Orazio Mazzoni

Synthesis and structure-activity relationships of 2-(substituted phenyl)-3-[3-(N, N-dimethylamino)propyl]-1,3-thiazolidin-4-ones acting as H1-histamine antagonists

2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidi n-4- ones (1-15) showed dependence of the potency of the H1-histamine antagonism on the m- and p-substituents suggesting that the aromatic moiety binds the receptor by a strong pi-interaction. Electron-withdrawing substituents decrease the potency while the electron-donating alkyl substituents, enhancing the aryl HOMO energy, increase the antihistamine activity. The m-substituents with the capability to form hydrogen bonds, seems to share an extra-interaction with hydrogen accepting or donating groups of the histamine receptor and exhibits very high potency.

PI3Kγ inhibition reduces blood pressure by a vasorelaxant Akt/L-type calcium channel mechanism

AIMS The lipid and protein kinase phosphoinositide 3-kinase γ (PI3Kγ) is abundantly expressed in inflammatory cells and in the cardiovascular tissue. In recent years, its role in inflammation and in cardiac function and remodelling has been unravelled, highlighting the beneficial effects of its pharmacological inhibition. Furthermore, a role for PI3Kγ in the regulation of vascular tone has been emphasized. However, the impact of this signalling in the control of blood pressure is still poorly understood. Our study investigated the effect of a selective inhibition of PI3Kγ, obtained by using two independent small molecules, on blood pressure. Moreover, we dissected the molecular mechanisms involved in control of contraction of resistance arteries by PI3Kγ. METHODS AND RESULTS We showed that inhibition of PI3Kγ reduced blood pressure in normotensive and hypertensive mice in a concentration-dependent fashion. This effect was dependent on enhanced vasodilatation, documented in vivo by decreased peripheral vascular resistance, and ex vivo by vasorelaxing effects on isolated resistance vessels. The vasorelaxation induced by PI3Kγ inhibition relied on blunted pressure-induced Akt phosphorylation and a myogenic contractile response. Molecular insights revealed that PI3Kγ inhibition affected smooth muscle L-type calcium channel current density and calcium influx by impairing plasma membrane translocation of the α1C L-type calcium channel subunit responsible for channel open-state probability. CONCLUSION Overall our findings suggest that PI3Kγ inhibition could be a novel tool to modulate calcium influx in vascular smooth muscle cells, thus relaxing resistance arteries and lowering blood pressure.

Cycloaddition reactions of thiazolidine derivatives. An approach to the synthesis of new functionalized heterocyclic systems

Abstract A one-pot procedure for the synthesis of two functionalized tricyclic systems having structures of benzo[ g ]isoquinoline-5,10-dione and dihydrothieno[2,3- b ]naphto-4,9-dione (DTNQ) is described. These new series were synthesized from cycloaddition reactions between naphthoquinone and arylthiazolidine derivatives, the latter acting, respectively, as highly reactive N -arylidenedehydroalanine ethyl esters (2-AD) or as amino ester nucleophilic species.

On the azetidin-2-one ring formation. A 1H NMR investigation

Abstract Azetidin-2-ones were prepared by addition of phenylacetic acid chloride to substituted benzal-anilines in DMF. The effect of temperature and substituents at the benzal-anilines on the reaction mechanism was investigated carrying out the reaction in DMF d7 in an NMR probe of a Bruker 400-MHz spectrometer at 25 and 60 °C. Proton signals, arising from two kinds of intermediates a 2-phenyl-N-(α-chlorobenzyl)-acetanilide (6) and a nitrogen-charged adduct (7) suggest that two competitive mechanisms play a role in the formation of trans and cis azetidin-2-ones. The Staudinger reaction mechanism was investigated by NMR experiments.

Synthesis and Pharmacological Evaluation of Some 4-Oxo- quinoline-2-carboxylic Acid Derivatives as Anti-inflammatory and Analgesic Agents

The synthesis and the pharmacological activity of a series of 1‐aroyl derivatives of kynurenic acid methyl ester (4‐oxo‐quinolin‐2‐carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described. The derivatives were screened in vivo for anti‐inflammatory and analgesic activities. Most of the compounds exhibited good anti‐inflammatory and analgesic activities. An automatic docking of the synthesized compounds was performed using X‐ray structures of COX‐1 and COX‐2. Docking results are in good accordance with the experimental biological data.

Antidiarrhoeal activity of new thiazolidinones related to loperamide.

A series of thiazolidinones related to loperamide was synthesized and evaluated for antidiarrhoeal activity in mice, using the castor oil test.

Binding Site of Loperamide: Automated Docking of Loperamide in Human μ‐ and δ‐Opioid Receptors

Loperamide is a piperidine analogue, acting as agonist on peripheral opioid receptors, exhibiting affinity and selectivity for the cloned μ human opioid receptor compared with the δ human opioid receptor. Automatic docking studies of loperamide, using AutoDock, on human μ‐ and δ‐opioid receptors is described. Whilst no meaningful difference was detected concerning the docking of the arylpiperidine moiety, μ/δ selectivity could be explained as a different accommodation of the two phenyl groups in two lipophylic pockets of receptors.

Synthesis and Pharmacological Activity of 2-(substituted)-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-ones

Loperamide is a well‐known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure–activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl‐cyano‐piperidinoalkyl‐thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2–6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15‐ to 80‐fold less active respect to the reference compound, Loperamide, they are much less toxic (≥1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2‐phenyl‐3‐{2‐[(4‐phenyl‐4‐cyano)piperidino]ethyl}‐1,3‐thiazolidin‐4‐one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.

Synthesis and Pharmacological Evaluation of Analogs of Indole‐Based Cannabimimetic Agents

Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids, are known to be capable of binding to cannabinoid receptors and of evoking cannabinomimetic responses. With the aim of investigating the structure–activity relationships (SAR) for the binding of non‐classical agonists to CB1 and CB2 cannabinoid receptors, we designed and synthesized a series of indole derivatives. The compounds were tested for their analgesic action by formalin test and compared to WIN 55212‐2, an AAI acting to the cannabinoid receptors. In receptor binding assay, compound 5 showed affinity for the CB1 receptor comparable to WIN 55212‐2.

Quantitative structure-activity relationships in a set of thiazolidin-4-ones acting as H1-histamine antagonists

A series of 2-(3- and 4-substituted phenyl)-3-[3-(N, N-dimethyl-amino)propyl]-1,3-thiazolidin-4-ones acting as H1-antihistaminics was investigated with a combined Hansch-CoMFA approach. The substituents at the 3- and 4-positions of the phenyl ring have been described through steric, electronic and hydrophobic parameters and correlated with pA2 values. The obtained quantitative models suggest that affinity to the receptor is promoted by hydrophobic and small 4-substituents and by 3- and 4-substituents generating a positive electrostatic potential towards a complementary receptor region.