the active compounds such as pitavastatin in which the desmethylmevalonic acid portion was linked through a trans-ethylene group to position 3 in quinoline, and a 4-fluorophenyl and 2-cyclopropyl groups were preferable substituents. The introduction of chloro, methyl, or methoxy group to the 6-, 7-, or 8-position of the quinoline nucleus may increase the inhibitory potency.

As part of our investigations on quinoline derivatives with pharmacological interests,7 we made our efforts toward optimization of the inhibition on HMG CoA reductase using a quinoline as the central ring. And herein, we describe the preparation of quinoline-containing mevalonolactones (compounds A), in which the lactone moiety was connected to position 3 of the quinoline nucleus via a trans-ethylene spacer and the nucleus was flanked at position 4 by substituted thiophenyl as a lipophilic group, and at position 6, 7, 8 by different groups, such an H, F, Cl substituted thiophenyl (see Fig. 1). The inhibition on HMG CoA reductase of these novel 4-thiophenyl quinoline derivatives will also be reported.

Section snippets

Chemistry

The new 4-thiophenyl quinoline derivatives (A) were synthesized in optically pure forms by the general method shown in Scheme 1.

The aromatic nucleophilic substitution (SNAr) reaction of ethyl halo-quinoline-3-carboxylates (i1i4) with thiophenol, 4-fluorothiophenol, 3-methoxythiophenol, or 4-isopropylthiophenol was highly regiospecific to afford the 4-monosubstituted (ii1ii16), 4,7-disubstituted (ii17ii28), 4,7,8-trisubstituted (ii29ii36) or 4,6,7,8-tetrasubstituted (ii36ii40) products by

Bioassay

The inhibitory activity of compounds A, with rosuvastatin, pitavastatin, atorvastatin, and fluvastatin as the references on rat liver HMG CoA reductase, was assayed spectrophotometrically, following the method of Kleinsek9 whereby the rate of decrease in absorbance at 340 nm due to the oxidation of NADPH was measured. The enzyme preparation and assay procedures used in this study were the same as those described in the literature.10, 11, 12, 13

Results and discussion

  • (1)

    Effects of modification of 4-position. For known pitavastatin analogues, a phenyl group is connected at position 4 in the quinoline and it is located in the ortho to the pharmacophore group at position 3. This substitution pattern is also found in other artificial HMG CoA inhibitors such as fluvastatin, atorvastatin, and rosuvastatin which belong to the indole, pyrrole and pyrimidine derivatives, respectively. The 4-thiophenyl, 4-(4-fluoro-thiophenyl), 4-(3-methoxy-thiophenyl) or

Conclusion

A series of 4-thiophenyl quinoline-based mevalonolactones was synthesized to evaluate their ability to inhibit HMG CoA reductase in vitro. It was found that substitution with a variety of thiophenyl groups at position 4 in quinoline resulted in retention or enhancement of the inhibition, and the preferable groups were 4-isopropyl-thiophenyl and 3-methoxy-thiophenyl. Secondly, in agreement with the previous literature, substitution at positions 6, 7, and 8 of the quinoline nucleus moderately

Experimental

Melting points were determined on an Electrothermal Melting Point Apparatus and were uncorrected. Samples were characterized on a 400 MHz Nuclear Magnetic Resonance Spectrometer with either deuterated dimethylsulfoxide or deuterated chloroform as solvent. Mass spectra were recorded by an LC–Platform Mass Spectrometer using Electrospray Ionization.

References and notes (13)

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