Structural determination of biological active N-phenyl-2-phthalimidoethanesulfonamide derivatives

WOS: 00047440660055

Unconventional amino acids in medicinal chemistry: First report on taurine merged within carbonic anhydrase inhibitors

akgul, ozlem/0000-0002-0011-7888; angeli, andrea/0000-0002-1470-7192WOS: 000575791300003PubMed: 32882441This study reports the design, synthesis of a series of taurine containing benzenesulfonamide derivatives which were all screened in vitro against the physiological relevant human (h) expressed Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, IX, XII isozymes. Compound 2, 5, 11-16 displayed superior inhibitory activities against the tumor associated hCA IX over the reference drug Acetazolamide (AAZ). Both hCA IX and XII isoforms were selectively inhibited only by compound 3, whereas the chloro-containing compound 12 was showed as the most selective and effective inhibitor profile for the CA IX isoforms. To the best of our knowledge the data reported herein are the first of this kind and introduce in the literature new compounds worth for future development within the Medicinal Chemistry field.Scientific and Technical Research Council of Turkey [TUBITAK]Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [116S705]; Ege UniversityEge University [BAP 2018.BIL.002]This project was supported by the Scientific and Technical Research Council of Turkey [TUBITAK 116S705] and Ege University [BAP 2018.BIL.002]

Substituent position effect on the crystal structures of N-phenyl-2-phthalimidoethanesulfonamide derivatives

WOS: 000419342700005PubMed ID: 29303494In order to determine the impact of different substituents and their positions on intermolecular interactions and ultimately on the crystal packing, unsubstituted N-phenyl-2-phthalimidoethanesulfonamide, C16H14N2O4S, (I), and the N-(4-nitrophenyl)-, C16H13N3O6S, (II), N-(4-methoxyphenyl)-, C16H16N3O6S, (III), and N-(2-ethylphenyl)-, as the monohydrate, C18H18N2O4S center dot H2O, (IV), derivatives have been characterized by single-crystal X-ray crystallography. Sulfonamides (I) and (II) have triclinic crystal systems, while (III) and (IV) are monoclinic. Although the molecules differ from each other only with respect to small substituents and their positions, they crystallized in different space groups as a result of differing intra-and intermolecular hydrogen-bond interactions. The structures of (I), (II) and (III) are stabilized by intermolecular N-H center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds, while that of (IV) is stabilized by intermolecular O-H center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds. All four structures are of interest with respect to their biological activities and have been studied as part of a program to develop anticonvulsant drugs for the treatment of epilepsy.Dokuz Eylul UniversityDokuz Eylul University [2010.KB.FEN.13]The authors acknowledge Dokuz Eylul University for the use of the Agilent Xcalibur Eos diffractometer (purchased under University Research grant No. 2010.KB.FEN.13)

Design, synthesis, cytotoxic activity, and apoptosis inducing effects of 4-and N-substituted benzoyltaurinamide derivatives

akgul, ozlem/0000-0002-0011-7888; Birim, Dervis/0000-0002-5094-9949; Gunduz, Cumhur/0000-0002-6593-3237; Erdogan, Mumin/0000-0003-0048-444XWOS:000599807000020PubMed: 33488262In this study, a group of 4-substituted benzoyltaurinamide derivatives were designed, synthesized, and investigated for their anticancer activity against three cancer cell lines and one nontumorigenic cell line by MTT assay. Among the final compounds, methoxyphenyl derivatives 14, 15, 16 were found to be effective against all the tested cancerous cell lines with promising selectivity. The most active compounds were further evaluated to determine the molecular mechanism of their anticancer activity by using western blot assay and the Annexin V-FITC/PI test. Compound 14 (in SH-SY5Y and MDA-MB-231 cell lines) and 15 (in SH-SY5Y cell line) were found to induce intrinsic apoptotic pathway by upregulating BAX, caspase-3, and caspase-9, while downregulating Bcl-2 and Bcl-xL expression levels. According to mechanistic studies, compounds displayed their anticancer activity via three different mechanisms: a. caspase-dependent, b. caspase-independent, and c. caspase-dependent pathway that excluded caspase-9 activation. As a result, this study provides interesting data which can be used to design new taurine-based anticancer derivatives.Scientific and Technological Research Council of Turkey [TUBITAK]Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [SBAG-118S667]This study was supported by research grants from The Scientific and Technological Research Council of Turkey [TUBITAK; Project number: SBAG-118S667]

Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of alpha-, beta- and gamma-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-alpha, VchCA-beta and VchCA-gamma) and Burkholderia pseudomallei (BpsCA-beta and BpsCA-gamma). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCA alpha inhibitors (K-I values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; K-I VchCA-alpha/K-I hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-gamma were also identified (K(I)s of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs. (C) 2021 Elsevier Masson SAS. All rights reserved.Scientific and Technical Research Council of Turkey [TUBITAK 117S516]; Ege University [16-ECZ-012]; Bando di Ateneo per il Finanziamento di Progetti Competitivi per Ricercatori a Tempo Determinato (RTD) dell'Universita di Firenze 2020-2021; Fondazione Cassa di Risparmio di Firenze [ECR2018.1001]; Italian Ministry of University and Research [FISR2019_04819 BacCAD]Ozlem Akgul (O.A.) is grateful to The Scientific and Technical Research Council of Turkey [TUBITAK 117S516] and Ege University [16-ECZ-012] which partially funded this work.; Fabrizio Carta (F.C.) is grateful to Bando di Ateneo per il Finanziamento di Progetti Competitivi per Ricercatori a Tempo Determinato (RTD) dell'Universita di Firenze 2020-2021, and Fondazione Cassa di Risparmio di Firenze (Grant Number ECR2018.1001) for partially supporting this work. This work was also financed by the Italian Ministry of University and Research, project FISR2019_04819 BacCAD (to CTS and CC)

Synthesis and cytotoxic activity of some 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetamide derivatives

WOS: 000317819800004Isatin, 1H-indoline-2,3-dione, an endogenous compound, is also a synthetically versatile molecule that possesses a diversity of biological activities including anticonvulsant, antibacterial, antifungal, antiviral, anticancer, and cytotoxic properties. Based on the promising cytotoxic activity studies on N-substituted isatin derivatives, a series of 18 derivatives of 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide were designed, synthesized, and characterized according to their analytical and spectral data. All of the compounds were evaluated for their cytotoxic activity against MCF7, A549, HeLa, and HEK293 cell lines by real time cell analyzer. Etoposide was used as a standard compound. Briefly, ortho substitutions gave better results compared to meta and para substitutions on the N-phenyl ring and compounds bearing ortho substitutions were more effective on MCF7 cell lines than A549 and HeLa cell lines. 2-(2,3-Dioxo-2,3-dihydro-1H-indol-1-yl)-N-(2-isopropylphenyl)acetamide was the most active compound against all the tested cell lines.Ege UniversityEge University [09/ECZ/036]This study was supported by a research grant from Ege University (Project number: 09/ECZ/036). We thank the Pharmaceutical Sciences Research Center (FABAL) of the Faculty of Pharmacy, Ege University, for support with the equipment

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis

akgul, ozlem/0000-0002-0011-7888; carta, fabrizio/0000-0002-1141-6146; Supuran, Claudiu/0000-0003-4262-0323; Bigagli, Elisabetta/0000-0003-1892-4343; Lucarini, Laura/0000-0001-9016-8429WOS: 000579944600001PubMed: 32927723Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. the pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. the activity of compound3, one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. the hybrid compounds showed a higher potency in inhibiting PGE(2)production, but not in modifying the platelet aggregation and the TXB(2)production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. in the in-vivo murine model, the compound3was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. in conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.PRIN 2015 from the Italian Ministry of Education, University and Research; Fondazione Cassa di Risparmio of Florence, ItalyThis research was funded by PRIN 2015 from the Italian Ministry of Education, University and Research, and by Fondazione Cassa di Risparmio of Florence, Italy

Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors

Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex. (C) 2020 Elsevier Masson SAS. All rights reserved.This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK; Project number: 116S705) and research grants from Ege University (Project number: 18-B_IL002).Scientific and Technological Research Council of Turkey (TUBITAK) [116S705]; Ege University [18-B_IL002