MAURIZIO ANZINI | University of Siena / Università di Siena (original) (raw)
Papers by MAURIZIO ANZINI
Journal of Medicinal Chemistry, Apr 11, 2013
A series of 3-substituted 1,5-diarylpyrroles bearing a nitro-oxyalkyl side chain linked to differ... more A series of 3-substituted 1,5-diarylpyrroles bearing a nitro-oxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitro-oxyalkyl-inverse esters,-carbonate and-ethers (7-10), as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9,10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitro-oxy derivatives showed NO-dependent vasorelaxing properties while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a, highlighted good anti-inflammatory and anti-nociceptive activities. Compound 9c was able to inhibit glycosaminoglycans (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling, 1 Hand 13 C-NMR studies performed on compounds 6c,d, 9c and 10b allowed the right conformation of nitro-oxyalkyl ester and-ether side chain of these molecules within the COX-2 active site to be assessed. ACS Paragon Plus Environment Journal of Medicinal Chemistry inflammatory disorders. 1 In addition, this class of drugs is widely used to treat mild to moderate pain. Their therapeutic effects are mediated by the inhibition of cyclooxygenase (COX)-2 which is the most important COX-isoform contributing to prostanoid generation at inflammatory sites and spinal cord. 3 Selective COX-2 inhibitors (coxibs) have been developed with the aim to produce an efficacy comparable to tNSAIDs while reducing gastrointestinal (GI) related adverse events which are mainly due to the inhibition of COX-1-derived cytoprotective prostanoids in the GI tract. 4,5 However, the use of tNSAIDs and coxibs is associated with an increased risk of thrombotic and renal adverse events. 6 This is due to their inhibitory effects on the biosynthesis of vascular prostacyclin (PGI2), a powerful platelet inhibitor and vasodilator, which is mainly derived from the haemodynamic shear induced by COX-2. 7 Recently, Yu et al showed that vascular COX-2 deletion ends in the reduction of the expression of endothelial nitric oxide (NO) synthase and consequent release of NO. 8 Similarly to prostacyclin, NO is endowed with important cardioprotective properties, such as vasodilation and inhibition of platelet function. 9 Suppression of PGI2 formation due to inhibition of vascular COX-2 is sufficient to account for the cardiovascular (CV) hazard from NSAIDs (traditional and selective for COX-2), 10 but it may be increased by secondary mechanisms such as suppression of NO production. 8 These findings justify the need to develop NSAIDs endowed with NO-releasing properties in order to mitigate their CV, and GI, hazard. Indeed, the novel class of anti-inflammatory agents, named COX-inhibiting nitric oxide-donors (CINODs), developed by linking a NO-releasing moiety to a tNSAID, has been shown to have a more favourable clinical profile than the parent tNSAIDs in randomized clinical trials. 11,12 This is plausibly due to the property of CINODs to release NO which may replace the functions of inhibited prostanoids by the tNSAIDs. 13
Journal of Medicinal Chemistry, Feb 1, 1998
Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivati... more Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a Ki value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximately 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.
PubMed, Nov 1, 1990
The syntheses as well as 5-HT and Benzodiazepine receptor binding studies of some 1,2,4-Triazolo[... more The syntheses as well as 5-HT and Benzodiazepine receptor binding studies of some 1,2,4-Triazolo[4',3':1,6]piridazino[4,5-b]quinoline and 2,3-Dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one derivatives are reported. While the triazole-containing heterocycles are devoid of any biological activity, 2-benzyl-2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one shows some affinity for the central type of benzodiazepine receptors.
Journal of Medicinal Chemistry, Dec 1, 2009
A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothia... more A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothiazole termed 2, 3, and 4, respectively, and structurally related to riluzole, a neuroprotective drug in many animal models of brain disease, have been synthesized. The biological activity of compounds 2a-e, 3a-f, and 4a,b was preliminarily tested by means of an in vitro protocol of ischemia/reperfusion injury. The results demonstrated that 2c and 3a-d significantly attenuated neuronal injury. Selected for testing of their antioxidant properties, compounds 3a-d were shown to be endowed with a direct ROS scavenging activity. Compounds 3b and 3d were also evaluated for their activity on voltage-dependent Na(+) and Ca(2+) currents in neurons from rat piriform cortex. At 50 microM, compound 3b inhibited the transient Na(+) current to a much smaller extent than riluzole, whereas 3d was almost completely ineffective.
ChemInform, Aug 5, 2010
Synthesis, Biological Evaluation and Molecular Docking Studies of 1,3,4-Thiadiazole Derivatives C... more Synthesis, Biological Evaluation and Molecular Docking Studies of 1,3,4-Thiadiazole Derivatives Containing 1,4-Benzodioxan as Potential Antitumor Agents.-Compound (Ic) shows the most potent biological activity against HEPG2 cancer cell line, which is comparable to the positive control.-(SUN,
ChemInform, Apr 4, 1989
ChemInform, Feb 13, 1990
ChemInform Abstract The chloromethylquinolines (III), synthesized from 2-aminobenzophenones (I) a... more ChemInform Abstract The chloromethylquinolines (III), synthesized from 2-aminobenzophenones (I) and ethyl 4-chloroacetoacetate (II), are converted into the amino acid esters (V). Methylamine (VI) reacts with (III), forming the lactams (VII). The affinity of (V) and (VII) to pre-and postsynaptic serotonin receptors is only weak.
journal of chemistry and chemical engineering, 2011
Capillary electrophoresis (CE) coupled with mass spectrometry (MS) with a sheath liquid interface... more Capillary electrophoresis (CE) coupled with mass spectrometry (MS) with a sheath liquid interface is nowadays recognized as a powerful separation technique for drugs and metabolites analysis in human urine and can be applied in numerous fields such as clinical toxicology, drug substitution monitoring, forensic sciences and antidoping. With an acidic background electrolyte containing 15 mM ammonium formate at pH 2.5 and a sheath liquid consisting in a mixture of isopropanol/water (50:50, v/v) with 0.5% formic acid, CE-ESI-MS in positive mode demonstrated excellent performance for simultaneous analysis of basic drugs of abuse and metabolites in urine (e.g. cocaine, amphetamine, morphine and phase II metabolites). To achieve the desired level of sensitivity, two injection modes and three sample pre-treatments were evaluated. The detection of basic drugs and phase II metabolites in diluted urine was achieved at concentrations above 1 μg/mL. In order to enhance sensitivity, a sample preparation was required. A liquid-liquid extraction (LLE) was compared with solid-phase extraction. LLE was performed at alkaline pH and samples were electrokinetically injected. A chemometric approach (Doehlert design) was carried out in order to determine optimized injection parameters. Limits of detection (LOD) down to 10 ng/mL were reached with field-amplified sample injection but phase II metabolites were not extracted. Therefore, instead of LLE a SPE was performed on C18 sorbent, and elution fraction after washing step containing phase II metabolites was loaded on mixed-mode anion exchanger cartridges. After electrokinetic injection, this two-step SPE allowed LOD ca. 10 ng/mL for drugs and phase II metabolites.
Journal of Medicinal Chemistry, May 31, 2017
LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the n... more LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the normal clearance of glutamate and providing neuronal protection. Since the pharmacologic activation of EAAT2 represents a valuable strategy to relieve neuropathic pain, we synthesized novel activators (4a−f) of EAAT2. Among them 4f, analyzed in comparison with 3 by different paradigms in a rat model of oxaliplatin-induced neuropathic pain, showed the better antihypersensitive profile being able to fully counteract the oxaliplatin-induced neuropathy.
Bioorganic & Medicinal Chemistry, Mar 15, 2008
The exploration of the structure-affinity relationships concerning a new class of peripheral benz... more The exploration of the structure-affinity relationships concerning a new class of peripheral benzodiazepine receptor (PBR) ligands related to alpidem has been pursued in order to evaluate the consistency of the structure-affinity relationships among different classes (and subclasses) of PBR ligands. The target amide derivatives were prepared following a previously published procedure based on the condensation of pyrrolo[3,4-b]quinoline derivatives 11a,b with glyoxylic acid mono-hydrate and the subsequent amidation of the acids obtained via mixed anhydride. On the other hand, the preparation of compound 9g lacking the pharmacophoric (delta1) carbonyl group involved: (a) the double sequential attack of the dimethylmethyleneammonium salt obtained from bis(dimethylamino)methane and acetyl chloride to pyrrolo[3,4-b]quinoline derivative 11b, (b) the quaternization of the obtained allylamine derivative 13 with methyl iodide, and (c) the palladium-catalyzed allylation of N-methyl-p-anisidine by quaternary allylammonium cation 14. The structure-affinity relationship trends observed in this subclass of tricyclic alpidem-related PBR ligands find correlations in other classes (or subclasses) of PBR ligands. This result supports the initial pharmacophoric hypothesis and suggests a common mode of interaction at the PBR binding site.
European journal of medicinal chemistry, 2017
Neurodegenerative diseases are disorders related to the degeneration of central neurons that grad... more Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved able to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate-and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na + and Ca 2+channels, showing a profile comparable with that of 1.
ChemMedChem, Apr 8, 2010
A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline... more A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline frameworks bearing a 4‐(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS‐5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS‐5 and ADAMTS‐4. Among the compounds containing the pyrrolo[3,4‐c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS‐5 and ADAMTS‐4, with IC50 values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS‐5 and ‐4. The structure–activity relationship analysis of pyrroloquinolinone derivatives 2 a–i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS‐5 and ‐4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS‐4 inhibitory activity and inhibit ADAMTS‐5 showing IC25 values in the micromolar range.
ChemMedChem, Feb 14, 2018
The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here... more The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, 1c was the most potent Zmp1 inhibitor known to date, and its binding mode was analysed both through kinetic studies and molecular modelling, identifying critical interactions of 1c with the zinc-ion and residues in the active site. Effect of 1c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1c displayed interesting in vitro antitubercular properties worth of further investigation.
Osteoarthritis and Cartilage, Apr 1, 2015
to directly characterize, for the first time, the role of the CTD of Cx43 on cartilage structure.... more to directly characterize, for the first time, the role of the CTD of Cx43 on cartilage structure. Our results strongly support the notion that the CTD of Cx43 plays an important role in chondrocyte phenotype. It is well know that through its CTD, Cx43 serves as scaffolding proteins that associates with structural and signaling molecules leading to regulation of intracellular signaling, independently of channel activity. This study illustrates that a complete isolation of Cx43 from its CTD may have a negative impact on cartilage structure and chondrocyte functions within the tissue.
Journal of Medicinal Chemistry, Apr 11, 2013
A series of 3-substituted 1,5-diarylpyrroles bearing a nitro-oxyalkyl side chain linked to differ... more A series of 3-substituted 1,5-diarylpyrroles bearing a nitro-oxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitro-oxyalkyl-inverse esters,-carbonate and-ethers (7-10), as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9,10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitro-oxy derivatives showed NO-dependent vasorelaxing properties while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a, highlighted good anti-inflammatory and anti-nociceptive activities. Compound 9c was able to inhibit glycosaminoglycans (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling, 1 Hand 13 C-NMR studies performed on compounds 6c,d, 9c and 10b allowed the right conformation of nitro-oxyalkyl ester and-ether side chain of these molecules within the COX-2 active site to be assessed. ACS Paragon Plus Environment Journal of Medicinal Chemistry inflammatory disorders. 1 In addition, this class of drugs is widely used to treat mild to moderate pain. Their therapeutic effects are mediated by the inhibition of cyclooxygenase (COX)-2 which is the most important COX-isoform contributing to prostanoid generation at inflammatory sites and spinal cord. 3 Selective COX-2 inhibitors (coxibs) have been developed with the aim to produce an efficacy comparable to tNSAIDs while reducing gastrointestinal (GI) related adverse events which are mainly due to the inhibition of COX-1-derived cytoprotective prostanoids in the GI tract. 4,5 However, the use of tNSAIDs and coxibs is associated with an increased risk of thrombotic and renal adverse events. 6 This is due to their inhibitory effects on the biosynthesis of vascular prostacyclin (PGI2), a powerful platelet inhibitor and vasodilator, which is mainly derived from the haemodynamic shear induced by COX-2. 7 Recently, Yu et al showed that vascular COX-2 deletion ends in the reduction of the expression of endothelial nitric oxide (NO) synthase and consequent release of NO. 8 Similarly to prostacyclin, NO is endowed with important cardioprotective properties, such as vasodilation and inhibition of platelet function. 9 Suppression of PGI2 formation due to inhibition of vascular COX-2 is sufficient to account for the cardiovascular (CV) hazard from NSAIDs (traditional and selective for COX-2), 10 but it may be increased by secondary mechanisms such as suppression of NO production. 8 These findings justify the need to develop NSAIDs endowed with NO-releasing properties in order to mitigate their CV, and GI, hazard. Indeed, the novel class of anti-inflammatory agents, named COX-inhibiting nitric oxide-donors (CINODs), developed by linking a NO-releasing moiety to a tNSAID, has been shown to have a more favourable clinical profile than the parent tNSAIDs in randomized clinical trials. 11,12 This is plausibly due to the property of CINODs to release NO which may replace the functions of inhibited prostanoids by the tNSAIDs. 13
Journal of Medicinal Chemistry, Feb 1, 1998
Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivati... more Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a Ki value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximately 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.
PubMed, Nov 1, 1990
The syntheses as well as 5-HT and Benzodiazepine receptor binding studies of some 1,2,4-Triazolo[... more The syntheses as well as 5-HT and Benzodiazepine receptor binding studies of some 1,2,4-Triazolo[4',3':1,6]piridazino[4,5-b]quinoline and 2,3-Dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one derivatives are reported. While the triazole-containing heterocycles are devoid of any biological activity, 2-benzyl-2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one shows some affinity for the central type of benzodiazepine receptors.
Journal of Medicinal Chemistry, Dec 1, 2009
A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothia... more A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothiazole termed 2, 3, and 4, respectively, and structurally related to riluzole, a neuroprotective drug in many animal models of brain disease, have been synthesized. The biological activity of compounds 2a-e, 3a-f, and 4a,b was preliminarily tested by means of an in vitro protocol of ischemia/reperfusion injury. The results demonstrated that 2c and 3a-d significantly attenuated neuronal injury. Selected for testing of their antioxidant properties, compounds 3a-d were shown to be endowed with a direct ROS scavenging activity. Compounds 3b and 3d were also evaluated for their activity on voltage-dependent Na(+) and Ca(2+) currents in neurons from rat piriform cortex. At 50 microM, compound 3b inhibited the transient Na(+) current to a much smaller extent than riluzole, whereas 3d was almost completely ineffective.
ChemInform, Aug 5, 2010
Synthesis, Biological Evaluation and Molecular Docking Studies of 1,3,4-Thiadiazole Derivatives C... more Synthesis, Biological Evaluation and Molecular Docking Studies of 1,3,4-Thiadiazole Derivatives Containing 1,4-Benzodioxan as Potential Antitumor Agents.-Compound (Ic) shows the most potent biological activity against HEPG2 cancer cell line, which is comparable to the positive control.-(SUN,
ChemInform, Apr 4, 1989
ChemInform, Feb 13, 1990
ChemInform Abstract The chloromethylquinolines (III), synthesized from 2-aminobenzophenones (I) a... more ChemInform Abstract The chloromethylquinolines (III), synthesized from 2-aminobenzophenones (I) and ethyl 4-chloroacetoacetate (II), are converted into the amino acid esters (V). Methylamine (VI) reacts with (III), forming the lactams (VII). The affinity of (V) and (VII) to pre-and postsynaptic serotonin receptors is only weak.
journal of chemistry and chemical engineering, 2011
Capillary electrophoresis (CE) coupled with mass spectrometry (MS) with a sheath liquid interface... more Capillary electrophoresis (CE) coupled with mass spectrometry (MS) with a sheath liquid interface is nowadays recognized as a powerful separation technique for drugs and metabolites analysis in human urine and can be applied in numerous fields such as clinical toxicology, drug substitution monitoring, forensic sciences and antidoping. With an acidic background electrolyte containing 15 mM ammonium formate at pH 2.5 and a sheath liquid consisting in a mixture of isopropanol/water (50:50, v/v) with 0.5% formic acid, CE-ESI-MS in positive mode demonstrated excellent performance for simultaneous analysis of basic drugs of abuse and metabolites in urine (e.g. cocaine, amphetamine, morphine and phase II metabolites). To achieve the desired level of sensitivity, two injection modes and three sample pre-treatments were evaluated. The detection of basic drugs and phase II metabolites in diluted urine was achieved at concentrations above 1 μg/mL. In order to enhance sensitivity, a sample preparation was required. A liquid-liquid extraction (LLE) was compared with solid-phase extraction. LLE was performed at alkaline pH and samples were electrokinetically injected. A chemometric approach (Doehlert design) was carried out in order to determine optimized injection parameters. Limits of detection (LOD) down to 10 ng/mL were reached with field-amplified sample injection but phase II metabolites were not extracted. Therefore, instead of LLE a SPE was performed on C18 sorbent, and elution fraction after washing step containing phase II metabolites was loaded on mixed-mode anion exchanger cartridges. After electrokinetic injection, this two-step SPE allowed LOD ca. 10 ng/mL for drugs and phase II metabolites.
Journal of Medicinal Chemistry, May 31, 2017
LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the n... more LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the normal clearance of glutamate and providing neuronal protection. Since the pharmacologic activation of EAAT2 represents a valuable strategy to relieve neuropathic pain, we synthesized novel activators (4a−f) of EAAT2. Among them 4f, analyzed in comparison with 3 by different paradigms in a rat model of oxaliplatin-induced neuropathic pain, showed the better antihypersensitive profile being able to fully counteract the oxaliplatin-induced neuropathy.
Bioorganic & Medicinal Chemistry, Mar 15, 2008
The exploration of the structure-affinity relationships concerning a new class of peripheral benz... more The exploration of the structure-affinity relationships concerning a new class of peripheral benzodiazepine receptor (PBR) ligands related to alpidem has been pursued in order to evaluate the consistency of the structure-affinity relationships among different classes (and subclasses) of PBR ligands. The target amide derivatives were prepared following a previously published procedure based on the condensation of pyrrolo[3,4-b]quinoline derivatives 11a,b with glyoxylic acid mono-hydrate and the subsequent amidation of the acids obtained via mixed anhydride. On the other hand, the preparation of compound 9g lacking the pharmacophoric (delta1) carbonyl group involved: (a) the double sequential attack of the dimethylmethyleneammonium salt obtained from bis(dimethylamino)methane and acetyl chloride to pyrrolo[3,4-b]quinoline derivative 11b, (b) the quaternization of the obtained allylamine derivative 13 with methyl iodide, and (c) the palladium-catalyzed allylation of N-methyl-p-anisidine by quaternary allylammonium cation 14. The structure-affinity relationship trends observed in this subclass of tricyclic alpidem-related PBR ligands find correlations in other classes (or subclasses) of PBR ligands. This result supports the initial pharmacophoric hypothesis and suggests a common mode of interaction at the PBR binding site.
European journal of medicinal chemistry, 2017
Neurodegenerative diseases are disorders related to the degeneration of central neurons that grad... more Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved able to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate-and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na + and Ca 2+channels, showing a profile comparable with that of 1.
ChemMedChem, Apr 8, 2010
A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline... more A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline frameworks bearing a 4‐(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS‐5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS‐5 and ADAMTS‐4. Among the compounds containing the pyrrolo[3,4‐c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS‐5 and ADAMTS‐4, with IC50 values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS‐5 and ‐4. The structure–activity relationship analysis of pyrroloquinolinone derivatives 2 a–i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS‐5 and ‐4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS‐4 inhibitory activity and inhibit ADAMTS‐5 showing IC25 values in the micromolar range.
ChemMedChem, Feb 14, 2018
The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here... more The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, 1c was the most potent Zmp1 inhibitor known to date, and its binding mode was analysed both through kinetic studies and molecular modelling, identifying critical interactions of 1c with the zinc-ion and residues in the active site. Effect of 1c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1c displayed interesting in vitro antitubercular properties worth of further investigation.
Osteoarthritis and Cartilage, Apr 1, 2015
to directly characterize, for the first time, the role of the CTD of Cx43 on cartilage structure.... more to directly characterize, for the first time, the role of the CTD of Cx43 on cartilage structure. Our results strongly support the notion that the CTD of Cx43 plays an important role in chondrocyte phenotype. It is well know that through its CTD, Cx43 serves as scaffolding proteins that associates with structural and signaling molecules leading to regulation of intracellular signaling, independently of channel activity. This study illustrates that a complete isolation of Cx43 from its CTD may have a negative impact on cartilage structure and chondrocyte functions within the tissue.