- Design, synthesis and biological evaluation of novel naphthoquinone-4-aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors
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A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and antiproliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, β1 subunit), trypsin-like (T-L, β2 subunit) and chymotrypsin-like (ChT-L, β5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC50 values of 9.90 ± 0.61, 44.83 ± 4.23 and 22.27 ± 0.15 μM against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC50 = 12.47 ± 0.21, 53.12 ± 2.56 and 26.37 ± 0.5 μM), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC50 = 1.72 ± 0.14–20.8 ± 0.5 μM and compounds 13 and 28 were found to be the most active compounds with IC50 values of 1.79 ± 0.21 and 1.72 ± 0.14 μM, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions.
- Uysal, Sirin,Soyer, Zeynep,Saylam, Merve,Tarikogullari, Ayse H.,Yilmaz, Sinem,Kirmizibayrak, Petek Ballar
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- Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27
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GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
- Blavier, Jeremy,Charles, Ma?lle,Hanson, Julien,Kronenberger, Thales,Laschet, Céline,Müller, Christa E.,Pillaiyar, Thanigaimalai,Rosato, Francesca,Wozniak, Monika
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- Synthesis, Computational Docking, and Antimycobacterial Study of Novel N'-phenyl-4-pyrrol-1-yl-benzenesulfonamide Derivatives
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Fresh sequences of pyrrole linked N'-phenyl-4-pyrrolyl-benzenesulfonamide derivatives were synthesized by different synthetic methods. Synthesis of the N'-phenyl-4-(1H-pyrrol-1-yl) benzenesulfonamides 5(a-e)/4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-phenylbenzenesulfonamides 6(a-e) was achieved by refluxing 2,5-dimethoxytetrahydrofuran/hexane 2,5-dione separately in presence of acetic acid. Further, synthesis of N-(4-(N'-phenylsulfamoyl)phenyl)-4-(1H-pyrrol-1-yl)benzamides 8(a-b)/4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(4-(N'-phenylsulfamoyl)phenyl)benzamides 10(a-b) was achieved by cold stirring of 4-(1H-pyrrol-1-yl)benzoic acid (7)/2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid (9) correspondingly in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, N', N'-diisopropylethylamine, and Dimethylformamide. In vitro anti-tubercular study of afresh compounds has shown good minimum inhibitory concentration values (0.4-12.5 μg/mL) counter to Mycobacterium tuberculosis H37Rv, while the corresponding study of reported molecules for antibacterial activity disclosed considerable inhibition values (0.4-25 μg/mL) counter to Escherichia coli (Gram-ve) than Staphylococcus aureus (Gram +ve).
- Alqahtani, Yahya S.,Joshi, Shrinivas D.,Kumar, S. R. Prem,Pavitra, H.
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p. 405 - 416
(2021/11/22)
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- Synthesis of 3-Methyl-1-Phenyl-5-Pyrazolones Containing Arylaminosulfonyl Groups
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N-Aryl-substituted 3(4)-aminobenzenesulfonamides were synthesized.They are the starting compounds for the production of the corresponding substituted 3(4)-(3-methyl-5-oxo-2-pyrazolin-1-yl)-N-phenylbenzenesulfonamides.Data from the IR, PMR, and mass spectra are presented, and the fragmentation of the molecules is discussed.
- Lisitsyn, V. N.,Sazonchik, O. B.
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p. 780 - 784
(2007/10/02)
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