Giovanni Morini

Heteroarylaminoethyl and heteroarylthioethyl imidazoles. Synthesis and H3-receptor affinity

Summary -- The synthesis of new H3-receptor antagonists, 4-(2-heteroarylaminoethyl) and 4-(2-heteroarylthioethyl) imidazoles and their H3-receptor affinity obtained from competitive binding curves vs [3H]-NC~-methylhistamine ([3H]NAMHA) on rat brain cortex membranes are described. These compounds are derived from structural modulations of thioperamide and were synthesized in order to study binding interactions with H3-receptors and find alternative lead compounds with H3-receptor antagonist activity. The new compounds differ from thioperamide by the following features: 1) the N-cyclohexylcarbothioamide moiety of thioperamide has been replaced by a benzothiazole (1); 2) the piperidine ring has been replaced by more flexible aminoethyl and thioethyl chains, in order to lower the excessive rigidity of 1 and to test the importance of the tertiary piperidine nitrogen; and 3) the benzothiazole moiety of 1 has been replaced by other heterocyclic nuclei, endowed with different lipophilic, steric and hydrogen-bonding features. Some of the compounds tested showed good affinity for central H3-receptors (pKi range: 5.89-7.96) and can be considered as lead compounds for further optimization studies. The most lipophilic compounds showed higher affinities among benzo-condensed compounds, while imidazolylthioethyl imidazoles were more potent in displacing [3H]NAMHA than thiazolylthioethyl and thiazolylaminoethyl imidazoles which suggests an interaction between the annular NH of the imidazolylthioethyl moiety and the binding site. heteroarylglaminoethylimidazole / heteroarylthioethylimidazole / histamine H3-receptor affinity / [3H]-Na-methylhistamine / rat brain cortex membrane

Dual-Acting Drugs: an in vitro Study of Nonimidazole Histamine H3 Receptor Antagonists Combining Anticholinesterase Activity

Dual‐acting compounds that combine H3 antagonism with anticholinesterase properties are currently emerging as a novel and promising therapeutic approach in the treatment of multifactorial disorders primarily characterized by cholinergic deficits such as Alzheimers disease. A series of novel nonimidazole H3 ligands was developed from the chemical manipulation of 1,1′‐octa‐, ‐nona‐, and ‐decamethylene‐bis‐piperidines—H3 antagonists that had been the subject of previous investigations. These compounds were evaluated for in vitro binding affinity, antagonistic potency, and selectivity at rodent and human histamine H3 receptors, inhibitory activity at rat brain cholinesterase, and in vivo CNS access and cholinomimetic effects. Within the present series, the tetrahydroaminoacridine hybrid 18 stands out as one of the most attractive molecules, synergistically combining nanomolar and selective H3 antagonism with remarkable anticholinesterase activity. From this original starting point, it is hoped that future investigations will lead to dual‐acting compounds that can selectively enhance central cholinergic neurotransmission and thus facilitate the treatment of cognitive disorders.

Effect of Cl-substitution on rooting-or cytokinin-like activity of diphenylurea derivatives

Twenty-eight Cl-substituted diphenylurea derivatives differing in either the number and the position of the substituents, or in the type of substitution, that is, symmetric or asymmetric, were synthesized. Their hypothetical enhancement of rooting activity was assayed using the mung bean shoot bioassay; their possible cytokinin-like activity was assessed using the betacyanin (so-called “amaranthin”) accumulation test and the tomato regeneration test. Seven Cl-substituted diphenylurea derivatives (2E, 4A, 4B, 4E, 4G, 6A, 6B) having two substituted phenyl rings showed the capacity to enhance adventitious root formation in mung bean shoots. Furthermore the presence of a halogen substituent was not sufficient to reach the adventitious rooting activities shown by the N,N ′-bis-(2,3-methylenedioxyphenylurea) and the N,N ′-bis-(3,4-methylenedioxyphenylurea), two diphenylurea derivatives for which an interaction with auxin was the first reported in enhancing adventitious root formation. Seven compounds (1B, 3E, 3D, 4B, 4E, 4F, 6B) showed cytokinin-like activity and three of them (4B, 4E, 6B) also evidenced rooting activity, once more demonstrating the wide action spectrum of diphenylurea derivatives.

Synthesis and biological assays of new H3-antagonists with imidazole and imidazoline polar groups

New histamine H3-receptor antagonists were synthesised and tested on rat brain membranes and on electrically stimulated guinea-pig ileum. The new compounds have a central polar group represented by a 2-alkylimidazole or a 2-thioimidazoline nucleus. The effect of the polar group basicity on the optimal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl ring, was investigated. The best affinity values, obtained by displacement of [3H]-RAMHA from rat brain, were obtained for the 2-alkylimidazole derivatives (2a-f) with tetramethylene chain (pKi 8.03-8.97), having an intermediate basicity between that of the previously reported 2-thioimidazoles (1a-i) and that of 2-alkylthioimidazolines (3a-h). In contrast, a general lowering of affinity (pKi 5.90-7.63) was observed for compounds of the last series (3a-h), with a complex dependence on the terminal lipophilic group and chain length.

Synthesis and cytokinin-like activity of 7-chloro-imidazo[1,2-c]pyrimidines

Abstract Some 5-amino substituted 7-chloro-imidazo[1,2- c ]pyrimidines and 7-chloro-8-methylthio-imidazo[1,2- c ]pyrimidines were synthesized for further information on the role of the purine ring in cytokinin structure/activity relationships. Their cytokinin-like activity was examined using four different tests: expansion of cucumber etiolated cotyledons; formation of chlorophyll in etiolated cotyledons of cucumber; preservation of chlorophyll breakdown in sections of barley leaves; inhibition of root growth in intact wheat seedlings. Compounds with the imidazopyrimidine ring were generally less active than those with the purine ring, with the exception of the pentenylamino derivatives, which showed an activity comparable with that of the control, kinetin.

Diheteroarylurea derivatives as adventitious rooting adjuvants in mung bean shoots and M26 apple rootstock

The present research investigates the biological profile of eight symmetrical diheteroarylureas and phenylheteroarylureas, testing their hypothetical cytokinin-like activity and rooting activity. Cytokinin-like activity was assayed by the betacyanin (so-called amaranthin) accumulation test and by the tomato regeneration test. The rooting activity was assessed using the mung bean rooting test, the apple stem slice test and the rooting of apple microcuttings. Three compounds, 1,3-di(pyrazin-2-yl)urea (3a), 1,3-di(benzo[d]oxazol-5-yl)urea (3b) and 1,3-di(benzo[d]oxazol-6-yl)urea (3c), enhanced adventitious root formation in apple stem slice test, but only 3b and 3c were active in the mung bean rooting test. Compound 3b, that showed the best rooting activity, was also able to enhance the adventitious root formation in apple microcuttings. None of the compounds showed cytokinin-like activity.

Benzisothiazoles and β-adrenoceptors: Synthesis and pharmacological investigation of novel propanolamine and oxypro-panolamine derivatives in isolated rat tissues

In an attempt to examine the ability of benzisothiazole-based drugs to interact with β-adreno-ceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the β-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the β1-and β3-adrenoceptor-mediated responses, respectively. None of these products showed any β- adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl,tert-butyl, benzyl, and piperonyl derivatives2a- d and3a- d elicited surmountable inhibition of the isoprena-line-induced chronotropic effects in the atria, suggesting competitive antagonism at the β1-recognition site. The pA2 values revealedtert-butyl3b and the isopropyl substituted piperonyl derivatives3a to be the most effective. Remarkably, many of the 2-substituted propanola-mines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the β3-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the β-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac β1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.

Synthesis and three-dimensional quantitative structure-activity relationship analysis of H3 receptor antagonists containing a neutral heterocyclic polar group.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.

Synthesis of 1,2-benzisothiazole derivatives and investigation of their putative histaminergic activity

Some new 2-(1,2-benzisothiazol-3-yl)ethylamine derivatives were synthesised and their putative histaminergic activity was investigated in in vitro gastrointestinal and cardiac preparations. In the isolated guinea pig duodenum, all the compounds induced a tetrodotoxin- and atropine-sensitive contractile activity, which was minimally affected by mepyramine in the case of the compound 2-(1,2-benzisothiazol-3-yl)ethylamine. In the same tissue, all the compounds were devoid of any H3 receptor agonistic or antagonistic activity, but caused a nicotinic and/or 5-HT3 receptor activation. None of these compounds induced any histamine H2 agonistic or antagonistic activity in the isolated guinea pig gastric mucosa or in the isolated papillary muscle. On this latter substrate, the compound N,N,N-trimethyl-2-(1,2-benzisothiazol-3-yl)ethylammonium iodide induced a positive inotropic activity, apparently due to a release of catecholamines. These results demonstrate the substantial inability of 1,2-benzisothiazole derivatives to interact with histamine receptors in functional tests. These compounds, however, possess gangliomimetic properties, related to the activation of 5HT3 and/or nicotinic receptors.

Anti-auxin effects of 3-oxo-1,2-benzisothiazolin-2-ylalkanoic acids

Abstract Some 3-oxo-1,2-benzisothiazolin-2-ylalkanoic acids were synthesized in order to gain further information on the role of the 3-oxo-benzisothiazoline ring in anti-auxin structure/activity relationships. The anti-auxin activity was examined in relation to inhibition of flax root growth and on the interaction of the newly synthesized compounds with IAA in the pea test using short term kinetics. All compounds tested were active anti-auxins. 2-(6-chloro-3-oxo-1,2-benzisothiazolin-2-yl) Propanoic acid showed the greatest activity.