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Federico Da Settimo - One of the best experts on this subject based on the ideXlab platform.
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progresses in the pursuit of Aldose Reductase Inhibitors the structure based lead optimization step
European Journal of Medicinal Chemistry, 2012Co-Authors: Anna Ramunno, Stefania Sartini, Sandro Cosconati, Concettina La Motta, Salvatore Di Maro, Vita Maglio, Sara Angiuoli, Valeria La Pietra, Mariateresa Giustiniano, Federico Da SettimoAbstract:Aldose Reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 Inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.
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Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies
Journal of Medicinal Chemistry, 2012Co-Authors: Stefania Sartini, Francesca Simorini, Sandro Cosconati, Salvatore Di Maro, Sabrina Taliani, Elisabetta Barresi, Luciana Marinelli, Anna Maria Marini, Silvia Salerno, Federico Da SettimoAbstract: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.
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Benzofuroxane Derivatives as Multi-Effective Agents for the Treatment of Cardiovascular Diabetic Complications. Synthesis, Functional Evaluation, and Molecular Modeling Studies
2012Co-Authors: Stefania Sartini, Francesca Simorini, Sandro Cosconati, Salvatore Di Maro, Sabrina Taliani, Elisabetta Barresi, Luciana Marinelli, Anna Maria Marini, Silvia Salerno, Federico Da SettimoAbstract: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
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Naphtho[1,2-d]isothiazole Acetic Acid Derivatives as a Novel Class of Selective Aldose Reductase Inhibitors
'American Chemical Society (ACS)', 2005Co-Authors: Federico Da Settimo, Stefania Sartini, Francesca Simorini, Concettina La Motta, Sabrina Taliani, Giampaolo Primofiore, M. A. Marini, Lavecchia Antonio, Novellino Ettore, Enrico BoldriniAbstract:Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel Aldose Reductase (ALR2) Inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde Reductase, sorbitol dehydrogenase, or glutathione Reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series
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Novel, highly potent Aldose Reductase Inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives
Journal of Medicinal Chemistry, 2003Co-Authors: Federico Da Settimo, Francesca Simorini, Concettina La Motta, Giovanni Greco, Antonio Lavecchia, Antonio Da Settimo, Giampaolo Primofiore, Ettore Novellino, Enrico BoldriniAbstract:Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of Aldose Reductase (ALR2) Inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC 50 value of 0.85 μM, similar to that of the well-known ARI sorbinil (IC 50 0.50 μM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl] acetic acid, which displayed the highest activity (IC 50 0.075 μM, very close to that of tolrestat IC 50 0.046 μM), with a good selectivity toward ALR2 compared with aldehyde Reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione Reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.
Changjin Zhu - One of the best experts on this subject based on the ideXlab platform.
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Pyridothiadiazine derivatives as Aldose Reductase Inhibitors having antioxidant activity
2016Co-Authors: Shaojuan Zhu, Shuzhen Zhang, Shagufta Parveen, Xin Hao, Xiangyu Qin, Shaoqi Yang, Changjin ZhuAbstract:A series of Aldose Reductase (ALR2) Inhibitors based on pyridothiadiazine were prepared and evaluated for their activities in ALR2 inhibition, DPPH scavenging, and MDA inhibition. Comparison studies were carried out between analogs having either hydroxyl or methoxy groups substituted on the N2-benzyl side chains of the compounds. Most of the hydroxy-substituted compounds were found to be more potent compared to their methoxy-substituted analogs with respect to DPPH inhibition (>93%) and MDA inhibition (>73%). However, ALR2 inhibitory activity was found to be affected by the electron-withdrawing substituent at the C7 position in addition to the effect of the N2-substituted benzyl group. These results provide an array of multifunctional ALR2 Inhibitors possessing capacities both for ALR2 inhibition and as antioxidants.
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design and synthesis of potent and multifunctional Aldose Reductase Inhibitors based on quinoxalinones
Journal of Medicinal Chemistry, 2015Co-Authors: Xiangyu Qin, Yanchun Yang, Shagufta Parveen, Chaojun Jing, Saghir Hussain, Shaojuan Zhu, Xin Hao, Hui Han, Changjin ZhuAbstract:Quinoxalin-2(1H)-one based design and synthesis produced several series of Aldose Reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032–0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 Inhibitors having both...
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structure activity relationships studies of quinoxalinone derivatives as Aldose Reductase Inhibitors
European Journal of Medicinal Chemistry, 2014Co-Authors: Saghir Hussain, Xin Chen, Yanchun Yang, Shuzhen Zhang, Shagufta Parveen, Shaojuan Zhu, Xin Hao, Xiangyu Qin, Wei Wang, Changjin ZhuAbstract:Abstract Novel quinoxalinone derivatives were synthesized and tested for their inhibitory activity against Aldose Reductase. Among them, N1-acetate derivatives had significant activity in a range of IC 50 values from low micromolar to submicromolar, and compound 15a bearing a C3-phenethyl side chain was identified as the most potent inhibitor with an IC 50 value of 0.143 μM. The structure–activity studies suggested that both C3-phenethyl and C6-NO 2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based Inhibitors.
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design and synthesis of potent and selective Aldose Reductase Inhibitors based on pyridylthiadiazine scaffold
European Journal of Medicinal Chemistry, 2011Co-Authors: Xin Chen, Changjin Zhu, Yanchun Yang, Shuzhen Zhang, Chaojun Jing, Dequan Gui, Saghir Hussain, Yan LiuAbstract:A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against Aldose Reductase (ALR2). These derivatives were found to be potent Aldose Reductase Inhibitors with IC50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these Inhibitors, compound 7d exhibited highest inhibition activity. Structure-activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.
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Acetic acid derivatives of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide as a novel class of potent Aldose Reductase Inhibitors.
Journal of Medicinal Chemistry, 2010Co-Authors: Xin Chen, Changjin Zhu, Fan Guo, Xiaowei Qiu, Yanchun Yang, Shuzhen Zhang, Shagufta Parveen, Chaojun JingAbstract:A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against Aldose Reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective Aldose Reductase Inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 μM. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure−activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a rema...
Chaojun Jing - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of potent and multifunctional Aldose Reductase Inhibitors based on quinoxalinones
Journal of Medicinal Chemistry, 2015Co-Authors: Xiangyu Qin, Yanchun Yang, Shagufta Parveen, Chaojun Jing, Saghir Hussain, Shaojuan Zhu, Xin Hao, Hui Han, Changjin ZhuAbstract:Quinoxalin-2(1H)-one based design and synthesis produced several series of Aldose Reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032–0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 Inhibitors having both...
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Design and Synthesis of Potent and Multifunctional Aldose Reductase Inhibitors Based on Quinoxalinones
2015Co-Authors: Xiangyu Qin, Yanchun Yang, Shagufta Parveen, Saghir Hussain, Shaojuan Zhu, Xin Hao, Hui Han, Chaojun JingAbstract:Quinoxalin-2(1H)-one based design and synthesis produced several series of Aldose Reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032–0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 Inhibitors having both potency for ALR2 inhibition and as antioxidants
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design and synthesis of potent and selective Aldose Reductase Inhibitors based on pyridylthiadiazine scaffold
European Journal of Medicinal Chemistry, 2011Co-Authors: Xin Chen, Changjin Zhu, Yanchun Yang, Shuzhen Zhang, Chaojun Jing, Dequan Gui, Saghir Hussain, Yan LiuAbstract:A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against Aldose Reductase (ALR2). These derivatives were found to be potent Aldose Reductase Inhibitors with IC50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these Inhibitors, compound 7d exhibited highest inhibition activity. Structure-activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.
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Acetic acid derivatives of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide as a novel class of potent Aldose Reductase Inhibitors.
Journal of Medicinal Chemistry, 2010Co-Authors: Xin Chen, Changjin Zhu, Fan Guo, Xiaowei Qiu, Yanchun Yang, Shuzhen Zhang, Shagufta Parveen, Chaojun JingAbstract:A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against Aldose Reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective Aldose Reductase Inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 μM. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure−activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a rema...
Stefania Sartini - One of the best experts on this subject based on the ideXlab platform.
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progresses in the pursuit of Aldose Reductase Inhibitors the structure based lead optimization step
European Journal of Medicinal Chemistry, 2012Co-Authors: Anna Ramunno, Stefania Sartini, Sandro Cosconati, Concettina La Motta, Salvatore Di Maro, Vita Maglio, Sara Angiuoli, Valeria La Pietra, Mariateresa Giustiniano, Federico Da SettimoAbstract:Aldose Reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 Inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.
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Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies
Journal of Medicinal Chemistry, 2012Co-Authors: Stefania Sartini, Francesca Simorini, Sandro Cosconati, Salvatore Di Maro, Sabrina Taliani, Elisabetta Barresi, Luciana Marinelli, Anna Maria Marini, Silvia Salerno, Federico Da SettimoAbstract: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.
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Benzofuroxane Derivatives as Multi-Effective Agents for the Treatment of Cardiovascular Diabetic Complications. Synthesis, Functional Evaluation, and Molecular Modeling Studies
2012Co-Authors: Stefania Sartini, Francesca Simorini, Sandro Cosconati, Salvatore Di Maro, Sabrina Taliani, Elisabetta Barresi, Luciana Marinelli, Anna Maria Marini, Silvia Salerno, Federico Da SettimoAbstract: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
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identification of 5 arylidene 4 thiazolidinone derivatives endowed with dual activity as Aldose Reductase Inhibitors and antioxidant agents for the treatment of diabetic complications
European Journal of Medicinal Chemistry, 2011Co-Authors: R Ottana, Sandro Cosconati, Luciana Marinelli, Ettore Novellino, Rosanna Maccari, Marco Giglio, Antonella Del Corso, Mario Cappiello, Umberto Mura, Stefania SartiniAbstract: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.
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Naphtho[1,2-d]isothiazole Acetic Acid Derivatives as a Novel Class of Selective Aldose Reductase Inhibitors
'American Chemical Society (ACS)', 2005Co-Authors: Federico Da Settimo, Stefania Sartini, Francesca Simorini, Concettina La Motta, Sabrina Taliani, Giampaolo Primofiore, M. A. Marini, Lavecchia Antonio, Novellino Ettore, Enrico BoldriniAbstract:Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel Aldose Reductase (ALR2) Inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde Reductase, sorbitol dehydrogenase, or glutathione Reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series
Rosanna Maccari - One of the best experts on this subject based on the ideXlab platform.
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identification of 5 arylidene 4 thiazolidinone derivatives endowed with dual activity as Aldose Reductase Inhibitors and antioxidant agents for the treatment of diabetic complications
European Journal of Medicinal Chemistry, 2011Co-Authors: R Ottana, Sandro Cosconati, Luciana Marinelli, Ettore Novellino, Rosanna Maccari, Marco Giglio, Antonella Del Corso, Mario Cappiello, Umberto Mura, Stefania SartiniAbstract: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.
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structure activity relationships and molecular modelling of 5 arylidene 2 4 thiazolidinediones active as Aldose Reductase Inhibitors
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Rosanna Maccari, C Curinga, Rosaria Ottana, M G Vigorita, Dietmar Rakowitz, Theodora M Steindl, Thierry LangerAbstract:Abstract The structure–activity relationships (SARs) of 5-arylidene-2,4-thiazolidinediones active as Aldose Reductase Inhibitors (ARIs) were extended by varying the substitution pattern on the 5-arylidene moiety and on N-3. In particular, the introduction of an additional aromatic ring or an H-bond donor group on the 5-benzylidene ring enhanced ALR2 inhibitory potency. Moreover, the presence of a carboxylic anionic chain on N-3 was shown to be an important, although not essential, structural requisite to produce high levels of ALR2 inhibition. The length of this carboxylic chain was critical and acetic acids 4 were the most effective Inhibitors among the tested derivatives. Molecular docking simulations into the ALR2 active site accorded with the in vitro inhibition data. They allowed the rationalization of the observed SARs and provided a pharmacophoric model for this class of ARIs.
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synthesis and Aldose Reductase inhibitory activity of 5 arylidene 2 4 thiazolidinediones
Bioorganic & Medicinal Chemistry, 2002Co-Authors: Giuseppe Bruno, Luca Costantino, C Curinga, Rosanna Maccari, F Monforte, Francesco Nicolo, Rosaria Ottana, M G VigoritaAbstract:Abstract Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as Aldose Reductase Inhibitors (ARIs). The most active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic side chain on N-3 of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery of a very potent ARI (4c), whose activity level (IC50=0.13 μM) was in the same range of Tolrestat. Moreover, the corresponding methyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstituted compounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of N-unsubstituted 2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than the para-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4.