Person: AKDEMİR, ATİLLA
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Publication Open Access Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII(2022-07-01T00:00:00Z) GÜMÜŞ PALABIYIK, ARZU; Bozdag, Murat; AKDEMİR, ATİLLA; Angeli, Andrea; Selleri, Silvia; Carta, Fabrizio; Supuran, Claudiu T.; AKDEMİR, ATİLLAA novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.Publication Metadata only rac- and meso-Cyclohexanoids: Their alpha-, beta-glycosidases, antibacterial, antifungal activities, and molecular docking studies(2020-01-10T00:00:00Z) Karakilic, Emel; Baran, Sule; Ogutcu, Hatice; AKDEMİR, ATİLLA; Baran, Arif; AKDEMİR, ATİLLAAn efficient and versatile synthesis method has been postulated for hydroxymethylated rac- and meso-cyclohexanoid derivatives. The synthesis of these stereoisomers was achieved easily with traditional methods using hexahydroisobenzofuran 6, prepared from commercially available cis-hydrophthalic anhydride. The study, involving diastereoselective epoxidation and cis-hydroxylation, was conducted to obtain epoxy-, cis-, and trans-diol-furans 7, 8, and 9. After sulfamic acid-catalyzed ring-opening reaction of the epoxide and furan rings, rac- and meso-tetraacetates 14, 15, and 16 were afforded. Hydrolysis of acetate groups with ammonia in absolute methanol yielded the desired tetrols rac-17, meso-18, and meso-19. All structures, after purification by chromatographic methods and elucidation by spectral techniques, were screened against alpha- and beta-glucosidases. Compounds 7, 8, 10, 17, 18, and 19 were also evaluated for their antibacterial and antifungal activity against some selected synthesized compounds with varying degrees of inhibitory effects on the growth of different pathogenic microorganisms by the well-diffusion method. In addition, Saccharomyces cerevisiae alpha-glucosidase molecular modeling studies were performed for all rac- and meso-compounds 7, 8, 10, 17, 18, and 19.Publication Open Access The neutralization effect of montelukaston SARS-CoV-2 is shown by multiscale in silicosimulations and combined in vitro studies(2021-10-19T00:00:00Z) Durdagi, Serdar; Avsar, Timucin; Orhan, Muge Didem; Serhatli, Muge; Balcioglu, Bertan Koray; Ozturk, Hasan Umit; Kayabolen, Alisan; Cetin, Yuksel; Aydinlik, Seyma; Bagci-Onder, Tugba; Tekin, Saban; Demirci, Hasan; Guzel, Mustafa; Akdemir, ATİLLA; Calis, Seyma; Oktay, Lalehan; Tolu, Ilayda; Butun, Yasar Enes; Erdemoglu, Ece; Olkan, Alpsu; Tokay, Nurettin; Işık, Şeyma; Ozcan, Aysenur; Acar, Elif; Buyukkilic, Sehriban; Yumak, Yesim; AKDEMİR, ATİLLASmall molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).Publication Metadata only Design and synthesis of novel peptidomimetics for cancer immunotherapy(2020-07-01T00:00:00Z) Kose, Ceyda; Uysal, Esra; Yazici, Busra; Tugay, Zeynep; Yanik, Hamdullah; Tavukcuoglu, Ece; Gulyuz, Sevgi; AKDEMİR, ATİLLA; ESENDAĞLI, GÜNEŞ; Yilmaz, Ozgur; Alptürk, Onur; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLATumor cells benefit from some certain signals, which are referred to as -immune checkpoints-, to escape immune-mediated destruction. With that in mind, it is believed that the blockade of these points, such as programmed cell death Ligand-1 (PD-L1) and programmed cell death 1 (PD-1), can restore an adaptative immune response against tumoral cells. In this study, we have designed and synthesized some novel peptidomimetics with a 2-aminobenzathiazole scaffold, which targets the PD-1/PDL-1 pathway. In the viability assay, it was found that these compounds decreased the proliferation of peripheral blood mononuclear cells in the concentration of 10 uM. Overall, our results indicate that these novel compounds are potential checkpoint inhibitors for cancer immunotherapy.Publication Metadata only New 1H-indole-2,3-dione 3-thiosemicarbazones with 3-sulfamoylphenyl moiety as selective carbonic anhydrase inhibitors(2022-05-01T00:00:00Z) Eraslan-Elma, Pinar; AKDEMİR, ATİLLA; Berrino, Emanuela; Bozdag, Murat; Supuran, Claudiu T.; Karali, Nilgun; AKDEMİR, ATİLLA1-Methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-diones (2, 3, and 4) were synthesized by reaction of 5-(un)substituted 1H-indole-2,3-diones (1) with methyl iodide, ethyl chloride, and benzyl bromide. (3-Sulfamoylphenyl)isothiocyanate (6) was obtained by the treatment of 3-aminobenzenesulfonamide (5) with thiophosgene. Compound 6 was reacted with hydrazine to yield 4-(3-sulfamoylphenyl)thiosemicarbazide (7). Novel 1-(un)substituted/methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-dione 3-[4-(3-sulfamoylphenyl)thiosemicarbazone] derivatives (8-11) were prepared by condensation of 7 and 1-4. The structures of the synthesized compounds were confirmed by elemental analysis and spectral data. Inhibition of the widely distributed cytosolic off-targets human carbonic anhydrases (hCAs) I and II, and two tumor-associated membrane-bound isoforms (hCAs IX and XII), by 8-11 was investigated. The hCA II inhibitory effects of all tested compounds were in the subnanomolar to low nanomolar levels (K-i = 0.32-83.3 nM), and generally high selectivity for hCA II isoenzyme over hCA I, IX, and XII isoenzymes was observed. The strongest inhibitors of hCA II, 1-benzyl-5-(trifluoromethoxy)-substituted 11c (K-i = 0.32 nM) and 1-ethyl-5-chloro-substituted 10e (K-i = 0.35 nM), were docked within the enzyme active site. Molecular modeling studies with the most effective hCA IX and XII inhibitors were also carried out.Publication Metadata only Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations(2022-04-01T00:00:00Z) Trawally, Muhammed; DEMİR YAZICI, Kübra; DİNGİŞ BİRGÜL, SERAP İPEK; Kaya, Kerem; AKDEMİR, ATİLLA; GÜZEL AKDEMİR, Özlen; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLA© 2022A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.Publication Open Access Synthesis and biological evaluation of new chloro/acetoxy substituted isoindole analogues as new tyrosine kinase inhibitors.(2020-01-01T00:00:00Z) Köse, A; Kaya, M; Kishalı, NH; Akdemir, ATİLLA; Şahin, E; Kara, Y; Şanlı-Mohamed, G; AKDEMİR, ATİLLAPublication Metadata only New Pyridinium Salt Derivatives of 2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5- sulfonamide as Selective Inhibitors of Tumour-Related Human Carbonic Anhydrase Isoforms IX and XII(2022-08-01T00:00:00Z) Güzel Akdemir, Özlen; Demir Yazıcı, Kübra; Akdemir, Atilla; AKDEMİR, ATİLLAPublication Metadata only Evaluation of new 2-hydroxy-N-(4-oxo-2-substituted phenyl-1,3- thiazolidin-3-yl)-2-phenylacetamide derivatives as potential antimycobacterial agents(2020-04-01T00:00:00Z) Guzel-Akdemir, Ozlen; DEMİR YAZICI, Kübra; Trawally, Muhammed; AKDEMİR, ATİLLA; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLAA small collection of 2-hydroxy-N-(5-methyl/nonsubstituted 4-oxo-2-substituted phenyl-1,3-thiazolidin-3-yl)-2-phenylacetamides (3-16) was synthesized from the cyclocondensation of 2-hydroxy-2-phenyl-N--[(substitutedphenyl)methylene]acetohydrazides (2) and mercaptoethanoic acid or 2-mercaptopropanoic acid, characterized with spectral and elemental analysis. In order to explore their antimycobacterial potential, newly synthesized fourteen compounds were screened for their inhibitory activity against Mycobacterium tuberculosis strain H37Rv at 6.25 mu g/mL with in-vitro primary tests. Compound 7 was found to provide the highest inhibition (98%) M. tuberculosis strain H37Rv, while most of the new derivatives showed different inhibition ratios. For the search of the putative targets which are considered as related to the antimycobacterial activity of these molecules, docking studies were performed. With molecular dynamic simulations, further possible interactions between ligands and the active site of the selected enzymes were investigated. Eventually, molecular modelling studies indicated that at least part of the mechanism of action of these compounds may be mediated by inhibition of MtInhA.Publication Metadata only Anticholinesterase and Antioxidant Activities of Natural Abietane Diterpenoids with Molecular Docking Studies(2020-01-01T00:00:00Z) TOPÇU, GÜLAÇTI; AKDEMİR, ATİLLA; Kolak, Ufuk; Ozturk, Mehmet; Boga, Mehmet; BAHADORİ, FATEMEH; Cakmar, Seda Damla Hatipoglu; TOPÇU, GÜLAÇTI; AKDEMİR, ATİLLA; BAHADORİ, FATEMEHBackground: Alzheimer-s Disease (AD) is one of the most prevalent causes of dementia in the world, and no drugs available that can provide a complete cure. Cholinergic neurons of the cerebral cortex of AD patients are lost due to increased activity of cholinesterase enzymes.