27 results on '"Da Settimo, F."'
Search Results
2. Pharmacological characterization of a new Ca2+ sensitizer
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Dorigo, P., Floreani, M., Santostasi, G., Maragno, I., Danieli-Betto, D., Germinario, E., Magno, S. M., Primofiore, G., Anna Maria Marini, and Da Settimo, F.
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Male ,Dose-Response Relationship, Drug ,Sarcoplasmic Reticulum Ca2+Release ,Papillary Muscle ,calcium sensitivity ,Guinea Pigs ,Imidazoles ,Myocardial Contraction ,Caffeine ,Animals ,Benzimidazoles ,Calcium ,Muscle Contraction - Abstract
The benzimidazole molecule was modified to synthesize a Ca(2+) sensitizer devoid of additional effects associated with Ca(2+) overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 microM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na(+)/K(+)-ATPase, sarcolemmal Ca(2+)-ATPase, Na(+)/Ca(2+) exchange carrier, or sarcoplasmic reticulum Ca(2+) pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca(2+).
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- 2000
3. Synthesis and local anaesthetic activity of some 7-amino-2-dialkylaminoalkylpyrrolo[3,4-c]pyridine derivatives
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Da Settimo F, Am, Marini, La Motta C, Simorini F, Luchetti E, and Simone Bertini
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Male ,Solubility ,Pyridines ,Animals ,Rabbits ,Anesthetics, Local - Abstract
A number of 7-amino-2-dialkylaminoalkylpyrrolo[3,4-c] pyridin-1,3(2H)-dione derivatives were synthesized and their local anaesthetic activity was evaluated in vivo by corneal anaesthesia in rabbits. Only compounds 3,9 and 14 showed any activity, albeit lower than that of the reference drug lidocaine.
4. Acid derivatives of benzisothiazole-1,1-dioxide as inhibitors of rat lens aldose reductase
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Da Settimo, A., Primofiore, G., La Motta, C., Da Settimo, F., Francesca SIMORINI, Boldrini, E., and Bianchini, P.
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Rats, Sprague-Dawley ,Structure-Activity Relationship ,Thiazoles ,Aldehyde Reductase ,Animals ,Aldose reductase inhibitors ,Enzyme Inhibitors ,Rats - Abstract
A number of 6-substituted 1, 2-benzisothiazole-1, 1-dioxide alkanoic acids were synthesized and evaluated for crude rat lens aldose reductase inhibitory activity. The inhibitory potency of the acetic (6a, 10a), propionic (6b, 10b, 11b), and isopropionic (6c, 10c, 11c) derivatives was very similar and generally lower than that of the reference compound, Sorbinil. The presence of an acyl moiety on the amino group in position 6, as in the acetic and propionic derivatives 14a-f and 15a, b, respectively, resulted in a significant increase in activity. A good potency was shown by compounds 14g and 15g, in which a second carboxylic function is present on the 6-acylamino group. Also the open products 16, which contain the phenylsulfonyl fragment found in several known inhibitors of aldose reductase, were obtained and tested in the rat lens assay.
5. Benzisothiazole-1,1-dioxide alkanoic acid derivatives as inhibitors of rat lens aldose reductase
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Primofiore, G., Da Settimo, F., La Motta, C., Francesca SIMORINI, Minutolo, A., and Boldrini, E.
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Galactosemias ,Rats, Sprague-Dawley ,Thiazoles ,Chemical Phenomena ,Aldehyde Reductase ,Chemistry, Physical ,Lens, Crystalline ,Animals ,Enzyme Inhibitors ,In Vitro Techniques ,Glutathione ,Rats - Abstract
Derivatives of 4-substituted 1,2-benzisothiazole-1,1-dioxide alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested in rat lens enzyme. The acetic derivatives 10, 12, and 16a-d proved to be much more potent inhibitors than the propionic derivatives 11, 13, and 17a-d. The presence of an acyl moiety on the amino group in position 4 of the acetic derivatives 16a-d led to a significant increase in activity with respect to the parent compound 14. One of the most active compounds in vitro, 10, was also evaluated in vivo as an inhibitor of glutathione lens depletion in galactosemic rats, but it did not show any activity in maintaining the rat lens glutathione level, probably due to problems of ocular bioavailability or metabolism.
6. Synthesis and benzodiazepine receptor activity of some 4,5-dihydro-1H-pyrazolo [4,3-c][1,8] naphthyridine derivatives
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Da Settimo, A., Primofiore, G., Da Settimo, F., Simorini, F., Barili, P. L., Senatore, G., Martini, C., and ANTONIO LUCACCHINI
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Structure-Activity Relationship ,Animals ,Cattle ,Naphthyridines ,Ligands ,Receptors, GABA-A - Abstract
The preparation of 5-substituted 1-aryl-4,5-dihydro-1H-pyrazolo[4,3- c][1,8] naphthyridines by reaction of 5-substituted 3-hydroxymethylene-2,3-dihydro-1,8-naphthyridin-4(1H)-ones with various phenylhydrazines is described. The benzodiazepine binding activity of these compounds was evaluated in vitro. Only the 5-methyl substituted derivatives showed affinity for the benzodiazepine receptor, with K1 values ranging from 2.9 to 0.195 microM for the para-phenyl substituted compounds. A hypothesis of interaction of these ligands with the receptor site is reported.
7. Novel N(2)-Substituted Pyrazolo[3,4-d]pyrimidine Adenosine A(3) Receptor Antagonists: Inhibition of A(3)-Mediated Human Glioblastoma Cell Proliferation (dagger)
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Luciana Marinelli, Concettina La Motta, Claudia Martini, Giovanni Greco, Sandro Cosconati, Federico Da Settimo, L. Mugnaini, Simona Daniele, Barbara Cosimelli, Anna Maria Marini, Silvia Salerno, Osele Ciampi, Francesca Simorini, Maria Letizia Trincavelli, Sabrina Taliani, Vittorio Limongelli, Ettore Novellino, Taliani, S., La Motta, C., Mugnaini, L., Simorini, F., Salerno, S., Marini, A. M., Da Settimo, F., Cosconati, S., Cosimelli, Barbara, Greco, Giovanni, Limongelli, Vittorio, Marinelli, Luciana, Novellino, Ettore, Ciampi, O., Daniele, S., Trincavelli, M. L., Martini, C., Taliani, S, La Motta, C, Mugnaini, L, Simorini, F, Salerno, S, Marini, Am, Da Settimo, F, Cosconati, Sandro, Cosimelli, B, Greco, G, Limongelli, V, Marinelli, L, Novellino, E, Ciampi, O, Daniele, S, and Trincavelli, Ml
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Agonist ,MAPK/ERK pathway ,Models, Molecular ,Pyrimidine ,medicine.drug_class ,Adenosine A3 Receptor Antagonists ,Antineoplastic Agents ,CHO Cells ,Binding, Competitive ,chemistry.chemical_compound ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Adenosine A3 Receptor Agonists ,Cell Line, Tumor ,Cricetinae ,Drug Discovery ,medicine ,Cyclic AMP ,Animals ,Humans ,Phosphorylation ,Cell Proliferation ,Mitogen-Activated Protein Kinase 1 ,Glioblastoma cell ,Mitogen-Activated Protein Kinase 3 ,Kinase ,Chemistry ,Molecular biology ,Adenosine ,Enzyme Activation ,Pyrimidines ,Biochemistry ,Chemotherapy, Adjuvant ,Molecular Medicine ,Pyrazoles ,Glioblastoma ,Intracellular ,medicine.drug - Abstract
Adenosine induces glioma cell proliferation by means of an antiapoptotic effect, which is blocked by cotreatment with selective A(3) AR antagonists. In this study, a novel series of N(2)-substituted pyrazolo[3,4-d]pyrimidines 2a-u was developed as highly potent and selective A(3) AR antagonists. The most performing compounds were derivatives 2a (R(1) = CH(3) and R(2) = COC(6)H(5); K(i) 334, 728, and 0.60 nM at the human A(1), A(2A), and A(3) ARs, respectively) and 2b (R(1) = CH(3) and R(2) = COC(6)H(4)-4-OCH(3); K(i) 1037, 3179, and 0.18 nM at the human A(1), A(2A), and A(3) ARs, respectively), which counteracted the effect of the A(3) AR agonists Cl-IB-MECA and IB-MECA on human glioma U87MG cell proliferation. This effect was concentration-dependent, with IC(50) values comparable to A(3) AR binding affinity values of 2a and 2b, thereby suggesting that their effects were receptor-mediated. Furthermore, the antiproliferative activity of the new compounds was demonstrated to be mediated by the block of A(3) AR agonist activation of intracellular kinases ERK 1/2.
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- 2010
8. Non-Nucleoside Inhibitors of Human Adenosine Kinase: Synthesis, Molecular Modeling, and Biological Studies
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Sandra Gemma, Giovanni Maga, Stefania Butini, Ettore Novellino, Federico Da Settimo, Giuseppe Borrelli, Valeria La Pietra, Andrea Lossani, Daniela M. Zisterer, F. Focher, Andrea Torti, Stefania Sartini, Isabella Fiorini, Seema-Maria Nathwani, Giuseppe Campiani, Stefania Lamponi, Luciana Marinelli, Concettina La Motta, Anna Maria Ponte, Margherita Brindisi, Butini, S., Gemma, S., Brindisi, M., Borrelli, G., Lossani, A., Ponte, A. M., Torti, A., Maga, G., Marinelli, Luciana, LA PIETRA, Valeria, Fiorini, I., Lamponi, S., Campiani, G., Zisterer, D. M., Nathwani, S. M., Sartini, S., La Motta, C., Da Settimo, F., Novellino, Ettore, and Focher, F.
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Models, Molecular ,Adenosine Kinase Inhibitors ,Molecular model ,Stereochemistry ,Antineoplastic Agents ,Apoptosis ,Adenosine kinase ,Mice ,Structure-Activity Relationship ,Allosteric Regulation ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Pyrroles ,Adenosine Kinase ,Cell Proliferation ,chemistry.chemical_classification ,Biological studies ,biology ,Chemistry ,Stereoisomerism ,DNA ,Adenosine ,Recombinant Proteins ,Oxazepines ,Enzyme ,Biochemistry ,biology.protein ,RNA ,Molecular Medicine ,Phosphorylation ,Drug Screening Assays, Antitumor ,Nucleoside ,Allosteric Site ,medicine.drug - Abstract
Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non-nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells.
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- 2011
9. Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one Ring System as a Useful Template To Obtain Potent Adenosine Deaminase Inhibitors
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Concettina La Motta, Mario Del Tacca, Matteo Fornai, Francesca Simorini, Silvia Salerno, Antonio Lavecchia, Ettore Novellino, Sabrina Taliani, Federico Da Settimo, Anna Maria Marini, Corrado Blandizzi, Luca Antonioli, L. Mugnaini, Stefania Sartini, LA MOTTA, C., Sartini, S., Mugnaini, L., Salerno, S., Simorini, F., Taliani, S., Marini, A. M., DA SETTIMO, F., Lavecchia, Antonio, Novellino, Ettore, Antonioli, L., Fornai, M., Blandizzi, C., and DEL TACCA, M.
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Pyridines ,Stereochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Adenosine deaminase ,In vivo ,Catalytic Domain ,Drug Discovery ,Adenosine Deaminase Inhibitors ,Animals ,Structure–activity relationship ,Enzyme Inhibitors ,chemistry.chemical_classification ,Trifluoromethyl ,Dose-Response Relationship, Drug ,biology ,Colitis ,Rats ,Enzyme ,chemistry ,Docking (molecular) ,biology.protein ,Pyrazoles ,Molecular Medicine ,Adenosine Deaminase Inhibitor - Abstract
A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure−activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors.
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- 2009
10. 5-Amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: A Versatile Scaffold To Obtain Potent and Selective A3 Adenosine Receptor Antagonists
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Concettina La Motta, Giampaolo Primofiore, Francesca Simorini, Adriano Martinelli, Ettore Novellino, V. Sergianni, Sabrina Taliani, Giovanni Greco, Maria Letizia Trincavelli, Claudia Martini, Tiziano Tuccinardi, B Cosimelli, Osele Ciampi, Anna Maria Marini, Silvia Salerno, Federico Da Settimo, Da Settimo, F., Primofiore, G., Taliani, S., Marini, A. M., La Motta, C., Simorini, F., Salerno, S., Sergianni, V., Tuccinardi, T., Martinelli, A., Cosimelli, Barbara, Greco, Giovanni, Novellino, Ettore, Trincavelli, M. L., and Martini, C.
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Models, Molecular ,Molecular model ,Stereochemistry ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Binding, Competitive ,Chemical synthesis ,Amidine ,Radioligand Assay ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cricetulus ,Cricetinae ,Amide ,Drug Discovery ,Cyclic AMP ,Animals ,Humans ,Moiety ,Receptor ,Triazines ,Chemistry ,Triazoles ,Adenosine receptor ,Docking (molecular) ,Molecular Medicine - Abstract
Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previously reported as ligands at the central benzodiazepine receptor (BzR), possess nanomolar affinity at the A3 AR. Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1, 2-a][1,2,4]benzotriazin-1-ones IX, which maintain a nanomolar potency at the A3 AR with selectivity over the BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1, A2A, and A2B ARs. The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1, 2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one (23), which displayed a K i of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level. © 2007 American Chemical Society.
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- 2007
11. Deepening the Topology of the Translocator Protein Binding Site by Novel N,N-Dialkyl-2-arylindol-3-ylglyoxylamides
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Barbara Cosimelli, Simona Daniele, Anna Maria Marini, Eleonora Da Pozzo, Francesca Simorini, Luciana Marinelli, Concettina La Motta, Elisabetta Barresi, Sabrina Taliani, Chiara Giacomelli, Claudia Martini, Federico Da Settimo, Sandro Cosconati, Silvia Salerno, Giovanni Greco, Agostino Bruno, Ettore Novellino, Barresi, Elisabetta, Bruno, Agostino, Taliani, Sabrina, Cosconati, Sandro, Da Pozzo, Eleonora, Salerno, Silvia, Simorini, Francesca, Daniele, Simona, Giacomelli, Chiara, Marini, Anna Maria, La Motta, Concettina, Marinelli, Luciana, Cosimelli, Barbara, Novellino, Ettore, Greco, Giovanni, Da Settimo, Federico, Martini, Claudia, Barresi, E, Bruno, A, Taliani, S, Da Pozzo, E, Salerno, S, Simorini, F, Daniele, S, Giacomelli, C, Marini, Am, La Motta, C, Marinelli, L, Cosimelli, B, Novellino, E, Greco, G, Da Settimo, F, and Martini, C.
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Binding Sites ,Indoles ,biology ,Ligand ,Stereochemistry ,Chemistry ,Drug Discovery3003 Pharmaceutical Science ,Rats ,Structure-Activity Relationship ,GABA metabolism ,Receptors, GABA ,Docking (molecular) ,Molecular Medicine ,Drug Discovery ,Mitochondrial Membranes ,Translocator protein ,biology.protein ,Structure–activity relationship ,Animals ,Binding site ,Group performance - Abstract
As a continuation of our studies on 2-phenylindol-3-ylglyoxylamides as potent and selective translocator protein (TSPO) ligands, two subsets of novel derivatives, featuring hydrophilic group (OH, NH2, COOH) at the para-position of the pendent 2-phenyl ring (8-16) or different 2-aryl moieties, namely, 3-thienyl, p-biphenyl, 2-naphthyl (23-35), were synthesized and biologically evaluated, some of them showing K-i values in the subnanomolar range and the 2-naphthyl group performance being the best. The resulting SARs confirmed the key role played by interactions taking place between ligands and the lipophilic Li pocket of the TSPO binding site. Docking simulations were performed on the most potent compound of the present series (29) exploiting the recently available 3D structures of TSPO bound to its standard ligand (PK11195). Our theoretical model was fully consistent with SARs of the newly investigated as well of the previously reported 2-phenylindol-3-ylglyoxylamide derivatives.
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- 2015
12. 2-(Benzimidazol-2-yl)quinoxalines: A Novel Class of Selective Antagonists at Human A1 and A3 Adenosine Receptors Designed by 3D Database Searching
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Annalisa Sala, Giampaolo Primofiore, Ettore Novellino, Karl-Norbert Klotz, Concettina La Motta, Antonio Da Settimo, Giovanni Greco, Federico Da Settimo, Maria Letizia Trincavelli, Sabrina Taliani, D. Tuscano, Claudia Martini, Antonio Lavecchia, Manuela Iadanza, B Cosimelli, Maria Grazia Rimoli, Marina Ehlardo, Novellino, Ettore, Cosimelli, Barbara, Ehlardo, M, Greco, Giovanni, Iadanza, M, Lavecchia, Antonio, Rimoli, MARIA GRAZIA, Sala, A, DA SETTIMO, A, Primofiore, G, DA SETTIMO, F, Taliani, S, LA MOTTA, C, Klotz, Kn, Tuscano, D, Trincavelli, Ml, and Martini, C.
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Adenosine ,Databases, Factual ,Receptor, Adenosine A2A ,Stereochemistry ,Adenosine A3 Receptor Antagonists ,Adenosine-5'-(N-ethylcarboxamide) ,CHO Cells ,Adenosine A1 Receptor Antagonists ,computer.software_genre ,Binding, Competitive ,Chemical synthesis ,chemistry.chemical_compound ,Quinoxaline ,Cricetinae ,Quinoxalines ,Drug Discovery ,Animals ,Humans ,Potency ,Database ,Bicyclic molecule ,Receptor, Adenosine A1 ,Chemistry ,Receptor, Adenosine A3 ,Antagonist ,Adenosine receptor ,In vitro ,Drug Design ,Xanthines ,Molecular Medicine ,Benzimidazoles ,Selectivity ,computer - Abstract
The Cambridge Structural Database (CSD) was searched through two 3D queries based on substructures shared by well-known antagonists at the A1 and A3 adenosine receptors (ARs). Among the resulting 557 hits found in the CSD, we selected five compounds to purchase, synthesize, or translate synthetically into analogues better tailored to interact with the biological targets. Binding experiments using human ARs showed that four out of five tested compounds turned out to be antagonists at the A1AR or A 3AR with Ki values between 50 and 440 nM. Lead optimizations of 2-(benzimidazol-2-yl)quinoxalines (BIQs, 3) gave the best results in terms of potency and selectivity at the A1 and A 3 ARs. Particularly, 2-(4-ethylthiobenzimidazol-2-yl)quinoxaline (3e) exhibited Ki values at the A1AR, A2AAR, and A3AR of 0.5, 3440, and 955 nM, respectively, whereas 2-(4-methylbenzimidazol-2-yl)quinoxaline (3b) displayed at the same ARs K i values of 8000, 833, and 26 nM, respectively. © 2005 American Chemical Society.
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- 2005
13. Structure–Activity Relationship Refinement and Further Assessment of 4-phenylquinazoline-2-carboxamide Translocator Protein (TSPO) Ligands as Antiproliferative Agents in Human Glioblastoma Tumors
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Luciana Marinelli, Federico Da Settimo, Giovanni Greco, Claudia Martini, Monica Viviano, Sabrina Taliani, Ciro Milite, Sandro Cosconati, Eleonora Da Pozzo, Ettore Novellino, Elisabetta Barresi, Gianluca Sbardella, Barbara Costa, Sabrina Castellano, Agostino Bruno, Castellano, S, Taliani, S, Viviano, M, Milite, C, Da Pozzo, E, Costa, B, Barresi, E, Bruno, A, Cosconati, Sandro, Marinelli, L, Greco, G, Novellino, E, Sbardella, G, Da Settimo, F, Martini, C., Sabrina, Castellano, Sabrina, Taliani, Monica, Viviano, Ciro, Milite, Eleonora Da, Pozzo, Barbara, Costa, Elisabetta, Barresi, Agostino, Bruno, Sandro, Cosconati, Marinelli, Luciana, Greco, Giovanni, Novellino, Ettore, Gianluca, Sbardella, Federico Da, Settimo, and Claudia, Martini
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Models, Molecular ,18 KDA ,Molecular Conformation ,Carboxamide ,Plasma protein binding ,translocator protein (TSPO), steroidogenesis, 4-phenylquinazoline-2-carboxamide derivatives, structure-activity relationships, pharmacophore model ,Kidney ,COLORECTAL-CANCER ,Drug Discovery ,PERIPHERAL BENZODIAZEPINE-RECEPTOR ,Inner mitochondrial membrane ,Membrane Potential, Mitochondrial ,biology ,Chemistry ,DERIVATIVES ,Brain Neoplasms ,glioblastoma tumor ,BINDING-SITES ,BIOLOGICAL EVALUATION ,TSPO EXPRESSION ,BREAST-CANCER ,CELLS ,APOPTOSIS ,Biochemistry ,Molecular Medicine ,Pharmacophore ,Intracellular ,Protein Binding ,medicine.drug_class ,Cell Survival ,Antineoplastic Agents ,Structure-Activity Relationship ,antiproliferative agents ,Receptors, GABA ,Cell Line, Tumor ,medicine ,Translocator protein ,TRANSLOCATOR PROTEIN ,Structure–activity relationship ,Animals ,Humans ,Binding site ,Dose-Response Relationship, Drug ,Computational Biology ,Rats ,Kinetics ,biology.protein ,Glioblastoma - Abstract
Structure-activity relationships (SARs) within the 4-phenylquinazoline-2- carboxamide series of translocator protein (TSPO) ligands have been explored further by the synthesis and TSPO binding affinity evaluation of N-benzyl-N-ethyl/methyl derivatives variously decorated at the 6-, 2′-, 4′-, and 4″-positions. Most of the compounds showed high affinity with Ki values in the nanomolar/subnanomolar range. A pharmacophore model was developed and employed to better address SAR data presented by the new TSPO ligands. A subset of the new compounds (5, 8, 12, and 19) were tested for their ability to inhibit the viability of human glioblastoma cell line U343. The observed antiproliferative effect was demonstrated to be specific for compound 19, endowed with the best combination of binding affinity and efficacy. Furthermore, the ability of 19 to induce mitochondrial membrane dissipation (Δψm) substantiated the intracellular pro-apoptotic mechanism activated by the binding of this class of ligands to TSPO. © 2014 American Chemical Society.
- Published
- 2014
14. 3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: Tricyclic Heteroaromatic Derivatives as a New Class of Benzodiazepine Receptor Ligands
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Ettore Novellino, F. Da Settimo, Letizia Trincavelli, G. Primofiore, Anna Maria Marini, Giovanni Greco, Marco Gesi, Claudia Martini, Sabrina Taliani, C. La Motta, Primofiore, G., DA SETTIMO, F., Taliani, S., Marini, A. M., LA MOTTA, C., Novellino, Ettore, Greco, Giovanni, Gesi, M., Trincavelli, L., and Martini, C.
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Flumazenil ,Models, Molecular ,Stereochemistry ,Convulsants ,In Vitro Techniques ,Ligands ,Partial agonist ,Chemical synthesis ,Mice ,Radioligand Assay ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Inverse agonist ,GABA Modulators ,chemistry.chemical_classification ,Diazepam ,Membranes ,Chemistry ,Aryl ,Brain ,Receptors, GABA-A ,Tautomer ,Lactam ,Molecular Medicine ,Anticonvulsants ,Benzimidazoles ,Cattle ,Tricyclic ,medicine.drug - Abstract
A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.
- Published
- 1999
15. N‘-Phenylindol-3-ylglyoxylohydrazide Derivatives: Synthesis, Structure−Activity Relationships, Molecular Modeling Studies, and Pharmacological Action on Brain Benzodiazepine Receptors
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Antonio Da Settimo, Antonio Lucacchini, Giovanni Greco, Claudia Martini, Marco Gesi, G. Primofiore, Federico Da Settimo, and Gino Giannaccini, A. M. Marini, Ettore Novellino, DA SETTIMO, A., Primofiore, G., DA SETTIMO, F., Marini, A. M., Novellino, Ettore, Greco, Giovanni, Gesi, M., Martini, C., Giannaccini, G., and Lucacchini, A.
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Flumazenil ,Models, Molecular ,Indoles ,Molecular model ,Stereochemistry ,Molecular Conformation ,Nitro compound ,Convulsants ,In Vitro Techniques ,Ligands ,Hydrazide ,Binding, Competitive ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Seizures ,In vivo ,Drug Discovery ,Animals ,GABA Modulators ,Cerebral Cortex ,Indole test ,chemistry.chemical_classification ,Diazepam ,Bicyclic molecule ,Chemistry ,Brain ,Glyoxylates ,Receptors, GABA-A ,Hydrazines ,Nitro ,Molecular Medicine ,Anticonvulsants ,Cattle - Abstract
A series of N'-phenylindol-3-ylglyoxylohydrazides, isosters of the N-benzylindol-3-ylglyoxylamide derivatives previously described by us, were synthesized and tested for their ability to displace [3H]Ro 15-1788 from bovine brain membranes. These compounds were designed with the aim of obtaining products which could exert an in vivo activity, thanks to a higher hydrosolubility and consequently a better bioavailability. Affinity was restricted to the derivatives unsubstituted in the 5 position of the indole nucleus (1, 6, 9, 12, 15, 18, 23, and 26), with Ki values ranging from 510 to 11 nM. The most active compounds (6, 9, 23, and 29) proved to be effective in antagonizing pentylenetetrazole-induced seizures. Molecular modeling studies were performed to rationalize the lack of affinity of hydrazides with a chloro or a nitro group in the 5 position of the indole nucleus. It was hypothesized that the conformational preference of the hydrazide side chain, characterized by a gauche disposition of lone pairs and substituents about the N-N bond, prevents all hydrazides from binding to the receptor similarly to other classes of indole analogues previously investigated. The potency of 5-H hydrazides was attributed to a binding mode which is not feasible for 5-Cl and 5-NO2 counterparts. This theoretical model of ligand-receptor interaction permitted a more stringent interpretation of structure-affinity relationships of hydrazides and of recently described benzylamide derivatives (Da Settimo et al. J. Med. Chem. 1996, 39, 5083-5091).
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- 1998
16. Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies
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Elisabetta Barresi, Stefania Sartini, Sabrina Taliani, Silvia Salerno, Francesca Simorini, Luciana Marinelli, Concettina La Motta, Sandro Cosconati, Federico Da Settimo, Salvatore Di Maro, Anna Maria Marini, Ettore Novellino, Sartini, S, Cosconati, Sandro, Marinelli, M, Barresi, E, DI MARO, Salvatore, Simorini, F, Taliani, S, Salerno, S, Marini, Am, Da Settimo, F, Novellino, E, La Motta, C., S., Sartini, S., Cosconati, Marinelli, Luciana, E., Barresi, F., Simorini, S., Taliani, S., Salerno, A. M., Marini, F., Da Settimo, Novellino, Ettore, and C., La Motta
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chemistry.chemical_classification ,Models, Molecular ,Aldose reductase ,Benzoxazoles ,Antioxidant ,Molecular model ,Chemistry ,medicine.medical_treatment ,medicine.disease ,Rats ,Pathogenesis ,Diabetes Complications ,Molecular Docking Simulation ,Enzyme ,Polyol pathway ,Biochemistry ,Liver ,Cardiovascular Diseases ,Diabetes mellitus ,Drug Discovery ,medicine ,Molecular Medicine ,Animals ,Humans ,IC50 - Abstract
Diabetes mellitus is the major risk factor for cardiovascular disorders. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the pathogenesis of diabetic complications. Accordingly, inhibition of this enzyme is emerging as a major therapeutic strategy for the treatment of hyperglycemia-induced cardiovascular pathologies. In this study, we describe a series of 5(6)-substituted benzofuroxane derivatives, 5a-k,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a-k,m showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multifunctional profile consisting of submicromolar ALR2 inhibitory efficacy (IC50 = 0.99 ± 0.02 μM), significant and spontaneous NO generation properties, and excellent hydroxyl radical scavenging activity. Computational studies of the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series. © 2012 American Chemical Society.
- Published
- 2012
17. 3-(Fur-2-yl)-10-(2-Phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a Novel Adenosine Receptor Antagonist with (2A)-Mediated Neuroprotective EffeCTS
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Alessia Scatena, Federico Da Settimo, Claudia Martini, Francesco Fornai, Isabella Pugliesi, Sabrina Taliani, Sandro Cosconati, Simona Daniele, Maria Letizia Trincavelli, Scatena, A, Fornai, F, Trincavelli, Ml, Taliani, S, Daniele, S, Pugliesi, I, Cosconati, Sandro, Martini, C, and Da Settimo, F.
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Cell viability ,1-Methyl-4-phenylpyridinium ,Physiology ,Pharmacology ,Biochemistry ,PC12 Cells ,Methamphetamine ,chemistry.chemical_compound ,Cricetinae ,AR antagonist ,Cyclic AMP ,PC12 cell ,Cell Death ,Triazines ,General Medicine ,Neuroprotection ,Adenosine A2 Receptor Antagonists ,Neuroprotective Agents ,Trypan blue ,Agonist ,Receptor, Adenosine A2A ,medicine.drug_class ,Cell Survival ,Cognitive Neuroscience ,Neurotoxins ,CHO Cells ,Adenosine receptor antagonist ,Receptors, N-Methyl-D-Aspartate ,medicine ,Animals ,Humans ,Computer Simulation ,Viability assay ,2A ,Membranes ,Human neuroblastoma cell ,Receptor, Adenosine A1 ,Receptors, Dopamine D2 ,Antagonist ,Cell Biology ,Meth ,Receptors, GABA-A ,Adenosine receptor ,Rats ,chemistry ,Benzimidazoles ,Indicators and Reagents ,Neurotoxin - Abstract
In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.
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- 2011
18. Identification of 5-arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications
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Mario Cappiello, Umberto Mura, Ettore Novellino, Federico Da Settimo, Stefania Sartini, Sandro Cosconati, Rosanna Maccari, Rosaria Ottanà, Luciana Marinelli, Concettina La Motta, Marco Giglio, Antonella Del Corso, Ottana, R, Maccari, R, Giglio, M, Del Corso, A, Cappiello, M, Mura, U, Cosconati, Sandro, Marinelli, L, Novellino, E, Sartini, S, La Motta, C, Da Settimo, F., Rosaria, Ottan, Rosanna, Maccari, Marco, Giglio, Antonella Del, Corso, Mario, Cappiello, Umberto, Mura, Sandro, Cosconati, Marinelli, Luciana, Novellino, Ettore, Stefania, Sartini, Concettina La, Motta, and Federico Da, Settimo
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Diabetes mellitu ,Antioxidant ,Antioxidant agent ,medicine.medical_treatment ,Aldose reductase ,Acetates ,medicine.disease_cause ,Antioxidants ,Diabetes Complications ,Structure-Activity Relationship ,Diabetes mellitus ,Aldehyde Reductase ,5-arylidene-4-thiazolidinones ,Molecular docking ,Drug Discovery ,5-arylidene-4- thiazolidinone ,medicine ,Structure–activity relationship ,Animals ,Humans ,Enzyme Inhibitors ,Pharmacology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,General Medicine ,medicine.disease ,Molecular Docking Simulation ,Oxidative Stress ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Cattle ,Thiazolidinediones ,Oxidative stress - Abstract
In continuing the search for more effective 5-arylidene-4-thiazolidinones as aldose reductase inhibitors, a new set of suitably substituted compounds (4, 5 and 8) was explored. Acetic acids 5, particularly 5a and 5h, proved to be interesting inhibitors of the enzyme as well as excellent antioxidant agents that are potentially able to counteract the oxidative stress associated with both diabetic complications as well as other pathologies. Molecular docking experiments supported SAR studies. © 2011 Elsevier Masson SAS. All rights reserved.
- Published
- 2011
19. Novel irreversible fluorescent probes targeting the 18 kDa translocator protein: synthesis and biological characterization
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Francesca Simorini, Anna Maria Marini, Eleonora Da Pozzo, Giovanni Greco, Claudia Martini, Federico Da Settimo, M Bellandi, S Bendinelli, Concettina La Motta, Ettore Novellino, Isabella Pugliesi, Silvia Salerno, Barbara Cosimelli, Sabrina Taliani, Taliani, S., Da Pozzo, E., Bellandi, M., Bendinelli, S., Pugliesi, I., Simorini, F., La Motta, C., Salerno, S., Marini, A. M., Da Settimo, F., Cosimelli, Barbara, Greco, Giovanni, Novellino, Ettore, and Martini, C.
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Cell Membrane Permeability ,In Vitro Techniques ,Kidney ,Ligands ,Binding, Competitive ,Mitochondrial Proteins ,Radioligand Assay ,Structure-Activity Relationship ,Receptors, GABA ,Isothiocyanates ,Cell Line, Tumor ,Drug Discovery ,Translocator protein ,Animals ,Humans ,Receptor ,Fluorescent Dyes ,biology ,Ligand ,Chemistry ,Receptors, GABA-A ,Fluorescence ,Rats ,Kinetics ,4-Chloro-7-nitrobenzofurazan ,Spectrometry, Fluorescence ,Biochemistry ,Covalent bond ,Electrophile ,biology.protein ,Molecular Medicine ,Target protein ,Molecular imaging ,Carrier Proteins ,Protein Binding - Abstract
The 18 kDa translocator protein (TSPO) is a mitochondrial protein whose basal density is altered in several diseases, with the result that the evaluation of its expression levels by means of molecular imaging techniques represents a promising diagnostic approach. Experimental procedures using a labeled ligand often cause loss of the bound probe, and consequently high affinity ligands covalently binding the receptor protein are needed to overcome this problem. We have previously described a series of N,N-dialkyl-(2-phenylindol-3-yl)glyoxylamides as potent and selective TSPO ligands. Starting from these derivatives, we designed novel TSPO irreversible ligands bearing an electrophilic isothiocyanato group (7, 8), together with an irreversible NBD-fluorescent probe (18). The TSPO affinity of the new irreversible ligands was measured on rat tissue homogenates by [(3)H]Ro 5-4864 radiobinding kinetic assays, all compounds showing high affinities for the target protein. Further biological characterization of the fluorescent irreversible TSPO probe 18 was carried out by using fluorescent spectroscopy in human glioma cells.
- Published
- 2010
20. Derivatives of 4-Amino-6-hydroxy-2-mercaptopyrimidine as Novel, Potent, and Selective A3 Adenosine Receptor Antagonists
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Maria Letizia Trincavelli, Tiziano Tuccinardi, Sabrina Taliani, Concettina La Motta, Giovanni Greco, Adriano Martinelli, Osele Ciampi, Federico Da Settimo, M Bellandi, Marina Ehlardo, Ettore Novellino, Claudia Martini, B Cosimelli, Cosimelli, Barbara, Greco, Giovanni, Ehlardo, M., Novellino, Ettore, Da Settimo, F., Taliani, S., La Motta, C., Bellandi, M., Tuccinardi, T., Martinelli, A., Ciampi, O., Trincavelli, M. L., and Martini, C.
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Models, Molecular ,Pyrimidine ,medicine.drug_class ,Stereochemistry ,Adenosine A3 Receptor Antagonists ,Carboxamide ,CHO Cells ,Adenosine A1 Receptor Antagonists ,Ligands ,Binding, Competitive ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cricetulus ,Cricetinae ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Computer Simulation ,Sulfhydryl Compounds ,Receptor ,Binding Sites ,Molecular Structure ,Chemistry ,Antagonist ,Stereoisomerism ,Ligand (biochemistry) ,In vitro ,Adenosine A2 Receptor Antagonists ,Pyrimidines ,Drug Design ,Molecular Medicine ,Selectivity - Abstract
A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine ( 5) were synthesized and biologically evaluated as A 3 adenosine receptor (A 3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A 3 AR, which had been previously identified using a 3D database search. Substituents R, R', and R'' attached to the parent compound 5 were chosen according to factorial design and stepwise lead optimization approaches, taking into account the essentially hydrophobic nature of the A 3 AR binding site. As a result, 5m (R = n-C 3H 7, R' = 4-ClC 6H 4CH 2, R'' = CH 3) was identified among the pyrimidine derivatives as the ligand featuring the best combination of potency and selectivity for the target receptor. This compound binds to the A 3 AR with a K i of 3.5 nM and is devoid of appreciable affinity for the A 1, A 2A, and A 2B ARs.
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- 2008
21. Anxiolytic-like Effects of N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides by Modulation of Translocator Protein Promoting Neurosteroid Biosynthesis
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B Cosimelli, Francesca Simorini, Barbara Costa, A. M. Marini, Sabrina Taliani, Claudia Martini, Nicola Simola, Micaela Morelli, M Bellandi, Federico Da Settimo, Eleonora Da Pozzo, Giovanni Greco, Silvia Salerno, Concettina La Motta, Ettore Novellino, Da Settimo, F., Simorini, F., Taliani, S., La Motta, C., Marini, A. M., Salerno, S., Bellandi, M., Novellino, Ettore, Greco, Giovanni, Cosimelli, Barbara, Da Pozzo, E., Costa, B., Simola, N., Morelli, M., and Martini, C.
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PK-11195 ,Neuroactive steroid ,medicine.drug_class ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Steroid biosynthesis ,Kidney ,Anxiolytic ,Compound 32 ,Steroid ,chemistry.chemical_compound ,Radioligand Assay ,Cell Line, Tumor ,Drug Discovery ,Translocator protein ,medicine ,Animals ,Maze Learning ,Cerebral Cortex ,biology ,Chemistry ,Cell Membrane ,Isoquinolines ,Amides ,Rats ,Biochemistry ,Anti-Anxiety Agents ,Pregnenolone ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
Novel N,N-disubstituted indol-3-ylglyoxylamides (1-56), bearing different combinations of substituents R 1-R 5, were synthesized and evaluated as ligands of the translocator protein (TSPO), the 18 kDa protein representing the minimal functional unit of the "peripheral-type benzodiazepine receptor" (PBR). Most of the new compounds showed a nanomolar/subnanomolar affinity for TSPO and stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classic TSPO ligands such as PK 11195. Moreover, when evaluated in vivo by means of the elevated-plus-maze (EPM) paradigm in the rat, compound 32, the best-performing derivative in terms of TSPO affinity and pregnenolone production, showed clear anxiolytic effects. The results of this study suggested that the novel N,N-disubstituted indol-3-ylglyoxylamides may represent a promising class of compounds potentially suited for the treatment of anxiety disorders.
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- 2008
22. Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands
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Giampaolo Primofiore, Federico Da Settimo, François Besnard, Vincenzo Calderone, V. Sergianni, Anna Maria Marini, Marina Montali, Claudia Martini, Francesca Simorini, Concettina La Motta, B Cosimelli, Ettore Novellino, Giovanni Greco, Maria Paola Patrizi, Sabrina Taliani, Primofiore, G., Taliani, S., Da Settimo, F., Marini, A. M., La Motta, C., Simorini, F., Patrizi, M. P., Sergianni, V., Novellino, Ettore, Greco, Giovanni, Cosimelli, Barbara, Calderone, V., Montali, M., Besnard, F., and Martini, C.
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Male ,Agonist ,Indoles ,Stereochemistry ,medicine.drug_class ,Molecular Conformation ,Substituent ,Carboxamide ,In Vitro Techniques ,Motor Activity ,Ligands ,Chemical synthesis ,Cell Line ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Hypnotics and Sedatives ,Moiety ,GABA-A Receptor Agonists ,Cerebral Cortex ,Mice, Inbred BALB C ,Bicyclic molecule ,Glyoxylates ,Ligand (biochemistry) ,Amides ,Rats ,chemistry ,Molecular Medicine ,Cattle ,Selectivity - Abstract
Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the alpha1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changes gave no shift of selectivity from the alpha1 toward the alpha2 or alpha5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits alpha1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the alpha1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative-hypnotic agent.
- Published
- 2007
23. Synthesis and Benzodiazepine Receptor Affinity of Derivatives of the New Tricyclic Heteroaromatic System Pyrido[3’,2’:5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one
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Francesca Simorini, Giampaolo Primofiore, Concettina La Motta, Letizia Trincavelli, Sabrina Taliani, Federico Da Settimo, Anna Maria Marini, Claudia Martini, Sonia Laneri, Primofioe, G, DA SETTIMO, F, Marini, A. M., Simorini, F, LA MOTTA, C, Taliani, S, Laneri, Sonia, Trincavelli, L, and Martini, C.
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medicine.drug_class ,Stereochemistry ,Phenylhydrazines ,Hydrazine ,Pharmaceutical Science ,Ligands ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,benzodiazepine receptor ligands ,Drug Discovery ,medicine ,Animals ,Receptor ,Glyoxylic acid ,chemistry.chemical_classification ,Benzodiazepine ,Biological activity ,General Medicine ,Receptors, GABA-A ,Pyridazines ,Membrane ,Diazepine ,chemistry ,Cattle ,Tricyclic - Abstract
Derivatives 7-13 of a new tricyclic heteroaromatic system, pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one, were prepared as potential ligands at the benzodiazepine receptor, in view of their structural analogy with potent ligands such as the pyrazoloquinolines of the CGS series II, and especially with the benzothiopyrano[4,3-c]pyridazinones VI. They were obtained starting from the versatile ketones 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-one 1 and the corresponding 7-methyl derivative 2, via condensation with glyoxylic acid, and reaction of the intermediate acid mixtures with hydrazine or substituted phenylhydrazines. When evaluated for their binding affinity at the benzodiazepine receptor in bovine cortical membranes, the target compounds 8-13 displayed an affinity in the micromolar/submicromolar order. A hypothesis is presented to rationalize these results.
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- 2005
24. High Affinity Central Benzodiazepine Receptor Ligands: Synthesis and Biological Evaluation of a Series of Phenyltriazolobenzotriazindione Derivatives (PTBTs)
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Claudia Martini, Silvia Salerno, François Besnard, Ettore Novellino, Marina Montali, Sabrina Taliani, Giovanni Greco, B Cosimelli, Barbara Costa, Giampaolo Primofiore, Federico Da Settimo, Primofiore, G, DA SETTIMO, F, Taliani, S, Salerno, S, Novellino, Ettore, Greco, Giovanni, Cosimelli, Barbara, Besnard, F, Costa, C, Montali, M, and Martini, C.
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Agonist ,Models, Molecular ,Molecular model ,medicine.drug_class ,Stereochemistry ,In Vitro Techniques ,Chemical synthesis ,Binding, Competitive ,Cell Line ,Radioligand Assay ,Structure-Activity Relationship ,Chlorides ,Drug Discovery ,medicine ,Structure–activity relationship ,Potency ,Animals ,Humans ,Protein Isoforms ,GABA-A Receptor Agonists ,GABA-A Receptor Antagonists ,Receptor ,Chemistry ,Triazines ,Antagonist ,Brain ,Triazoles ,Recombinant Proteins ,Rats ,Molecular Medicine ,Cattle - Abstract
A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these compounds was designed by formally combining the N-C=O moieties of the known BzR ligands, triazoloquinoxalines (IV) and triazinobenzimidazoles (ATBIs) (VI). Most of the PTBTs displayed submicromolar/nanomolar potency at the BzR. The 9-chloro derivatives (45-49) were generally found to be more potent than their 9-unsubstituted counterparts (37-44). Compound 45 turned out to be the most potent of the PTBTs (K(i) 2.8 nM). A subset of compounds (37, 42, 45, 49), when tested for their affinity on recombinant rat alpha1beta2gamma2, alpha2beta2gamma2, and alpha5beta3gamma2 GABA(A)/Bz receptor subtypes, showed enhanced affinities for the alpha1beta2gamma2 isoform, with compounds 45 and 49 exhibiting the highest selectivity. Moreover, compounds 45 and 49 were found to display a full agonist efficacy profile at alpha1 and alpha2 receptor subtypes, and an antagonist efficacy at alpha5-containing receptors.
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- 2005
25. Design, synthesis and biological evaluation of novel N-alkyl- and N-acyl-(7-substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs) as novel A(1) adenosine receptor antagonists
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Claudia Martini, Ettore Novellino, Antonio Lavecchia, Maria Grazia Rimoli, Enrico Abignente, Giovanni Greco, Sonia Laneri, Barbara Cosimelli, Letizia Trincavelli, Federico Da Settimo, Giampaolo Primofiore, D. Tuscano, Manuela Iadanza, Novellino, E., ABIGNENTE DI FRASSELLO, Enrico, Cosimelli, B., Greco, Giovanni, Iadanza, M., Laneri, S., Lavecchia, A., Rimoli, M. G., DA SETTIMO, F., Primofiore, G., Tuscano, D., and Martini, C.
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chemistry.chemical_classification ,Cerebral Cortex ,Models, Molecular ,Ketone ,Bicyclic molecule ,Stereochemistry ,Ligand ,Triazines ,Imidazoles ,In Vitro Techniques ,Chemical synthesis ,Adenosine receptor ,Binding, Competitive ,Corpus Striatum ,Radioligand Assay ,Structure-Activity Relationship ,chemistry ,Purinergic P1 Receptor Antagonists ,Docking (molecular) ,Drug Discovery ,Molecular Medicine ,Animals ,Cattle ,Pharmacophore ,Selectivity - Abstract
Prompted by pharmacophore and docking based models, we have synthesized and tested a number of N-alkyl and N-acyl-(7-substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs, 7) designed as a new class of A(1) adenosine receptor (A(1)AR) antagonists. Binding affinities at the A(1)AR, A(2A)AR, and A(3)AR were determined using bovine cerebral membranes. Most of the compounds displayed K(i) values at the A(1)AR in the submicromolar or even in the low nanomolar range, thus confirming the rationale leading to their synthesis. All or most of the ligands turned out to be selective for the A(1)AR over the A(2A)AR and A(3)AR subtypes, respectively. Structure-affinity relationships at the A(1)AR were rationalized by docking simulations in terms of putative ligand/receptor interactions. Among the ITAs investigated, 1-[(7-methyl-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amino]acetone (7j) exhibited the best combination of affinity at the A(1)AR (K(i) = 12 nM) and selectivity over the A(2A)AR and A(3)AR subtypes (K(i)s10000 nM).
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- 2002
26. Novel N-(Arylalkyl)indol-3-ylglyoxylyamides Targeted as Ligands of the Benzodiazepine Receptor: Synthesis, Biological Evaluation, and Molecular Modeling Analysis of the Structure-Activity Relationships
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Barbara Costa, Letizia Trincavelli, Claudia Martini, Antonio Lavecchia, Giovanni Greco, Ettore Novellino, Anna Maria Marini, Sabrina Taliani, Federico Da Settimo, François Besnard, Giampaolo Primofiore, Primofiore, G., DA SETTIMO, F., Taliani, S., Marini, A. M., Novellino, Ettore, Greco, Giovanni, Lavecchia, Antonio, Besnard, F., Trincavelli, L., Costa, B., and Martini, C.
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Models, Molecular ,Indoles ,Molecular model ,Stereochemistry ,Nitro compound ,In Vitro Techniques ,Ligands ,Chemical synthesis ,Radioligand Assay ,Structure-Activity Relationship ,chemistry.chemical_compound ,Amide ,Drug Discovery ,medicine ,Animals ,Alanine ,chemistry.chemical_classification ,Bicyclic molecule ,Brain ,Glyoxylates ,Receptors, GABA-A ,Amides ,Affinities ,chemistry ,Flumazenil ,Molecular Medicine ,Cattle ,medicine.drug - Abstract
A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [(3)H]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N'-phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha(1)beta(2)gamma(2), alpha(3)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO(2)) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K(i) of 5a = 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO(2) (R)-1-indanylamides 7b (K(i) 80 nM) and 7c (K(i) 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K(i) 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L(1) (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha(1)beta(2)gamma(2) subtype compared with the alpha(3)beta(2)gamma(2) and alpha(5)beta(3)gamma(2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with K(i) values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.
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- 2001
27. [1,2,4]Triazino[4,3-a]benzimidazole Acetic Acid Derivatives: a New Series of Selective Aldose Reductase Inhibitors
- Author
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A. Da Settimo, E. Boldrini, G. Primofiore, F. Da Settimo, Ettore Novellino, Sabrina Taliani, Francesca Simorini, Giovanni Greco, Antonio Lavecchia, C. La Motta, DA SETTIMO, F., Primofiore, G., DA SETTIMO, A., LA MOTTA, C., Taliani, S., Simorini, F., Novellino, Ettore, Greco, Giovanni, Lavecchia, Antonio, and Boldrini, E.
- Subjects
Galactosemias ,Models, Molecular ,Benzimidazole ,Tolrestat ,Stereochemistry ,Sorbitol dehydrogenase ,Carboxylic acid ,Acetates ,Cataract ,chemistry.chemical_compound ,Acetic acid ,Structure-Activity Relationship ,Aldehyde Reductase ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,chemistry.chemical_classification ,Aldose reductase ,Binding Sites ,biology ,Triazines ,Stereoisomerism ,Rats ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Benzimidazoles ,Ophthalmic Solutions ,Protein Binding - Abstract
Acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-a]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC(50) = 0.36 microM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.
- Published
- 2001
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