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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, Kadir
The 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.
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, Hakan
In 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.
Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors
(Academic Press Inc Elsevier Science, 2021) Askin, Sercan; Tahtaci, Hakan; Turkes, Cuneyt; Demir, Yeliz; Ece, Abdulilah; Ciftci, Gulsen Akalsn; Beydemir, Sukru
Imidazole and thiadiazole derivatives display an extensive application in pharmaceutical chemistry, and they have been investigated as bioactive molecules for medicinal chemistry purposes. Classical carbonic anhydrase (CA) inhibitors are based on sulfonamide groups, but inhibiting all CA isoforms nonspecifically, thereby causing undesired side effects, is the main drawback of these types of inhibitors. Here we reported an investigation of novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (9a-k, 10a, and 11a) and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (12a-20a) that do not possess the zinc-binding sulfonamide group for the inhibition of human carbonic anhydrase (hCA, EC 4.2.1.1) I and II isoforms and also of acetylcholinesterase (AChE, EC 3.1.1.7). Imidazo[2,1-b][1,3,4]thiadiazoles demonstrated low nanomolar inhibitory activity against hCA I, hCA II, and AChE (KIs are in the range of 23.44-105.50 nM, 10.32-104.70 nM, and 20.52-54.06 nM, respectively). Besides, compound 9b inhibit hCA I up to 18-fold compared to acetazolamide, while compound 10a has a 5-fold selectivity towards hCA II. The synthesized compounds were also evaluated for their cytotoxic effects on the L929 mouse fibroblast cell line. Molecular docking simulations were performed to elucidate these inhibitors' potential binding modes against hCA I and II isoforms and AChE. The novel compounds reported here can represent interesting lead compounds, and the results presented here might provide further structural guidance to discover and design more potent hCA and AChE inhibitors.
Design, Synthesis, SAR and Molecular Modeling Studies of Novel Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Highly Potent Antimicrobial Agents
(Wiley-V C H Verlag Gmbh, 2018) Tahtaci, Hakan; Karacik, Hatice; Ece, Abdulilah; Er, Mustafa; Seker, Mine Gul
In this study, a novel series of phenyl substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized, characterized and explored for antibacterial activity against Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus and Bacillus subtilis and antifungal activity against Candida albicans. Most of the synthesized compounds exhibited remarkable antimicrobial activities, some of which being ten times more potent than positive controls. The most promising compound showed excellent activity with MIC value of 0.03g/ml against both S. aureus and B. subtilis (MIC values of positive compound Chloramphenicol are 0.4g/ml and 0.85g/ml, respectively). Furthermore, structure-activity relationship was also investigated with the help of computational tools. Some physicochemical and ADME properties of the compounds were calculated too. The combination of electronic structure calculations performed at PM6 level and molecular docking simulations using Glide extra-precision mode showed that the hydrophobic nature of keto aryl ring with no electron withdrawing substituents at para position enhances activity while electron-donating substituents at the second aryl ring is detrimental to activity.
Imidazole-Derived Alkyl and Aryl Ethers: Synthesis, Characterization, In Vitro Anticancer and Antioxidant Activities, Carbonic Anhydrase I-II Inhibition Properties, and In Silico Studies
(Amer Chemical Soc, 2024) Faris, Mays; Bostanci, Hayrani Eren; Ozcan, Ibrahim; Ozturk, Mustafa; Kocyigit, Umit Muhammed; Erdogan, Taner; Tahtaci, Hakan
Imidazole derivatives display extensive applications in pharmaceutical chemistry and have been investigated as bioactive compounds for medicinal chemistry. In this study, besides the starting materials (3a-c and 4a-c), synthesis, characterization, and biological activity studies were conducted on a total of 18 compounds, nine of which are known and the other nine are original. The compounds investigated in the study are a series of alkyl (7-15) and aryl (16-24) ether derivatives bearing substituted phenyl and imidazole rings, which were characterized using various methods including H-1 NMR, C-13 NMR, FT-IR analysis, elemental analysis, and mass spectroscopy. Computer-aided drug design studies have been carried out to predict the biological activities of compounds. Besides DFT calculations, the binding affinities of the compounds to EGFR, VEGFR2, FGFR1, HSP90, hCA I, and hCA II were investigated. Additionally, drug-likeness and ADME analyses were performed on the compounds. Anticancer, antioxidant, and enzyme inhibition activity tests were performed in biological activity studies on the synthesized compounds. Among the synthesized compounds, compounds 17 and 19-24 generally exhibited inhibition profiles against the widespread cytosolic hCA I isozyme with IC50 values ranging from 4.13 to 15.67 nM and cytosolic hCA II isozyme with IC50 values ranging from 5.65 to 14.84 nM. L929 (mouse fibroblast cell line) was used as the control healthy cell line, and MCF7 (breast cancer), C6 (rat glioblastoma), and HT-29 (colon cancer) cells were used in cell culture studies as cancer cell lines. Before the study on cancer cells, all compounds were examined on healthy cells, and their cytotoxicity was determined. As a result of these data, studies continued with six compounds determined to be nontoxic. On cancerous cells, it was determined that compounds 3a, 3b, 4a, 4b, 4c, and 7 had cytotoxic effects on both colon cancer and brain tumors. It was found that compound 3b had a more toxic effect than cisplatin on the glioma cell line with an IC50 value of 10.721 +/- 0.38 mu M, and compound 3a had a more toxic effect on the colon cancer cell line with an IC50 value of 20.88 +/- 1.02 mu M. However, it was determined that the same compounds did not have a statistically significant effect on breast cancer. Flow cytometry studies also showed that when the IC50 dose of compound 3b was applied to the C6 cell line, the cells tended to early and late apoptosis. Additionally, it has been shown by flow cytometry that the cell cycle stops in the G0/G1 phase. A similar effect was observed in the colon cancer cell line with compound 3a. Compound 3b caused early and late apoptosis of the colon cancer cell line with the applied IC50 dose and stopped the cell cycle in the G0/G1 phase. Finally, the FRAP method studied all synthesized compounds' antioxidant effects. According to the measured antioxidant power results, it was determined that no compound had a more effective reducing power than vitamin E.
An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study
(Springeropen, 2018) Er, Mustafa; Abounakhla, Abdulati Miftah; Tahtaci, Hakan; Bawah, Ali Hasin; Cinaroglu, Suleyman Selim; Onaran, Abdurrahman; Ece, Abdulilah
BackgroundThis study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to find out a potential target and enlighten the inhibition mechanism.ResultsAs a first step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a-n and 7a-n) were then synthesised with moderate to high yields (56-87%) by reacting 3 and 4 with various acyl chloride derivatives (5a-n). The synthesized compounds were characterized using the IR, H-1-NMR, C-13-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro antifungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values (LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods. As an initial step, similarity search was carried out and the resulting proteins that belong to Homo sapiens were used as reference in sequence similarity search to find the corresponding amino acid sequences in target organisms. Homology modelling was used to construct the protein structure. The stabilised protein structure obtained from molecular dynamics simulation was used in molecular docking.ConclusionThe overall results presented here might be a good starting point for the identification of novel and more active compounds as antifungal agents.
Novel 2-amino-1,3,4-thiadiazoles and their acyl derivatives: Synthesis, structural characterization, molecular docking studies and comparison of experimental and computational results
(Elsevier Science Bv, 2016) Er, Mustafa; Isildak, Gamze; Tahtaci, Hakan; Karakurt, Tuncay
This study aims to synthesize and characterize compounds containing 2-amino-1,3,4-thiadiazole and compare experimental results to theoretical results. For this purpose, firstly mono, di and tetra 2-amino-1,3,4-thiadiazole compounds (2a-c, 14, 20 and 25) were synthesized in relatively high yields (74-87%). The target compounds (3-11, 15-17, 21-23 and 26-28) were then synthesized in moderate to high yields (65-85%) from the reactions of 2-amino-1,3,4-thiadiazole compounds with various acyl chloride derivatives. The structures of all synthesized compounds were elucidated by IR, H-1 NMR, C-13 NMR, elemental analyses and mass spectroscopy techniques. The structures of 2b (C9H8N4O2S) and 2c (C11H13N3O2S) were also elucidated by X-ray diffraction analysis. Lastly, IR spectrum, H-1 NMR and C-13 NMR chemical shift values, frontier molecular orbital (FMO) values of these molecules containing heteroatoms were examined using the Becke-3- Lee-Yang-Parr (B3LYP) method with the 6-31G(d) basis set. Two different molecular structures containing 2-amino-1,3,4-thiadiazole (2b, 2c) were used in our study to examine these properties. Also, compounds 2b and 2c form a stable complex with beta-Lactamase as can be understood from the binding affinity values and the results show that the compound might inhibit the beta-Lactamase enzyme. It was found that theoretical and experimental results obtained in the experiment were compatible with each other and with the values found in the literature. (C) 2016 Elsevier B.V. All rights reserved.
Novel aldehyde and thiosemicarbazone derivatives: Synthesis, spectroscopic characterization, structural studies and molecular docking studies
(Elsevier, 2016) Karakurt, Tuncay; Tahtaci, Hakan; Subasi, Nuriye Tuna; Er, Mustafa; Agar, Erbil
In this study our purpose is that, synthesis and characterization of compounds containing the aldehyde and thiosemicarbazone groups and comparison of the theoretical results with the experimental results. The structures of all synthesized compounds were elucidated by IR, H-1 NMR, C-13 NMR, elemental analyses techniques. The structure of compound (4) (C9H8N4O2S) was also elucidated by X-ray diffraction analysis. In addition, the theoretical IR spectrum, H-1 NMR and C-13 NMR chemical shift values, frontier molecular orbital values (FMO) of these molecules were analyzed by using Becke-3- Lee-Yang-Parr (B3LYP) method with LanL2DZ basis set. Finally, molecular docking studies were performed on synthesized compounds using the 4DKI beta-lactam protein structure to determine the potential binding mode of inhibitors. (C) 2016 Elsevier B.V. All rights reserved.
A Novel Class Substituted Imidazo[2,1-b][1,3,4]thiadiazole Derivatives: Synthesis, Characterization, In Vitro Biological Activity, and Potential Inhibitors Design Studies
(Wiley-V C H Verlag Gmbh, 2019) Er, Mustafa; Ahmadov, Farid; Karakurt, Tuncay; Direkel, Sahin; Tahtaci, Hakan
In this study, imidazo[2,1-b][1,3,4]thiadiazole derivatives were designed and synthesized. All of the synthesized compounds were characterized by H-1 and C-13 nuclear magnetic resonance (H-1 NMR and C-13 NMR), fourier-transform infrared spectroscopy (FT-IR), elemental analysis, mass spectrometry, and X-ray diffraction. The synthesized compounds were tested for antileishmanial activity against two Leishmania species and antibacterial activity against nine bacterial species in the study. It was observed that 2-(4-Fluorobenzylthio)-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazole (5) had the highest antileishmanial activity (MIC: 625 mu g/mL). Also, 4-(2-(4-fluorobenzylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzonitrile (10), 2-(4-fluorobenzylthio)-6-(4-phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazole (11), and 4-(2-(4-methoxybenzyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzonitrile (25) were found to be effective at different studied concentrations. PyRx software, which uses a Lamarckian genetics algorithm, was utilized to find the affinity values of all compounds in molecular docking simulations. Pharmacokinetic properties and toxicities of the ligands were then researched using PROTOX (a webserver for the prediction of oral toxicities of small molecules) and FAF-Drugs (free adsorption distribution, metabolism, excretion (ADME) tox filtering tool). The study showed that the ligands had acceptable toxicity and ADME properties for the inhibition of the 3JUS receptor.
Novel olefinic-centered macroacyclic compounds involving tetrasubstituted 4-hydroxybenzoic acid fragments: Synthesis, structural characterization and comparison of experimental and computational results
(Pergamon-Elsevier Science Ltd, 2015) Er, Mustafa; Degirmencioglu, Ismail; Tahtaci, Hakan
Dialkyl 4,4'-(2-(1,3-bis(4-(alkoxycarbonyl)phenoxy)propan-2-ylidene)propane-1,3-diyl)bis (oxy)dibenzoate 6a,b were synthesized through the reaction of ethene-1,1,2,2,-tetra-yl-tetra methylene tetra bromide 1 with methyl 4-hydroxy benzoate or ethyl 4-hydroxy benzoate 2a,b. In addition, compounds 6a,b were obtained by using the esterification reaction from the reaction compound 5 with methyl and ethyl alcohol in high yields. Compound 4 was synthesized from the reaction of ethene-1,1,2,2,-tetra-yl-tetra methylene tetra bromide 1 with 4-hydroxy benzonitrile 3. The structures of the novel synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, COSY, elemental analysis, and mass spectral data. Compound 6b, C42H44O12, was also characterized with additional analysis such as UV-vis, and X-ray spectral techniques. The electronic structure of compound 6b was studied by DFT level 6-31G*(d,p) using X-ray crystallographic data. The results obtained from this study are consistent with the X-ray data. In order to understand the electronic transitions of the compound 6b, time dependent density functional theory (TD-DFT) calculations were carried out. TD-DFT studies showed that the low-energy excitations are consistent with the experimental results. (C) 2014 Elsevier B.V. All rights reserved.
Novel substituted benzothiazole and Imidazo[2,1b][1,3,4]Thiadiazole derivatives: Synthesis, characterization, molecular docking study, and investigation of their in vitro antileishmanial and antibacterial activities
(Elsevier, 2019) Er, Mustafa; Ozer, Arif; Direkel, Sahin; Karakurt, Tuncay; Tahtaci, Hakan
In this study, we synthesized new imidazo[2,1-b][1,3,4]thiadiazole derivatives containing benzothiazole group. To this end, we firstly obtained the benzo[d]thiazol-2-ylthio/oxy acetonitrile compounds (3a,b), the starting materials, in high yields (82% and 87%, respectively). Then, we synthesized the 2-amino-1,3,4-thiadiazole derivatives (4a,b) from the reaction of these nitrile derivatives (3a,b) with thio-semicarbazide in trifluoroacetic acid (TFA) (in yields of 83% and 84%). Finally, we synthesized the imidazo [2,1-b][1,3,4]thiadiazole derivatives (5-24) containing benzothiazole group, which are the target compounds, from reactions of 2-amino-1,3,4-thiadiazole derivatives (4a,b) with phenacyl bromide derivatives (in yields of 53%-73%). All of the compounds synthesized were characterized with H-1 NMR, C-13 NMR, FT-IR, elemental analysis, and mass spectroscopy. Antileishmanial and antibacterial activity tests were applied to the compounds synthesized in the study. It was observed that compound 8 had the highest antileishmanial activity (MIC = 10 000 mu g/mL). Also, compounds 7 and 17 were found to be effective at the highest concentration studied (MIC = 20 000 mu g/mL). In terms of antibacterial activity, compounds 4b and 7 were found to be the most effective compounds against Escherichia coli (MIC = 625 mu g/mL). Theoretical calculations were performed to support the experimental results. To this end, we performed Molecular Docking studies to determine whether or not the compounds (4a, 4b, 7 and 13) optimized with Gaussian09 using the DET/B3LYP/6-31G(d,p) theory, which is a quantum chemical calculation, could be an inhibitor agent for the 2eg7 Escherichia coli protein structure. Also, we investigated the relationship between the calculated HOMO values of these four ligands and docking studies. (C) 2019 Elsevier B.V. All rights reserved.
Novel Substituted Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Molecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
(Wiley, 2019) Er, Mustafa; Tahtaci, Hakan; Karakurt, Tuncay; Onaran, Abdurrahman
In this study, a new series of substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized. To this end, first 2-amino-1,3,4-thiadiazole derivatives (compounds 2a and 2b), the starting materials, were synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1-b][1,3,4]thiadiazole derivatives (4-16), the target compounds, were synthesized from reactions of 2-amino-1,3,4-thiadiazole derivatives (2a and 2b) with 2-bromoacetophenone derivatives (3a-3i) (in yields of 52% to 71%). All of the synthesized compounds were characterized by H-1 NMR, C-13 NMR, Fourier transform infrared, elemental analysis, mass spectroscopy, and X-ray diffraction analysis (compounds 4-12, 14, and 15) techniques. In vitro antifungal activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibition, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target compounds were determined against some plant pathogens. According to the results of the biological activity tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical calculations were performed to support the experimental results. The geometric parameters of selected compounds (5, 6, and 8) were optimized using the density functional theory B3LYP/6-31G(d) method in the Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital-lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were performed for antifungal activity studies of the selected compounds and to determine whether or not these compounds could be inhibitor agents for the 2RKV protein structure.
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, Hakan
In 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.
A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction
(Taylor & Francis Inc, 2019) Tahtaci, Hakan; Aydin, Gozde
In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S(N)2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH4. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature. [GRAPHICS] .
Structure of (2E)-Ethyl 2-((4-(cyanomethoxy)benzylidene)hydrazono)-3,4-dimethyl-2,3-dihydrothiazole-5-carboxylate Studied by X-ray and DFT Calculations
(Pleiades Publishing Inc, 2017) Ustabas, Resat; Er, Mustafa; Tahtaci, Hakan; Coruh, Ufuk
The molecular structure of (2E)-ethyl 2-((4-(cyanomethoxy)benzylidene)hydrazono)-3,4-dimethyl-2,3-dihydrothiazole-5-carboxylate was determined using X-ray diffraction. The crystals are triclinic: sp. gr. P (1) over bar; Z = 2; the unit cell parameters a = 8.4747(7)angstrom, b = 8.9382(8)angstrom , c = 11.9913(10)angstrom . The title compound has two C-H center dot center dot center dot O type intramolecular hydrogen bonds, one C-H center dot center dot center dot O and one C-H center dot center dot center dot N type intermolecular hydrogen bonds. For theoretical calculations, the molecular structure was investigated by DFT/B3LYP method with 6-311G(d) and 6-311G(d, p) basis sets. The calculated and experumental results (bond lenghts, bond angles, and dihedral angles) were compared with each other. Total energy, dipole moment, and mulliken atomic charges were calculated using two different basis sets.
SYNTHESIS AND CHARACTERIZATION OF NOVEL 1,3-THIAZOLE AND 2-AMINO-1,3,4-THIADIAZOLE DERIVATIVES
(Soc Chemists Technologists Madeconia, 2014) Er, Mustafa; Sahin, Ayse; Tahtaci, Hakan
Thiosemicarbazone derivatives 3a-e were synthesized by the reaction of various aldehydes 1a-e with 4-methyl thiosemicarbazide 2 in 78% to 90% yield. Then, the thiazole moieties of the target materials 5a-e were obtained in high yields (71-93%) using the Hantzsch reaction utilizing thiosemicarbazone derivatives 3a-e with ethyl-2-chloroacetoacetic ester. The substituted nitrile derivatives 7a-e were obtained in moderate to high yield (58-84%) from the reaction of compounds 5a-e with chloroacetonitrile by the nucleophilic aliphatic substitution reaction in the presence of anhydrous potassium carbonate. Finally, substituted 2-amino-1,3,4-thiadiazole compounds 9a-e were obtained in moderate to good yields (51-62%) from the reaction of thiosemicarbazide with substituted nitrile derivatives 7a-e. As a result, compounds that all share a high disposition for biological activities were obtained. The structures of the newly synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, elemental analysis, and mass spectrometric techniques.
Synthesis and Characterization of Oxime Derivatives and their Some Transition Metal Complexes with Thiadiazole Groups: Biological Activities, and Molecular Docking Studies of the Ligands
(Wiley-V C H Verlag Gmbh, 2024) Otaiwi, Ahmed Saleem; Mirghani, Ahmed Hamdi; Bostanci, Hayrani Eren; Coskun, Ahmet; Tahtaci, Hakan; Uysal, Saban
This study involved the synthesis and investigation of the anticancer and antioxidant capabilities of six newly developed ligands generated from 1,3,4-thiadiazole and diphenyl ether keto oxime which has never been synthesized before, together with their transition metal complexes. The obtained ligands were characterized using elemental analysis, FTIR, 1H NMR, 13C NMR, and mass spectroscopy. Polymeric complexes of the obtained ligands were synthesized by reacting all ligands with MCl2.nH2O (M: Mn2+/Co2+)/Ni2+/Cu2+)) salts. The polymeric complexes ' structures were determined using elemental analysis, ICP-AES, FTIR spectroscopy, UV-vis spectroscopy, magnetic susceptibility analysis, and thermogravimetric analysis. Subsequently, the ligands were examined for their anticancer properties. To achieve this objective, the HT-22 cell line, which consists of healthy mouse hippocampus neuronal cells, is utilized as the control group. Additionally, the MCF7 (breast cancer), MDA-MB-231 (breast cancer), C6 (rat glioma), HT-29 (colon cancer), and A549 (lung carcinoma) cell lines are employed in cell culture research as representatives of cancerous cell lines. Based on the cell culture investigations, some of the synthesized ligands showed moderate to good anti-cancer activity, especially for both colon cancer and brain tumors. Finally, a molecular docking analysis was conducted utilizing MOE software to ascertain the binding affinity between the synthesized ligands and the specific proteins of interest. This study includes the synthesis of transition metal complexes of six new ligands obtained from 1,3,4-thiadiazole and diphenyl ether keto oxime and the investigation of the anticancer and antioxidant properties of the ligands. Finally, a molecular docking analysis was performed to determine the binding affinity between the synthesized ligands and specific proteins of interest. image
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, Saban
In 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.
Synthesis and characterization of tetra-armed-thiosemicarbazone and its salen/salophen capped transition metal complexes: Investigation of their thermal and magnetic properties
(Taylor & Francis Inc, 2016) Uysal, Saban; Er, Mustafa; Tahtaci, Hakan
In this work, we aimed to synthesize and characterize a novel tetra-directional ligand, (2E,2E)-2,2-((((2-(1,3-bis(4-((E)-(2-carbamothioylhydrazono)methyl)phenoxy)propan-2-ylidene)propane-1,3-diyl)bis(oxy))bis(4,1-phenylene))bis(methanylylidene))bis(hydrazinecarbothioamide) (5), including thiosemicarbazone group and its novel tetra-directional-tetra-nuclear Schiff base complexes. For this purpose, we used 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene (2) as starting material. 4,4-((2-(1,3-Bis(4-formylphenoxy)propan-2-ylidene)propane-1,3-diyl) bis(oxy))dibenzaldehyde (3) was synthesized by the reaction of an equivalent 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene (2) and 4 equivalents of 4-hydroxybenzaldehyde. Then, compound 5 was synthesized in high yield (86%) by a condensation reaction of compound 3 with thiosemicarbazide (4). Finally, four novel tetra-nuclear Cr(III) or Fe(III) complexes of compound 5 were synthesized. The synthesized compounds were characterized using elemental analyses, H-1 NMR, Fourier transform-infrared spectrometry, liquid chromatography-mass spectrometry (ESI+), and thermal analyses. The metal ratios of the prepared complexes were determined using an atomic absorption spectrophotometer. We also investigated their effects on the magnetic behaviors of [salen, salophen, Cr(III)/Fe(III)] capped complexes. The complexes were found to be low-spin distorted octahedral Fe(III) and distorted octahedral Cr(III), all bridged by thiosemicarbazone. [GRAPHICS]
Synthesis and characterization of the Co(II) and Ni(II) complexes of 1,3,4-thiadiazole-derived ketones and secondary alcohols: thermal and magnetic properties
(Taylor & Francis Ltd, 2021) Erdogan, Melih; Kiymaz, Kubra; Tahtaci, Hakan; Uysal, Saban
Compounds containing both ketone and amide carbonyl groups were reduced with sodium borohydride (NaBH4). In this way, secondary alcohols, which are very important compounds for the synthesis of drugs, agricultural chemicals, food chemicals, and other chemicals, were obtained with regioselectivity. To do this, the starting compound 2-(5-amino-1,3,4-thiadiazol-2-yl)thio)-1-(3,4-dichlorophenyl)ethanone (3) was obtained. Subsequently, 10 ketone derivatives (5a-j) were synthesized from the reaction of 3 with the appropriate substituted acyl halide derivatives (4a-j). Then, secondary alcohol derivatives (6a-j), which came from the regioselective reduction of the ketone derivatives (5a-j), were synthesized with NaBH4. The molecular structures of ketone and alcohol derivatives were elucidated using H-1 NMR, C-13 NMR, FTIR, and MS. In the last step of the study, binuclear metal complexes of all alcohol and ketone derivatives were synthesized in DMF and characterized using FTIR and MS. The magnetic properties and thermal stability of these complexes were investigated using magnetic susceptibilities and determined using a Gouy magnetic susceptibility apparatus and a TGA analyzer, respectively. The complexes are distorted octahedral low-spin (S = 3/2) Co(II) and distorted octahedral (S = 1) Ni(II). Finally, the metal ratios of the complexes were determined by using ICP-AES.

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