Synthesis and Antidepressant Activity of Some New Coumarin Derivatives

Nehad A Abdel-Latif

doi:10.3797/scipharm.aut-05-15

Abstract

The coumarin-3-cinnamoyl derivatives 2a-d were prepared via Claisen-Schmidt condensation of 3-acetylcoumarin 1 with different aromatic aldehydes. Cycloaddition reaction of 2b,e with guanidine and thiourea yielded the corresponding aminopyrmimidine 3a,b and thioxypyrimidine derivatives 4a,b, respectively. Compounds 4a,b were condensed with chloroacetic acid or 3-bromopropionic acid to yield coumarin 3-thiazolo-pyrimidine 5a,b and thiazinopyrimidine 6a,b derivatives, respectively. Compounds 4a,b were condensed with chloroacetic acid and aromatic aldehyde to yield the aryl methylene derivatives 7a,b which could be prepared directly by condensation of compounds 5a,b with aromatic aldehydes. Compounds 2a-e were condensed with malononitrile or ethyl cyano acetate in presence of ammonium acetate to yield cyanopyridine 8a,b and cyanopyridone 9a-d derivatives, respectively, which were prepared by condensation of 3-acetylcoumarin 1, malononitrile or ethylcyanoacetate and aromatic aldehydes in presence of ammonium acetate. Condensation of compounds 2a,b,e with o-phenylenediamine in refluxing ethanol led to the formation of 10a-c as intermediate, followed by cleavage by thermolysis to benzimidazole derivative 11 along with compounds 12a-c as mixture, which were obtained directly by fusion of a,&unsaturated ketones 2 with ophenylene diamine at 200-220°C, while compound 11 could be prepared in pure form by fusion of 1 with o-phenylene diamine at the same temperature. The pharmacological screening showed that many of these obtained compounds have good antidepressant activity comparable to Tranylcypromine® as reference drugs.

Highlights

Coumarins have been found to be physiologically active in animals as well as in man [I]
Many biological properties for coumarins have been reported such as dermal photosensitizing activity [2-41, antimicrobial [5-71, diuretic [8,9], molluscicidal and anthelminitic [I0,l I ], vasodilatory [ I2,131, estrogenic [14], anticoagulant [ I5181and antitumor [ I9-22] activities
Based on the previous findings, it is of interest to synthesize some new coumarin-3-derivatives starting with 3-acetylcoumarin and incorporating to biologically active moieties such as pyrimidine, cyanopyridine and cyanopyridone

Summary

Introduction

Coumarins have been found to be physiologically active in animals as well as in man [I]. The reaction mixture was refluxed for 5-7 hr, allowed to cool, poured onto cold water, the solid formed was collected by filtration and crystallized from the proper solvent to give compounds 3a,b, respectively. The reaction mixture was cooled and poured onto ice-water, the obtained solid was collected by filtration and crystallized from the proper solvent to give compounds 7a,b. Method 6: A mixture of compound 5a,b (2 mmol), the appropriate aldehydes (2 mmol), acetic acid (30 ml) and acetic acid anhydride (10 ml) was refluxed for 2-3 hr., allowed to cool, poured onto water the solid formed was collected by filtration and crystallized from the proper solvent to yield the title compounds 7a,b. The rest of compounds showed less than 4 folds of the activities of reference drug

Results and Discussion

Further Research on the Diuretic Activity of Newly Synthesized Coumarin

Synthesis and AntidepressantActivity of Some New Coumarin Derivatives