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Öğe Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19-associated main enzymes(Elsevier Sci Ltd, 2022) Alici, Hakan; Tahtaci, Hakan; Demir, KadirThe novel coronavirus disease (COVID-19) is a highly contagious disease caused by the SARS-CoV-2 virus, leading severe acute respiratory syndrome in patients. Although various antiviral drugs and their combinations have been tried so far against SARS-CoV-2 and they have shown some effectiveness, there is still a need for safe and cost-effective binding inhibitors in the fight against COVID-19. Therefore, phytochemicals in nature can be a quick solution due to their wide therapeutic spectrum and strong antiviral, anti-inflammatory, and antioxidant properties. In this context, the low toxicity, and high pharmacokinetic properties of curcumin, which is a natural phytochemical, as well as the easy synthesizing of its derivatives reveal the need for investigation of its various derivatives as inhibitors against coronaviruses. The present study focused on curcumin derivatives with reliable ADME profile and high molecular binding potency to different SARS-CoV-2 target enzymes (3CLPro, PLpro, NSP7/8/12, NSP7/8/12 +RNA, NSP15, NSP16, Spike, Spike+ACE). In the molecular docking studies, the best binding scores for the 22 proposed curcumin derivatives were obtained for the PLpro protein. Furthermore, MD simulations were performed for high-affinity ligand-PLpro protein complexes and subsequently, Lys157, Glu161, Asp164, Arg166, Glu167, Met208, Pro247, Pro248, Tyr264, Tyr273 and Asp302 residues of PLpro was deter-mined to play key role for ligand binding by Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis. The results of the study promise that the proposed curcumin derivatives can be potent inhibitors against SARS-CoV-2 and be converted into pharmaceutical drugs. It is also expected that the findings may provide guiding insights to future design studies for synthesizing different antiviral derivatives of phytochemicals.Öğe Design, Synthesis, Characterization, Antiproliferative Activity, and In Silico Studies of Novel Alkyl Ether Derivatives Containing 1H-1,2,4-Triazole Ring(Wiley-V C H Verlag Gmbh, 2022) Yilmaz, Osman; Capanlar, Seval; Akkoc, Senem; Alici, Hakan; Ozcan, Ibrahim; Tahtaci, HakanIn this study, starting from 1H-1,2,4-triazole, a new series of aliphatic ether derivatives containing phenyl and 1H-1,2,4-triazole groups together were synthesized using reduction and Williamson ether synthesis mechanisms, respectively. The molecular structures of the synthesized compounds were characterized by fourier-transform infrared spectroscopy (FT-IR), H-1 and C-13 nuclear magnetic resonance (H-1 NMR and C-13 NMR), mass spectroscopy, and elemental analysis techniques. All synthesized compounds were screened against three different human cancer cell lines, including colon, lung, and liver cancer cells. Some of the compounds showed exceptionally high antiproliferative effects against all three cancer cell lines, with IC50 values much lower than the positive control drug bendamustine. In addition, molecular docking studies were performed to support the in vitro results and the interaction types and amino acids that play key roles in the binding of the compounds to enzymes were identified. Finally, the potential of these compounds to be drugs and their drug-likeness properties were evaluated by absorption, distribution, metabolism, and excretion-toxicity (ADMET) calculations and it was determined that the compounds could be drug candidates with the capacity to be effective and safe drugs for use in the treatment of different diseases.Öğe Novel Thioether-Bridged 2,6-Disubstituted and 2,5,6-Trisubstituted Imidazothiadiazole Analogues: Synthesis, Antiproliferative Activity, ADME, and Molecular Docking Studies(Wiley-V C H Verlag Gmbh, 2023) Ozcan, Ibrahim; Akkoc, Senem; Alici, Hakan; Capanlar, Seval; Sahin, Onur; Tahtaci, HakanIn this study, starting from 2-amino-1,3,4-thiadiazole derivatives (3-5), a new series of 2,6-disubstituted (compounds 7-15) and 2,5,6-trisubstituted (compounds 16-33) imidazo[2,1-b][1,3,4]-thiadiazole derivatives were synthesized using cyclization and Mannich reaction mechanisms, respectively. All synthesized compounds were characterized by H-1-NMR, C-13-NMR, FT-IR, elemental analysis, and mass spectroscopy techniques. Also, X-ray diffraction analysis were used for compounds 4, 7, 11, 17, and 19. The cytotoxic effects of the new compounds on the viability of colon cancer cells (DLD-1), lung cancer cells (A549), and liver cancer cells (HepG2) were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method in vitro. Compound 15 was found to be the most potent anticancer drug candidate in this series with an IC50 value of 3.63 mu M against HepG2 for 48 h. Moreover, the absorption, distribution, metabolism, and excretion (ADME) parameters of the synthesized compounds were calculated and thus, their potential to be safe drugs was evaluated. Finally, to support the biological activity experiments, molecular docking studies of these compounds were carried out on three different target cancer protein structures (PDB IDs: 5ETY, 1M17, and 3GCW), and the amino acids that play key roles in the binding of the compounds to these proteins were determined.Öğe Synthesis and characterization of schiff bases and their Ag(I) complexes containing 2,5,6-trisubstituted imidazothiadiazole derivatives: molecular docking and in vitro cytotoxic effects against nonsmall lung cancer cell line(John Wiley & Sons, 2025-01-20) Mirghani, Ahmed Hamdi; Pehlivanoglu, Suray; Alici, Hakan; Tahtaci, Hakan; Uysal, SabanIn this study, four novels 2,5,6-trisubstituted imidazothiadiazole derivative ligands and their Ag(I) complexes were synthesized and characterized using various spectroscopic analysis techniques. First, imidazo[2,1-b][1,3,4]thiadiazole derivative (3) was obtained from the reaction of 5-amino-1,3,4-thiadiazole-2-thiol with benzyl bromide in the presence of KOH in an ethanolic medium. In the next step, the resultant compound reacted sequentially with four substituted phenacyl bromide derivatives (4a–4d) under refluxed ethanol for 24 h to obtain substituted 2-(benzylthio)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole derivatives (5–8). Compounds (9–12) were obtained by attaching a carbonyl group to carbon number 5 of the imidazothiadiazole group in these compounds with the help of Vilsmeier–Haack reagent. The resultant compounds were reacted in an ethanolic medium to synthesize the novel (13–16) ligands by adding ethylenediamine in a 1:2 molar ratio. The Ag(I) complexes of the resultant ligands were synthesized by mixing silver acetate with the ligands in a dimethyl sulfoxide medium to obtain (17–20) complexes. All the synthesized compounds were analyzed using FTIR, 1H NMR, 13C NMR, mass spectroscopy, magnetic susceptibility, ICP-OES, and thermogravimetric analysis techniques. The study also investigates the in vitro cytotoxic effect of the ligands and complexes on A549 (nonsmall cell lung cancer) cells using the MTT assay and shows that the 13, 15, and 16 ligands, together with their complexes, exhibit potent cytotoxicity. In addition, in silico molecular docking simulations were conducted both to support the in vitro cytotoxicity experiments and to ascertain the active binding sites and interactions of the ligands and complexes on the EGFR receptor. The result indicates that ligands and complexes may serve as promising candidates for further investigation as anticancer agents.Öğe Synthesis, Characterization, Antimicrobial Evaluation, and Computational Investigation of Substituted Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives(Wiley-V C H Verlag Gmbh, 2020) Dagli, Meltem; Er, Mustafa; Karakurt, Tuncay; Onaran, Abdurrahman; Alici, Hakan; Tahtaci, HakanIn this study, a novel series of 2,6-disubstituted and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized starting from 2-amino-1,3,4-thiadiazole derivatives. Structures of the synthesized compounds were characterized using various analysis techniques. Then, in vitro biological activity tests were carried out for all synthesized compounds and they were found to show moderate to good activity against all bacteria and fungi tested. Next, molecular docking simulations were performed to observe the inhibition effect of the synthesized compounds on the 3R9C receptor and support their biological activity results. Finally, the pharmacokinetic, ADME and toxicity properties of all compounds were examined using FAF-Drugs and ProTox webservers and it was concluded that they had acceptable toxicity and ADME properties.Öğe Synthesis, Characterization, Theoretical Analyses, and Investigation of Their Biological Activities of Acetovanillone-Derived Novel Benzyl Ethers(Taylor & Francis Ltd, 2022) Calkilic, Nazire Merve; Alici, Hakan; Direkel, Sahin; Tahtaci, HakanIn this study, acetovanillone-derived novel benzyl ethers were synthesized as target compounds. For the synthesis of these target compounds, ketone derivatives (3a-b) were synthesized as the starting compounds. Compounds 4a-b, which are alcohol derivatives, were then synthesized from the reduction of these ketone derivatives. In the last stage of the synthesis study, benzyl ether derivatives (6a-h, 7a-h), the target compounds containing acetovanillone, were synthesized from the reaction of the alcohol derivatives (4a-b) with various benzyl halides (5a-h). The structures of the synthesized compounds were characterized by various spectroscopic methods (FT-IR, H-1 NMR, C-13 NMR, mass spectrometry, and elemental analysis). In vitro antileishmanial and antibacterial activity tests were then performed for all synthesized compounds. Biological activity tests showed that while only a few of the compounds had antileishmanial activity, most had antibacterial activity. In addition, the ADME parameters, pharmacokinetic properties, and drug-like nature of all compounds were theoretically investigated using the SwissADME webserver. Finally, molecular docking simulations were carried out to support in vitro investigations and evaluate the inhibition effect of the synthesized compounds on the 3IW2 (Mycobacterium tuberculosis (Mtb) Cyp125; Pdb ID: 3IW2) receptor structure. Also, possible binding sites of some compounds with high affinity to Mtb Cyp125 according to docking results were identified.Öğe Synthesis, in silico ADME, molecular docking and in vitro cytotoxicity evaluation of stilbene linked 1,2,3-triazoles(Elsevier Sci Ltd, 2021) Das, Arnika; Kumar, Sujeet; Persoons, Leentje; Daelemans, Dirk; Schols, Dominique; Alici, Hakan; Tahtaci, HakanSeries of (E)-1-benzyl-4-((4-styrylphenoxy)methyl)-1H-1,2,3-triazoles 7a-x were obtained by Wittig reaction between 4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehydes 5a-d and benzyl triphenyl phosphonium halides 6a-f in benzene. The structures of the synthesized compounds were confirmed by FTIR, NMR (H-1 and C-13 NMR)spectroscopy, and mass spectrometry. All synthesized compounds were screened for their cytotoxic activity against human cancer cell lines including pancreatic carcinoma, colorectal carcinoma, lung carcinoma, and leukemias such as acute lymphoblastic, chronic myeloid, and non-Hodgkinson lymphoma cell lines. In vitro cytotoxicity data showed that compounds 7c, 7e, 7h, 7j, 7k, 7r, and 7w were moderately cytotoxic (11.6 -19.3 mu M) against the selected cancer cell lines. These cytotoxicity findings were supported using molecular docking studies of the compounds against 1TUB receptor. The drug-likeness properties of the compounds evaluated by in silico ADME analyses. Resveratrol linked 1,2,3-triazoles were more sensitive towards human carcinoma cell lines but least sensitive towards leukemia and lymphoma cell lines.Öğe Synthesis, structural characterization, biological activity, and theoretical studies of some novel thioether-bridged 2,6-disubstituted imidazothiadiazole analogues(Wiley, 2021) Tunel, Hasan; Er, Mustafa; Alici, Hakan; Onaran, Abdurrahman; Karakurt, Tuncay; Tahtaci, HakanIn this study, thioether-bridged imidazo[2,1-b][1,3,4]thiadiazole derivatives that contained both imidazole and 1,3,4-thiadiazole (compounds 7a-7i and 8a-8i) were synthesized from the reactions of 2-amino-1,3,4-thiadiazole with phenacyl bromide (6a-6i) (at yields of 59% to 74%). The structure of the synthesized compounds was characterized using H-1 NMR, C-13 NMR, Fourier-transform infrared spectroscopy, elemental analysis, mass spectroscopy, and X-ray diffraction analysis. Mycelial growth, mycelial growth inhibition, minimum inhibitory concentration, minimum fungicidal concentration, and lethal dose values against various plant pathogenic fungi were determined for all of the target compounds synthesized in the study. The test results showed that most of the compounds had moderate to good antifungal activity. In addition, the absorption, distribution, metabolism, excretion (ADME) parameters of the compounds were calculated, and it was observed that all of the compounds met the drug-likeness rules in general. Finally, using docking simulations, it was found that compounds 7h, 7i, 8h, and 8i showed high affinity to PDB ID:5TZ1, which is an CYP51 antifungal target structure.
