Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic ac... more Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) were used to discriminate the enantiomers of the chiral H(3)-antagonist 2-[3-(1H-imidazol-4-ylmethyl)piperidin-1-yl]-1H-benzimidazole. Chemical-shift differences (Delta delta) in NMR spectra strongly depend on solvent and stoichiometric ratio. The better observable differentiation occurred for the proton at the 2-position of the imidazole ring.
A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of ... more A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a ...
... aDipartimento Farmaceutico, Università degli Studi di Parma, V.le GP Usberti, 27/A, I-43100 P... more ... aDipartimento Farmaceutico, Università degli Studi di Parma, V.le GP Usberti, 27/A, I-43100 Parma, Italy, bDepartment of Anesthesiology, University of Virginia ... [8] Rivara, M.; Baheti, AR; Fantini, M.; Cocconcelli, G.; Ghiron, C.; Kalmar, CL; Singh, N.; Merrick, EC; Patel, MK; Zuliani ...
H3-antagonists possess promising pharmacological effects on awakening, learning and memory, but f... more H3-antagonists possess promising pharmacological effects on awakening, learning and memory, but few data on their access to the central nervous system (CNS) have been reported so far. The purpose of this work was to investigate the relationships between ...
We report the design, synthesis, QSPR and QSAR of a new class of H 3 -antagonists, having a 2-ami... more We report the design, synthesis, QSPR and QSAR of a new class of H 3 -antagonists, having a 2-aminobenzimidazole moiety connected to the 4(5) position of an imidazole ring through di-or tri-methylene chains. Eleven substituents, selected by experimental design to obtain ...
Sodium (Na) channels continue to represent an important target for the development of novel antic... more Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal NaV1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D7.4) and basicity (pKa) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC50 values that were considerably lower than our lead compound. In particular, the m-CF3 disubstituted 22 was the most active compound, inhibiting hNaV1.2 currents within the nanomolar concentration range (IC50 = 200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC50’s values that were greater than 100 μM.The synthesis, biological evaluation for block of hNaV1.2 sodium channels and physico-chemical properties of a series of 2,4(5)-diarylimidazoles with different substituents on phenyl rings are described and discussed. The most active compound obtained inhibits hNaV1.2 currents within the nanomolar concentration range.
A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synt... more A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNav1.2 sodium channel currents. One member of this series (4) exhibited profound inhibition of Nav1.2 currents, emerging as a promising lead compound for further structure–activity relationship studies for the development of novel sodium channel blockers.A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNav1.2 sodium channel currents.
Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis a... more Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists. A putative binding site for classical, imidazole-derived H(3) antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H(3) antagonist (compound 1, pK(i)=8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H(3) antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H(3) antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.
Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic ac... more Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) were used to discriminate the enantiomers of the chiral H(3)-antagonist 2-[3-(1H-imidazol-4-ylmethyl)piperidin-1-yl]-1H-benzimidazole. Chemical-shift differences (Delta delta) in NMR spectra strongly depend on solvent and stoichiometric ratio. The better observable differentiation occurred for the proton at the 2-position of the imidazole ring.
Advances in experimental medicine and biology, 2003
Melatonin (MLT) is known for its radical scavenger activity, which had been related to its abilit... more Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed. Other indole derivatives are also known to possess antioxidant and cytoprotective activity. In order to dissociate the cytoprotective effect of MLT from its receptor affinity, and to investigate the structure-activity relationships (SAR) between this effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of MLT w...
European journal of medicinal chemistry, Jan 5, 2015
TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. The co-in... more TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. The co-infection with HIV and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. In the attempt to respond to the constant need of novel therapeutic options, we herein report the discovery of 2,4-diphenyl-1H-imidazoles as effective antitubercular agents, with MIC in the low micromolar range against actively replicating and persistent M. tuberculosis strains. The good activity, along with the lack of toxicity and the feasible synthesis, underscore their value as novel scaffolds for the development of new anti-TB drugs.
Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic ac... more Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) were used to discriminate the enantiomers of the chiral H(3)-antagonist 2-[3-(1H-imidazol-4-ylmethyl)piperidin-1-yl]-1H-benzimidazole. Chemical-shift differences (Delta delta) in NMR spectra strongly depend on solvent and stoichiometric ratio. The better observable differentiation occurred for the proton at the 2-position of the imidazole ring.
A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of ... more A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a ...
... aDipartimento Farmaceutico, Università degli Studi di Parma, V.le GP Usberti, 27/A, I-43100 P... more ... aDipartimento Farmaceutico, Università degli Studi di Parma, V.le GP Usberti, 27/A, I-43100 Parma, Italy, bDepartment of Anesthesiology, University of Virginia ... [8] Rivara, M.; Baheti, AR; Fantini, M.; Cocconcelli, G.; Ghiron, C.; Kalmar, CL; Singh, N.; Merrick, EC; Patel, MK; Zuliani ...
H3-antagonists possess promising pharmacological effects on awakening, learning and memory, but f... more H3-antagonists possess promising pharmacological effects on awakening, learning and memory, but few data on their access to the central nervous system (CNS) have been reported so far. The purpose of this work was to investigate the relationships between ...
We report the design, synthesis, QSPR and QSAR of a new class of H 3 -antagonists, having a 2-ami... more We report the design, synthesis, QSPR and QSAR of a new class of H 3 -antagonists, having a 2-aminobenzimidazole moiety connected to the 4(5) position of an imidazole ring through di-or tri-methylene chains. Eleven substituents, selected by experimental design to obtain ...
Sodium (Na) channels continue to represent an important target for the development of novel antic... more Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal NaV1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D7.4) and basicity (pKa) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC50 values that were considerably lower than our lead compound. In particular, the m-CF3 disubstituted 22 was the most active compound, inhibiting hNaV1.2 currents within the nanomolar concentration range (IC50 = 200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC50’s values that were greater than 100 μM.The synthesis, biological evaluation for block of hNaV1.2 sodium channels and physico-chemical properties of a series of 2,4(5)-diarylimidazoles with different substituents on phenyl rings are described and discussed. The most active compound obtained inhibits hNaV1.2 currents within the nanomolar concentration range.
A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synt... more A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNav1.2 sodium channel currents. One member of this series (4) exhibited profound inhibition of Nav1.2 currents, emerging as a promising lead compound for further structure–activity relationship studies for the development of novel sodium channel blockers.A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNav1.2 sodium channel currents.
Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis a... more Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists. A putative binding site for classical, imidazole-derived H(3) antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H(3) antagonist (compound 1, pK(i)=8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H(3) antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H(3) antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.
Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic ac... more Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) were used to discriminate the enantiomers of the chiral H(3)-antagonist 2-[3-(1H-imidazol-4-ylmethyl)piperidin-1-yl]-1H-benzimidazole. Chemical-shift differences (Delta delta) in NMR spectra strongly depend on solvent and stoichiometric ratio. The better observable differentiation occurred for the proton at the 2-position of the imidazole ring.
Advances in experimental medicine and biology, 2003
Melatonin (MLT) is known for its radical scavenger activity, which had been related to its abilit... more Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed. Other indole derivatives are also known to possess antioxidant and cytoprotective activity. In order to dissociate the cytoprotective effect of MLT from its receptor affinity, and to investigate the structure-activity relationships (SAR) between this effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of MLT w...
European journal of medicinal chemistry, Jan 5, 2015
TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. The co-in... more TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. The co-infection with HIV and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. In the attempt to respond to the constant need of novel therapeutic options, we herein report the discovery of 2,4-diphenyl-1H-imidazoles as effective antitubercular agents, with MIC in the low micromolar range against actively replicating and persistent M. tuberculosis strains. The good activity, along with the lack of toxicity and the feasible synthesis, underscore their value as novel scaffolds for the development of new anti-TB drugs.
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Papers by M. Rivara