Abstract

The increasing life expectancy in our population makes Alzheimer’s disease (AD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that monoamine oxidase-B (MAO-B) inhibitors and antiinflammatory agents might be effective in treating AD. Therefore, a novel series of 1-thiocarbamoyl-3-substituted phenyl-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole derivatives as promising MAO-B inhibitors was synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). Most of the synthesized compounds showed high activity against both the MAO-A (compounds 3e–3h) and the MAO-B (compounds 3i–3l) isoforms. All the synthesized compounds were also tested for their in vivo antiinflammatory activity by two different bioassays namely, carrageenan-induced oedema and acetic acid-induced increase in capillary permeability in mice. In addition, analgesic and ulcerogenic activities were determined. The combined antiinflammatory data from in vivo animal models showed that compound 3k exhibited anti-inflammatory activity comparable to that of indomethacin with no ulcerogenic effects. Since compound 3k exhibits both antiinflammatory-analgesic activity and MAO-B inhibition, it needs further detailed studies.

Graphical abstract

A novel series of pyrazole derivatives was synthesized and investigated for the inhibition of MAO-A and MAO-B. The compounds were also evaluated for their antiinflammatory and analgesic activity as well as ulcerogenic risk.

Full-size image (13K)

Keywords: Alzheimer; Pyrazole derivatives; Monoamine oxidase-A/B inhibition; Analgesic-antiinflammatory activity

Article Outline

1. Introduction

2. Results and discussion

2.1. Chemistry

2.2. Biochemistry

2.3. Pharmacology

2.3.1. Analgesic activity

2.3.2. Antiinflammatory activity

2.4. Ulcerogenic liability

3. Conclusion

4. Experimental

4.1. Chemistry

4.2. Preparation of 1,3-diphenyl-2-propen-1-ones (chalcones) (2a–2c) (general procedure)

4.3. Preparation of 1-thiocarbamoyl-3,5-diphenyl-2-pyrazolines (3a–3l) (general procedure)

4.3.1. 1-N-Methylthiocarbamoyl-3-(4-methylphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.2. 1-N-Ethylthiocarbamoyl-3-(4-methylphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.3. 1-N-Allylthiocarbamoyl-3-(4-methylphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.4. 1-N-Phenylthiocarbamoyl-3-(4-methylphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.5. 1-N-Methylthiocarbamoyl-3-(4-chlorophenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.6. 1-N-Ethylthiocarbamoyl-3-(4-chlorophenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.7. 1-N-Allylthiocarbamoyl-3-(4-chlorophenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.8. 1-N-Phenylthiocarbamoyl-3-(4-chlorophenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.9. 1-N-Methylthiocarbamoyl-3-(4-methoxyphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.10. 1-N-Ethylthiocarbamoyl-3-(4-methoxyphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.11. 1-N-Allylthiocarbamoyl-3-(4-methoxyphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.3.12. 1-N-Phenylthiocarbamoyl-3-(4-methoxyphenyl)-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole

4.4. Single crystal X-ray crystallographic data of 3k

4.5. Biochemistry

4.5.1. Purification of MAO from the liver homogenates

4.5.2. Measurement of MAO activity

4.5.3. Selective measurement of MAO-A and MAO-B activities

4.5.4. Analysis of the kinetic data

4.5.5. Protein determination

4.6. Pharmacology

4.6.1. Animals

4.6.2. Preparation of test samples for bioassay

4.6.3. Analgesic activity

4.6.3.1. p-Benzoquinone-induced abdominal constriction test in mice

4.6.4. Anti-inflammatory activity

4.6.4.1. Carrageenan-induced oedema

4.6.4.2. Acetic acid-induced increase in capillary permeability

4.6.5. Ulcerogenic adverse effect

4.6.6. Statistical analysis of data

Acknowledgements

References