Franco Gatta

Synthesis of imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines and 1,2,4-triazolo[5,1-i]purines: new potent adenosine A2 receptor antagonists

Abstract A number of 2- or 4-fluorobenzylderivatives of imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[5,1-i] purine have been synthesized. The interaction with the adenosine A2 and A1 receptors was evaluated using selected biological assays. The highest degree of activity was displayed by the 5-amino-2-(2-furyl)-7-(or 8-)-fluorobenzyl-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine 13e, f and 18e, f and -3-fluorobenzyl-1-2-4-triazolo[5,1-i] purines 19e, f. The compound 18f was found to be the most potent A2 antagonist in our series with a selectivity similar to that of the reference compound CGS 15943, but with 75-fold more activity in the platelet aggregation model.

Development of a tandem thin-layer chromatography–high-performance liquid chromatography method for the identification and determination of corticosteroids in cosmetic products

Abstract A solid-phase extraction clean-up and and a liquid chromatographic method with ultraviolet detection were developed for the analysis of 51 corticosteroids in cosmetic samples in order to screen commercial samples for the presence of undeclared synthetic corticosteroids. A thin-layer chromatographic analysis was carried out on silica gel plates, using different eluants and detection reagents. When such a preliminary chromatographic separation gave some indications about the presence of steroid compounds, the methanol extracts from real samples were applied to a solid-phase extraction C 18 cartridge, and the analytes eluted with ethyl ether. The high-performance liquid chromatographic separation was then carried out for the identification and determination of the analytes using a Purospher RP-18 column, an isocratic or a gradient elution with a mixture acetonitrile–water and a photodiode-array detector. The accuracy of the method was determined by spiking experiments on home-made cosmetic samples. The analytical recoveries were satisfactory.

Effects of the new A2 adenosine receptor antagonist 8FB-PTP, an 8 substituted pyrazolo-triazolo-pyrimidine, on in vitro functional models.

1 We have characterized the in vitro pharmacological profile of putative A2 adenosine antagonists, two non‐xanthine compounds, 5‐amino‐8‐(4‐fluorobenzyl)‐2‐(2‐furyl)‐pyrazolo [4,3‐e]‐1,2,4‐triazolo[1,5‐c] pyrimidine (8FB‐PTP) and 5‐amino‐9‐chloro‐2‐(2‐furyl 1,2,4‐triazolo [1,5‐c] quinazoline (CGS 15943), and the xanthine derivative (E)7‐methyl‐8‐(3,4‐dimethoxystyryl)‐1,3‐dipropyl‐xanthine (KF 17837). 2 In binding studies on bovine brain, 8FB‐PTP was the most potent (Ki = 0.074 nm) and selective (28 fold) drug on A2 receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. 3 In functional studies, 8FB‐PTP antagonized 5′‐N‐ethyl‐carboxamidoadenosine (NECA)‐induced vasorelaxation of bovine coronary artery (pA2 = 7.98) and NECA‐induced inhibition of rabbit platelet aggregation (pA2 = 8.20). CGS 15943 snowed weak activity in the platelet aggregation model (pA2 = 7.43) and failed to antagonize NECA‐induced vasodilatation. KF 17837 was ineffective in both models up to micromolar concentrations. 4 Antagonism of A1‐mediated responses was tested versus 2‐chloro‐N6‐cyclopentyladenosine (CCPA) in rat atria. 8FB‐PTP and CGS 15943 also antagonized competitively the negative chronotropic response induced by CCPA. Conversely, KF 17837 was unable to reverse A1‐mediated responses. 5 8FB‐PTP is a potent and competitive antagonist of responses mediated by A2 adenosine receptors. The data provided a basis to reduce, by further chemical modifications, the affinity at A1 receptor and therefore enhance A2 receptor selectivity.

Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease.

In order to develop new cholinesterase agents effective against Alzheimers disease (AD) we synthesized some phenylcarbamates structurally related to Rivastigmine and evaluated their in vitro and in vivo biological activity. Among the compounds which displayed the most significant in vitro activity, 1-[1-(3-dimethylcarbamoyloxyphenyl)ethyl]piperidine (31b), in addition to a simple and cheaper synthesis, showed lower toxicity and very similar therapeutic index in comparison with Rivastigmine.

(E)-1-(Heterocyclyl or cyclohexyl)-2-[1,3,7-trisubstituted (xanthin-8-yl)] ethenes as A2a adenosine receptor antagonists

Some 1,3,7-trisubstituted-8-styrylxanthine analogues, with the aryl group replaced by a heterocycle or cyclohexane ring, were prepared and evaluated for their interaction with the A1 and A2a adenosine receptors. The highest degree of activity was displayed by the 1,3-dipropyl-7-methyl-8-[2-(3-thienyl)ethenyl]xanthine 4cdi, which was found to be a potent and selective A2a antagonist in binding assays (Ki = 19 nM, A1/A2a ratio = 30).

Synthesis of 1,2,3,4-Tetrahydroacridine and 5,6,7,8-Tetrahydroquinoline Derivatives as Potential Acetylcholinesterase Inhibitors

This paper describes the synthesis of 1,3,4,5-tetrahydropyrazolo[3,4,5-kl]acridine and 11-amino-1,3,4,5-tetrahydroazepino[3,2-b]quinolin-2-one obtained by Schmidt reaction of 9-amino-3,4-dihydroacridin-1(2H)-one and the preparation of 4,5-dihydro-3H-isoxazolo[3,4,5-kl]acridine obtained in the same manner starting from 3,4-dihydroacridine-1,9(2H,10H)-dione. The corresponding pyrazolo[3,4,5-de]quinoline and isoxazolo[5,4,3-de]quinoline are also reported. The compounds have been prepared with the aim of studying their possible activity as acetylcholinesterase inhibitors

Physostigmine analogs anticholinesterases: effects of the lengthening of the N-carbamic chain of the inhibition kinetics

Data are presented about the inhibitor power of new carbamates against acetylcholinesterase. The study was carried out on two series of physostigmine analogs, N-alkyl and N-methyl,N-alkylphysostigmines. For these inhibitors, the second-order rate constants for inhibition, ki, and the first-order rate constants of reactivation, k3, have been determined. From the reported results, electronic, hydrophobic and steric effects, due to the enhancement of the alkyl chain, may have influenced all kinetics parameters discussed. In comparison to physostigmine, both the new N-methyl,N-alkylphysostigmines and the N-alkylphysostigmines showed a non-linear decrease in the values of ki and k3. This study presents the hydrophobic interactions as an important factor not only in determining carbamylation but also decarbamylation rates constants.

Synthesis of some 1-(dihydroxypropyl)pyrazolo[3,4-d]-pyrimidines and in vivo evaluation of their antileishmanial and antitrypanosomal activity

Abstract A number of 1-(2,3-dihydroxypropyl)- and 1-[2-(1,3-dihydroxypropyl)]pyrazolo[3,4-d]pyrimidines were synthesized. Some of these compounds were evaluated for their activity against Leishmania infantum and Trypanosoma brucei brucei in mice. The highest degree of antileishmanial activity was displayed by the 4-amino-1-(RS)-(2,3-dihydroxypropylpyrazolo[3,4-d]pyrimidine 11a , which yielded a 87% and 96% parasite inhibition in a standard 5-day test and in a long-term (14 days) treatment, respectively, though full cures of animals were not achieved. On the contrary, this derivative did not significantly prolong the survival of T b brucei infected mice.

Isomeric methoxypyridine-1-oxides and 1-methoxypyridones electronic spectra and structure

Abstract The electronic spectra of the isomeric forms of hydroxypyridine-1-oxides and 1-hydroxypyridones were calculated by the CNDO/CI method. Transition energies, intensities and assignments were compared with the u.v. spectra recorded for the first time on all the methyl-substituted isomers under similar conditions in non-aqueous solvents. Ground state properties of the same compounds were calculated after a full geometry optimization using the CNDO/2 and MINDO/3 approximations.

Studies on a new series of THA analogues: Effects of the aromatic residues that line the gorge of AChE

A series of N‐monoalkylsubstituted 1,2,3,4‐tetrahydro‐9‐aminoacridines have been prepared after modelling simulation of the AChE–inhibitor complex. Molecular modelling has predicted a number of hydrophobic residues to be involved in the catalytic mechanism of this interaction between the binding sites of AChE and this series of aminoacridines. In these compounds the acridine moiety becomes sandwiched between the rings of PHE330 and TRP84. In particular, the alkyl chain shows the important role of aromatic groups as binding sites. Their in vitro inhibitory properties (enzyme from Electrophorus electricus) confirm the aromatic groups as a general and significant characteristic of the mechanism of AChE inhibition.