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Öğe Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors(Elsevier Masson s.r.l., 2021) Akgul O.; Singh S.; Andring J.T.; McKenna R.; Selleri S.; Carta F.; Supuran C.T.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. © 2020 Elsevier Masson SASÖğe New electroactive hybridization indicators 2-phthalimido-N-substitutedphenylethanesulfonamide derivatives for biosensor applications: Ring substituent effect on interaction between compound and DNA(2010) Ozkan-Ariksoysal D.; Akgul O.; Aydinlik S.; Topkaya S.N.; Aladag N.; Ozsoz M.In this work, an electrochemical DNA-based sensor was developed for the detection of the interaction between the anticonvulsant compounds 2-phthalimido-N-substituted phenylethanesulfonamides (PMPES-derivatives) and 24-mer short DNA sequences by using differential pulse voltammetry (DPV) based on both compound and guanine oxidation signals at the renewable carbon graphite electrode (CGE) surface. The influence of compounds on DNA showed differences depending on the nature and position of the substituent on the N-phenyl ring. Compounds bearing 3-methoxy, 4-chloro and 2,6-dimethyl substituents bind to single stranded probe DNA more strongly than the other derivatives of PMPES. Thus, these compounds were evaluated for use as an electrochemical hybridization label (indicator). © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Öğe Pain relieving effect of-NSAIDS-CAIs hybrid molecules: Systemic and intra-articular treatments against rheumatoid arthritis(MDPI AG, 2019) Micheli L.; Bozdag M.; Akgul O.; Carta F.; Guccione C.; Bergonzi M.C.; Bilia A.R.; Cinci L.; Lucarini E.; Parisio C.; Supuran C.T.; Ghelardini C.; Di Cesare Mannelli L.To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated per os treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg-1) or single i.a injection (1 mg ml-1, 50 µL) with NSAIDs-CAIs hybrid molecules, named 4 and 5, was evaluated. The molecules 4 and 5, which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, 4 and 5 were formulated in liposomes (lipo 4 and lipo 5, both 1 mg ml-1) and directly administered by a single i.a. injection seven days after CFA injection. Lipo 5 decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.Öğe Synthesis and anticonvulsant activity of some N-phenyl-2- phtalimidoethanesulfonamide derivatives(2007) Akgul O.; Kilic F.S.; Erol K.; Pabuccuoglu V.In this study, inspired by the structures of the taltrimide, 2-phthalimidoethanesulphonamide, and the anilide pharmacophore known to be synthetically produced anticonvulsant compounds, fifteen N-phenyl-2- phtalimidoethanesulfonamide derivatives bearing substituents with diverse electronic and hydrophobic features on N-phenyl ring were synthesized. The structural confirmation of the title compounds was achieved by interpretation of spectral and analytical data. The anticonvulsant activity of the title compounds was determined against maximal electroshock seizure in mice at a dose level of 100 mg/kg. The preliminary screening results indicated that the exchange of the N-isopropyl moiety for an N-phenyl ring in the taltrimide molecule abolished the anticonvulsant activity. However, introducing certain substituents, such as nitro, methyl, and chloro, into the N-phenyl ring lead to more active compounds in comparison to the unsubstituted derivatives. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.Öğe Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of ?-, ?- and ?-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei(Elsevier Masson s.r.l., 2021) Akgul O.; Angeli A.; Selleri S.; Capasso C.; Supuran C.T.; Carta F.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-?, VchCA-? and VchCA-?) and Burkholderia pseudomallei (BpsCA-? and BpsCA-?). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCA? inhibitors (KI values spanning within the 6.1–9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-?/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-? were also identified (KIs 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. © 2021 Elsevier Masson SAS
