Monoamine oxidase inhibitor properties of some benzazoles: structure-activity relationships.

Benzazoles containing two or three nitrogen atoms were screened for their inhibitory activity toward monoamine oxidases MAO-A and MAO-B. In order to clarify the mechanism of interaction of these compounds with the enzyme, their electronic structure was calculated at the ab initio level and the influence of lipophilicity on activity was investigated. The mode of binding of benzazoles to MAO-B appears different from that of previously investigated heterocycles.

Preparation and local anaesthetic activity of N-[2-(tert-amino)ethyl]- and N-(lupinyl)-benzotriazol-1/2-ylacetamides.

Two sets of N-[2-(tert-amino)ethyl]- and N-[(quinolizidin-1 alpha-yl) methyl]-benzotriazol-2-ylacetamides, bearing substituents on position 5 or 5 and 6, were prepared and tested for local anaesthetic activity in comparison with lidocaine. Most of the prepared compounds exhibited a fairly good activity comparable or superior to that of lidocaine. The introduction of substituents on the benzene ring and the replacement of the usual tert-amino alkyl chains with the quinolizidin-1 alpha-ylmethyl (lupinyl) moiety were quite profitable for both the intensity and duration of activity. One selected compound was subjected to a large pharmacological screening and found endowed with a good level of the purported antiarrhythmic activity without any other disturbing activity.

Synthesis of substituted DL-3(5-benzazolyl)alanines as dopa and alpha-methyldopa analogs and their effects on dopamine beta-hydroxylase, tyrosinase and diphenoloxidase.

The influence of bioisosteric replacement of catechol moiety of L-Dopa and alpha-Methyldopa with benzimidazole and benzotriazole ring has been examined on dopamine beta-hydroxylase and tyrosinase, in order to evidentiate an inhibitory activity on the synthesis of catecholamines and a possible antihypertensive action. The preliminary results obtained so far showed that inhibition of dopamine hydroxylase occurs at 5 x 10(-4) M concentration for the most active compounds bearing a trifluoromethyl group in the azole ring (2a,c). An analogous result was observed in the case of tyrosinase inhibition with compound 2c, while other compounds (2a,e) were equiactive (92% inhibition) at higher concentration (1 x 10(-3) M). Compound 2c was also the most active in inhibition of diphenoloxidase (83% at 6 x 10(-5) M concentration).

[Quinolozidinylalkylamines with antihypertensive activity]. / Chinolizidinilalchilammine ad azione antiipertensiva.

Since lupinylamine [(I); R = H] exhibits hypotensive activity, mainly due to ganglionic blocking properties, and it is known that a high degree of steric hindrance around the basic function of other ganglioplegic amines is of paramount importance for optimal activity, several guinolizidine derivatives were prepared. They differ in the length of the alkyl chain connected to the ring and in the position of the amino group along the chain. Some N-substituted derivatives of 2-quinolizidin-1'alpha-yl-ethylamine (II) together with O-lupinylhydroxylamine and 2-quinolizidin-1'beta-yl-ethylamine, respectively isosteric and epimeric to it, were also prepared. When administered orally to spontaneously hypertensive rats, the amines (II), (III) and (XI) produced high and long-lasting antihypertensive activity, while the remaining compounds so far tested were inactive or had only modest effect on blood pressure. Compared with alpha-methyl-DOPA, amine (II) appears to be approximately two to three times as potent. The antihypertensive activity of (II) appears to be linked to glanglionic blocking properties, since this amine proved 1,2 times as potent as mecamylamine in the inhibition of cat nictitating membrane response to stimulation of the preganglionic sympathetic nerve.