Synthesis of Some Pyridazinylacetic Acid Derivatives as a Novel Class of Monoamine Oxidase-A Inhibitors

Abstract

NotesMonoamic oxidase (MAO) (EC 1.4.3.4) is an integral flavin-containing enzyme of the outer mitochondrial membrane which is responsible for regulation and metabolism of major monoamine neurotransmitters such as serotonin (5-OH tryptamine), noradrenaline and dopamine. It is also involved in the biodegradation of exogenic amines such as benzylamine, tyramine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTT), 1-methyl-4-phenyl pyridium (MPP ϩ ), and a Parkinsonian-producing neurotoxin.2) It is found in two different isoforms designated as MAO-A and MAO-B which are encoded by two different genes 3) and distinguished by different substrate specificities and sensitivities to the selective inhibitors. 4)The new generation of MAO inhibitors is characterized by their relative specificities for the MAO subtypes and in some cases by the reversibility of their actions. In spite of considerable progress in our understanding of the interactions of the two enzyme forms with their preferred substrates and inhibitors, no general rules are yet available for the rational design of potent and selective inhibitors of MAO. This is partly due to the fact that the mechanism of interaction of several new drugs with MAOs has not been fully characterized. Therefore, the discovery of several selective MAO inhibitors has relied on serendipity. Preferential MAO-A inhibitors have been recognized as therapeutically useful antidepressants 5) , while MAO-B inhibitors have been found to be beneficial in the treatment of Parkinson's disease and Alzheimer's disease. 6,7)Recently, we have demonstrated a series of 3-benzyl-2-substituted quinoxalines as selective MAO-A inhibitors bearing substituted amino or hydrazino functionalities at position 2 (e.g. 2-morpholinoethylamino, 2-hydroxyethylamino, hydrazino, etc).8) The rational design of these compounds was based on a hybrid structure of known inhibitors. The aim of the present study was to design MAO-A inhibitors while taking into consideration various factors responsible for selectivity against the A isoform, 9) namely i) the presence of electron-rich aromatic moieties (e.g. Bazinaprine 10) ), ii) the presence of hydrazido functionality (e.g. Iproniazid 11) ), iii) the presence of an ethoxycarbonyl methylene group side chain of an aromatic system (e.g. Eugenol analog 12) ); exchanging the ester group with an amido group was also considered, and iv) the benzyl group was retained in the new model compounds in Fig. 1.The new substituted pyridazine-1-yl acetic acid derivatives (2, 3, 5) were designed as selective monoamine oxidase-A inhibitors. The synthesis and biological evaluation of these compounds were described. As a preliminary result of the biological investigation, compound 5d showed the highest MAO-A selectivity and could be the lead compound for designing more potent and selective MAO-A inhibitors.First, the 4-benzyl-2H-pyridazin-3-one derivatives 1 were prepared. The reaction of the 4-benzyl-2H-pyridazin-3-one derivatives 1 with bromo ethyl acetate in dimethyl formamide in the presence...

α-Ketoamino acid ester derivatives as promising MAO inhibitors

“…In the course of our ongoing studies aimed at the synthesis of heterocyclic compounds of potential pharmaceutical relevance, [9][10][11] here we focused on a novel family of a-ketoamino acid ester derivatives as MAO inhibitors.…”

“…7,8 Among the compounds studied as MAO inhibitors, heterocyclic hydrazines and hydrazides are prevalent. N 0 -Propan-2-ylpyridine-4-carbohydrazide, under the trade names of ipronid, iprozid, marsilid, propilniazida and rivivol, was the first modern antidepressant to be introduced into the market.In the course of our ongoing studies aimed at the synthesis of heterocyclic compounds of potential pharmaceutical relevance, [9][10][11] here we focused on a novel family of a-ketoamino acid ester derivatives as MAO inhibitors.The rational design of these compounds was based on hybrid structure of known inhibitors and previous reported substituted pyridazine-1-yl acetic acid derivatives I which were established as selective monoamine oxidase-A inhibitors. 11 The aim of the http://dx.…”

“…11 The aim of the present study was tailoring MAO-A inhibitors considering some factors responsible for selectivity against A isoform 12 which are (i) the presence of electron-rich aromatic moieties (e.g., pargyline), (ii) the presence of amide functionality (e.g., Iproniazid 13 ), (iii) the presence of ethoxycarbonyl methylene group (e.g., Eugenol analog 14 ), (iv) the presence of amino acid moiety (I), 11 Figure 1.…”

Synthesis and Preliminary Biological Evaluation of 1,3,5-Triazine Amino Acid Derivatives to Study Their MAO Inhibitors

“…In addition, substituted pyridazine-1-yl acetic acid derivatives [9], and α-ketoamino acid ester derivatives [10] were established as selective monoamine oxidase-A inhibitors.…”

“…The aim of the present study was to tailor MAO-A inhibitors by designing a hybrid from different possible active sites of previously known MAO-A inhibitors, based on the following considerations: (i) the presence of electron-rich aromatic moieties (e.g., moclobemide [34],bazinaprine [35], quinoxaline derivatives [7,8]); (ii) the presence of morpholine moiety (e.g., moclobemide [34], bazinaprine [35]); and (iii) the presence of amino acid moiety [9,10]). The target compounds were designed to study the effect of molecular variation on MAO inhibitory activity, Figure 1. …”