Interaction of rat lung SSAO with the novel 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-(2-pyrolyl)-2-pyrazoline derivatives

Abstract

Interactions of twelve new synthesized 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-pyrolyl-2-pyrazoline derivatives with rat lung semicarbazide-sensitive amine oxidase (SSAO) were assessed. Pyrazoline derivatives were synthesized according to previous methods and SSAO was purified from the crude microsomal fractions of rat lung.Three compounds (3e, 3f, 3k) with a p-methoxy group at the phenyl ring inhibited rat lung SSAO non-competitively and irreversibly, and showed higher affinity towards SSAO when expressed in terms of IC(50) for SSAO/Monoamine oxidase B (MAO-B). Since these novel pyrazoline derivatives have been found to act as suicide inhibitors of SSAO, the semicarbazide group in these molecules may be responsible for the SSAO inhibitory action. It is suggested that these compounds cannot enter the first small active site cavity of SSAO and may interact tightly with another binding site or with some other reactive groups present in the molecule. Compound 3e showed the highest inhibitory activity on rat lung SSAO. The novel pyrazoline derivatives may be used to discriminate between Cu- and FAD-containing amine oxidases and may have promising features as anti-Parkinson agents if the SSAO-inhibitory effects can be supported by in vivo studies.

The State of the Art of Pyrazole Derivatives as Monoamine Oxidase Inhibitors and Antidepressant/Anticonvulsant Agents

“…4) and exhibited a high synthetic accessibility which permitted a large number of chemical changes. Many works explored all the possible substitutions of this nucleus with particular attention to the N1, C3, and C5 positions and presented a plethora of pyrazolines which were reported to have MAO inhibitory, antidepressant activity, different amine oxidase (AO) inhibition activities [18], such as swine kidney diamine oxidase (SKDAO), bovine serum amine oxidase (BSAO), and semicarbazide sensitive amine oxidase (SSAO), comparable to or higher than the reference compounds. At the same time, some of the pyrazoles, which were presented as selective MAO-B inhibitors, were also found to inhibit acetylcholinesterase (AChE) activity, and have been suggested for the treatment of cognitive dysfunction in AD.…”

“…The same derivatives have been also assayed as SSAO inhibitors because increased plasma SSAO activities were reported in alcoholics, and in patients with diabetes, Alzheimer's, Parkinson's, and vascular diseases. Thus, the design and synthesis of new compounds of this scaffold as specific SSAO inhibitors may be also useful for discriminating between MAO and SSAO and for developing novel therapeutic agents [18].…”

Parkinson's Disease Management. Part II- Discovery of MAO-B Inhibitors Based on Nitrogen Heterocycles and Analogues

“…derivatives were found to be potent and selective MAO-B inhibitors [72][73][74][75]. These derivatives were investigated for their interaction with rat lung semicarbazide-sensitive amine oxidases (SSAOs) [74] and as dual target agents (MAO-B inhibitors and anti-inflammatory/analgesics) for the treatment of Alzheimer's Disease [66].…”

“…These derivatives were investigated for their interaction with rat lung semicarbazide-sensitive amine oxidases (SSAOs) [74] and as dual target agents (MAO-B inhibitors and anti-inflammatory/analgesics) for the treatment of Alzheimer's Disease [66]. The synthesis, MAO-B inhibition assays, and pharmacophoric features of a series of 1-acetyl-3-aryl-4,5-dihydro-(1H)-pyrazoles have also been reported and the results indicate that these derivatives are very potent and selective towards MAO-B [75].…”

Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors

“…1). [22][23][24][25][26][27][28][29][30][31] The discovery of this class of drugs has led to a considerable increase in modern drug development and also pointed out the unpredictability of biological activity arising from structural modifications of a prototype drug molecule.…”