Paola Massarelli

Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, β-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities

Aseries of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vasodilating activities in the canine heart, affinity to beta(1)-adrenergic receptor in turkey erythrocytes and affinity to the beta(2)-adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1-fold more potent affinity to the beta(1) receptor than propranolol and 7-(3-tert-butylamino-2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the beta(2) receptor and furthermore 4386-fold more potent selectivity to the beta(2) receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 1.1-fold more potent affinity to the beta(1) receptor than propranolol and also 1147-fold more potent selectivity to the beta(1) receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the 4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative actions in the 6-oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to beta(1)-adrenoceptor nor coronary vasodilator action related with affinity to beta(2)-adrenoceptor were observed. 4-acetyl-7-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the absence of beta(1)-adrenoceptor affinity and disappearance of activity in the presence of a beta-blocker.

Chelating agents as potential antitumorals. 2-quinolylhydrazones and bis-2-quinolylhydrazones. I

Summary A number of pyruvic acid, methylpyruvate and pyruvic carboxaldehyde 2-quinolylhydrazones have been synthesized. Some bis-2-quinolylhydrazones were also obtained during the reaction with pyruvic carboxaldehyde. All these compounds have been evaluated for cytotoxicity and most display a significant in vitro activity against a variety of cell lines.

Predicting targets of compounds against neurological diseases using cheminformatic methodology

Recently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer’s disease, obsessive disorders, and Parkinson’s disease. A probabilistic method, the Parzen–Rosenblatt window approach, was used to build a “predictor” model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Molecular structures were represented based on the circular fingerprint methodology. The same approach was used to build a “predictor” model from the DrugBank dataset to determine the main pharmacological groups of the compound. The study of off-target interactions is now recognised as crucial to the understanding of both drug action and toxicology. Primary pharmaceutical targets and off-targets for the novel multi-target ligands were examined by use of the developed cheminformatic method. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. The cheminformatic targets identifications were in agreement with four 3D-QSAR (H3R/D1R/D2R/5-HT2aR) models and by in vitro assays for serotonin 5-HT1a and 5-HT2a receptor binding of the most promising ligand (71/MBA-VEG8).

Efficient microwave combinatorial synthesis of novel indolic arylpiperazine derivatives as serotoninergic ligands

An easy and convenient microwave-assisted synthesis of a small library of indolic arylpiperazine derivatives is described. Parallel and mixed pool combinatorial methods are reported and compared. The described reactions are nucleophilic substitutions of several aromatic piperazines in presence of K(2)CO(3). Good yields and short reaction times are the main aspect of these procedures. Binding assays shed additional light on the influence of the LCAPs on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors affinity and allowed to disclose three interesting compounds as 5-HT(2C), mixed 5-HT(2A)/5-HT(2C) and 5-HT(1A)/5-HT(2C) ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or atypical antipsychotic agent therapeutical profiles.

Synthesis, binding affinity and selectivity of new β1- and β2-adrenoceptor blockers

Abstract The synthesis of a new series of sesamol derivatives with β-adrenergic blocking activity is described. The affinity and selectivity of these compounds for β1- and β2-adrenoceptors were studied in comparison with those of ICI-118551 and propranolol. Some of the synthesized compounds show very good affinity for the β2-receptors of rat lung membranes and two of them provide interesting selectivity.

Anti-tumor activity of the methanolic extracts of Salvia menthifolia

In the present research we investigated the anti-proliferative activity of Salvia menthifolia Ten. (formerly Salvia menthaefolia), Lamiaceae, on a glioblastoma cell line, since up to date poor therapeutic results have been reported for treatment of malignant glioblastoma. Methanol extracts from different anatomical parts of S. menthifolia were tested on DBTRG-05MG cell line by MTT assay. The most active primary stems extract was also evaluated for apoptosis induction. Results confirmed the anti-tumor property of all the organs and demonstrated that the primary stems extract induced apoptosis after 4 h with the highest values of DNA fragmentation after 6 to 24 h. Some extracts were also HPLC analyzed for polyphenols, althought activities could be due also to other constituents and to synergistic interactions. Rosmarinic acid, caffeic acid, luteolin-7-O-glucosyde and quercitrin were found in all the extracts. The good performance revealed for S. menthifolia towards this extremely aggressive human glioblastoma cell line confirms that the genus Salvia is a natural source of anti-tumor agents though there are great differences among the various species.

Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most important neuromediator involved in numerous physiological and pathophysiological processes. In addition it is well established that 5-HT acts as a growth factor on several types of non-tumoral and tumoral cells, and recently it was also related to oncogenes. 5-HT1A receptor expression was identified in prostatic tumor cell lines (PC3 cells) and in human hormone refractory prostate cancer tissue. Based on these observations, development of 5-HT1A antagonists could be useful in inhibiting the growth of cancer cells. In order to investigate on potential use of 5-HT1A ligands as antiproliferative agents, we have analyzed a new set of 1-naphtylpiperazine derivatives. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1 and α2). All compounds were then evaluated in order to assess their antiproliferative activity using PC3 cells and the most active compounds (1 and 2) were fully characterized to define the mechanism responsible for the observed antiproliferative effect.

Synthesis, β-adrenergic blocking activity and β-receptor binding affinities of 1-substituted-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalates

Abstract The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate ( 5 ) and 1- tert -butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate ( 6 ) were synthesized from thymol ( 1 ), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 μg/kg, i.v.) and 6 (50 μg/kg, i.v.) antagonized isoprenaline (2 μg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 μg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro β 1 - and β 2 -adrenergic receptor binding assay using turkey erythrocyte membrane (β 1 ) and lung homogenate of rats (β 2 ). Both 5 and 6 showed β-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one β-adrenergic receptor. These results suggest that both the compounds possess non-selective β-adrenergic blocking activity, with the tert -butyl derivative 6 being more active than the isopropyl derivative 5 .

Synthesis and in vitro pharmacological evaluation of novel 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands.

This paper reports the synthesis of new norbornene and exo‐N‐hydroxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboximide derivatives and their binding to the 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors, in order to identify selective ligands for these 5‐hydroxytryptamine (5‐HT, serotonine) receptor subtypes. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4‐substituted piperazine) known to be critical for affinity to 5‐HT1A receptors and the proper selection of substituents led to compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected and further evaluated for their binding affinities to D1, D2 dopaminergic and α1, α2 adrenergic receptors. 4‐[3‐[4‐(2‐Furoyl)piperazin‐1‐yl]propoxy‐2‐ol]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione 3e with Ki = 5.04 ± 0.227 nM was the most active and selective derivative for the 5‐HT2C receptor with respect to other serotonin receptors, and the most selective derivative versus dopaminergic and adrenergic receptors.

New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation

Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki=0.046nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki=0.0224nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki=0.8nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.