Cesarino Balsamini

Switchable Reactivity of Acylated α, β-Dehydroamino Ester in the Friedel−Crafts Alkylation of Indoles by Changing the Lewis Acid

Highly regioselective electrophilic substitution of indoles with N-acetylated alpha,beta-dehydroalanine methyl ester, promoted by different transition metal salts was achieved. The orthogonal regioselectivity provides an efficient protocol toward highly functionalized 3-indolyl-alpha-amino acids. The mechanism of the reactions was explored by NMR studies.

Structural requirements for inhibitors of poly(ADP-ribose) Polymerase

SummaryThe purpose of this study was to examine the structure/activity relationships of a series of substituted benzamides as poly(ADP-ribose) polymerase inhibitors. The experimental approach has involved the use of in vitro and in vivo assays in order to gather information either on the intrinsic activity of the benzamides or on the effect of various pharmacodynamic parameters on the activity in vivo. Although some discrepancies between the data obtained in vivo and in vitro were found in this study, results seem to indicate that most powerful inhibitors were characterized by acylation of the -NH2 function in the 3 position or by substitution in this same position with hydroxy or methoxy groups. The best inhibitors were not cytotoxic under these experimental conditions. Computed calculations of molecular electrostatic potential of these molecules were also performed and a good correlation was found between the similarity index and the experimental inhibitory activity.

A new melatonin receptor ligand with mt1‐agonist and MT2‐antagonist properties

It has been difficult, so far, to obtain melatonin analogs possessing high selectivity for the respective melatonin receptors, mt1 and MT2. In the present work, we report the synthesis and pharmacological characterization of a new compound N‐{2‐[5‐(2‐hydroxyethoxy)‐1H‐indol‐3‐yl)] ethyl} acetamide or 5‐hydroxyethoxy‐N‐acetyltryptamine (5‐HEAT). To assess the activity of the compound, the following tests were performed: affinity determination for the high‐ and low‐affinity receptor states (2‐[ I]iodomelatonin binding), potency and intrinsic activity in inducing G protein activation ([ S]GTPγS binding assay). 5‐HEAT showed little selectivity for the mt1 receptor, with pKi values of 7.77 for mt1 and 7.12 for the MT2 receptors, respectively. 5‐HEAT was able to differentiate between the high‐ and the low‐affinity receptor states in the mt1 but not in the MT2 receptor. 5‐HEAT induced a high level of G protein activation when acting through the mt1 receptor, with a relative intrinsic activity of 0.92. On the contrary, it elicited only minimal MT2 receptor‐mediated G protein activation, with a relative intrinsic activity of 0.16, and was also able to inhibit the melatonin‐induced MT2 receptor‐mediated G protein activation, with a pKB value of 7.4. In conclusion, it appears that 5‐HEAT possesses very different efficacies at the two melatonin receptors, behaving as a full melatonin receptor agonist at the mt1 and as an antagonist/weak partial agonist at the MT2 receptor. Therefore, it is a promising ligand for use in functional studies aimed at distinguishing between the effects mediated by the different melatonin receptors in the human.

Reactions of 3-carbomethoxy-2-aza-1,3-butadiene derivatives with dienophiles

Abstract The reactions of 1,1-diphenyl-3-carbomethoxy-2-aza-1,3-butadiene derivatives la-e (on C4 : H,H or H,CH3 or H,C6H5, both E and Z isomers), and of the C4 unsubstituted 1 -phenyl-1-ethoxy analogue 2, were studied with a number of electron-rich and electron-poor dienophiles, with results showing that la-e give heterocycloadducts in Diels-Alder reactions with electron-poor dienophiles. Michael adducts were obtained from the EtAlCl2 catalyzed reactions of these compounds with dimethyl acetylendicarboxylate. Compound 2 gave heterocyclic adducts as well but behaved like a nucleophile, at least in the case of the reactions with dimethyl acetylendicarboxylate and ethyl propynoate: these reactions afforded 2-azatrienes as Michael adducts that gave pyridine derivatives upon heating. The synthesis of the new 1-ethoxy-2-aza-1,3-butadiene 2 is also reported.

Synthesis of 1-(isoxazol-3-yl)triazene derivatives. Antimetastatic activity of 3,3-dimethyl-1-(5-methylisoxazol-3-yl)triazene

Summary The synthesis of some 3,3-dialkyl-1-(isoxazol-3-yl)triazenes is reported, together with preliminary biological tests on 3,3-dimethyl-1-(5-methylisoxazol-3-yl)triazene 3a . This compound exerts a selective antimetastatic action in mice bearing Lewis lung carcinoma, reducing the weight but not the number of metastases. Some unfavorable properties in the toxicological profile of 3a have discouraged further investigation of this class of compounds.

Synthesis of new C-6 alkyliden penicillin derivatives as β-lactamase inhibitors

Abstract New penicillin, penicillin sulfone and sulfoxide derivatives bearing a C-6-alkyliden substituent were prepared. Their chemical synthesis, in vitro antibacterial activity and inhibition properties against two selected enzymes representing Class A and C β-lactamases are reported. Compounds 3a – c , 7a – c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli ) or P-99 (a Class C enzyme, from E. cloacae ), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate. However, when tested in combination with amoxicillin, the same compounds did not show synergistic effects against E. coli and E. cloacae strains producing TEM-1 and P99 enzymes, respectively. This finding is most likely related to poor penetration through the bacterial cell wall, as shown by using a more permeable isogenic E. coli strain. Interestingly, a synergistic effect against a strain of S. aureus which produces PC1-enzyme (a Class A β-lactamase) was observed for compound 3a when used in combination with amoxicillin.

Synthesis and biological evaluation of 6-bromo-6-substituted penicillanic acid derivatives as β-lactamase inhibitors

The synthesis of a selected set of 6-bromopenicillanic acid derivatives with an additional C6 substituent is reported. All these substances were tested as inhibitors of class A and C β-lactamase enzymes derived from Escherichia coli (TEM-1) and E. cloacae (P99). As 6-(1-hydroxyethyl) derivatives 4c and 6c were found to be weak β-lactamase inhibitors, they were further investigated in combination with amoxicillin against a series of β-lactamase-producing bacterial strains. Some structure-activity relationships are discussed.

1-Aminocylopropane-1-carboxylic acid derivatives as ligands at the glycine-binding site of the N-methyl-D-aspartate receptor

Several 1-aminocyclopropane-1-carboxylic acid derivatives were prepared and tested for activity at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. Structural modifications involved the amino group, the carboxylic function or position 2 of the ring. When tested in a [3H]-MK-801 binding assay in the presence of glutamic acid, some of the compounds were able to activate the receptor. Two of them (3e and 6) are selective ligands for the glycine site of the NMDA receptor.

Substituent effects on 1,3-dipolar cycloadditions to some 1,1-diphenyl-2-aza-1,3-butadiene derivatives.

Abstract The reactivity and in particular the siteselectivity of [3+2] electrocyclic additions to 1,1-diphenyl-2-aza -1,3-butadienes, substituted or not on the terminal carbon with methyl and phenyl, and with a 3-carbomethoxyl group, have been investigated with the 1,3-dipolar reagents 4-nitrobenzonitrile oxide and diazomethane. The role of the 3-carbomethoxy substituent in determining the siteselectivity observed in these reactions is discussed in relation to experimental results and to conformational models of some of the tested 2-azadiene dipolarophiles calculated on AM1 bases.

3-(2-Carbamoylvinyl)-4,5-dimethylpyrrole-2-carboxylic acids as ligands at the NMDA glycine-binding site: a study on the 2-carbamoylvinyl chain modification

Twenty 4,5-dimethylpyrrole-2-carboxylic acids (5a-t) with different 2-carbamoylvinyl chains in position 3 were prepared to further investigate the relationships between structure and in vitro affinity for the strychnine-insensitive glycine-binding site. None of these compounds was superior to (E)-3-(N-phenyl-2-carbamoylvinyl)-4,5-dimethylpyrrole-2-carb oxylic acid III (pKi = 6.70), which was taken as a reference standard, but overall the results obtained indicate that the N-phenyl-2-carbamoylvinyl substituent of III may be replaced with the N-(1-adamantyl)-2-carbamoylvinyl group as in 5h (pKi = 6.20) without considerable loss of affinity. This finding adds to previous knowledge.