Practical Synthesis of Hydroxychromenes and Evaluation of Their Biological Activity

Jae-Chul Jung,Seikwan Oh

doi:10.3390/molecules17010240

Abstract

A simple and efficient seven steps synthesis of brodifacoum and difethialone from phenylacetyl chloride is described. The key synthetic strategies involve Friedel-Crafts acylation, intramolecular ring cyclization and condensation reaction in the presence of Brønsted-Lowry acids. It was found that brodifacoum showed favorable inhibiting activities on LPS-stimulated nitrite production in BV-2 microglia cells. Brodifacoum exhibited superior anti-inflammatory effects than difethialone. We expect that an efficient linear synthesis of 4-hydroxycoumarin derivatives and key fragments that are useful agents for the modulation of inflammation as well as inhibition of coagulation will be of practical use.

Highlights

Introduction4-Hydroxycoumarin-based anticoagulants such as the first generation anticoagulant warfarin and its related second generation anticoagulants such as brodifacoum, bromadiolone, chlorophacinone, difenacoum, coumatetralyl, flocoumafen, and difethialone are effective anticoagulant rodenticides
A simple and efficient seven steps synthesis of brodifacoum and difethialone from phenylacetyl chloride is described
The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides. These results revealed that the superwarfarins such as difenacoum, brodifacoum, flocoumafen, and difethialone showed higher anticoagulant effect than that of warfarin [1]

Summary

Introduction

4-Hydroxycoumarin-based anticoagulants such as the first generation anticoagulant warfarin and its related second generation anticoagulants such as brodifacoum, bromadiolone, chlorophacinone, difenacoum, coumatetralyl, flocoumafen, and difethialone are effective anticoagulant rodenticides. The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides. These results revealed that the superwarfarins such as difenacoum, brodifacoum, flocoumafen, and difethialone showed higher anticoagulant effect than that of warfarin [1]. A number of comparative pharmacological investigations of 4-hydroxycoumarin derivatives have shown good anticoagulant activity with low side effects and little toxicity (Figure 1). They have evoked a great deal of interest due to their biological properties and characteristic conjugated molecular architecture. Many of them possess important pharmacological efficacies including analgesic [2], anti-arthritis [3], anti-inflammatory [4], anti-pyretic [5], anti-bacterial [6], anti-viral [7], and anti-cancer [8] effects

Warfarin

Chemistry

Biology

General

Nitric Oxide Assay

Conclusions