Sahin, Dicle; Kepekci, Remziye Aysun; Türkmenoğlu, Burçin; Akkoc, Senem

Three new thymol-based molecules were synthesized and evaluated as anticancer, antimicrobial and antioxidant agents. Liver, colon, lung and prostate cancer cell lines were utilized in cytotoxicity tests. The results demonstrated that synthesized molecules had a cytotoxic effect against the screened cell lines. One of the molecules (4a) was found to have a higher efficacy towards the colon cancer cell line (DLD-1) with an IC50 value of 12.39 µM and the other (4c) towards the prostate cancer cell line (PC3) with an IC50 value of 7.67 µM than the positive control drug cisplatin. To assess the antimicrobial activity of molecules (4a–c), Gram-positive bacteria, Gram-negative bacteria and yeast were subjected to agar disc diffusion and broth microdilution assays. The investigation of antioxidant potential was conducted using the DPPH radical scavenging activity assay. While all compounds displayed strong cytotoxic and antioxidant properties, they exhibited only moderate antimicrobial activity. Molecular docking studies were performed on epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR-2), focal adhesion kinase (FAK), B-Raf and phosphoinositide 3-kinase (PI3K). The binding energies and interactions obtained from the docking results of compounds (4a–c) supported the experimental results. Drug similarity rates and pharmacokinetic properties were analyzed with the absorption, distribution, metabolism and excretion (ADME) method. Geometric parameters such as chemical potential (µ), electrophilicity index (ω) and chemical softness (σ) of compounds (4a–c) were calculated using the 6-31*G basis set B3LYP method.

Başaran, Eyüp; Çakmak, Reşit; Sahin, Dicle; Köprü, Semiha; Türkmenoğlu, Burçin; Akkoc, Senem

Cancer is a global public health problem affecting millions of people every year. New anticancer drug candidates are needed to overcome the resistance to drugs used in the treatment of various types of cancer. In this study, two new series of benzenesulfonate-based thymol derivatives (14–19 and 20–25) were synthesized for the first time as promising chemotherapeutic agents and characterized using FT-IR, 1D NMR (1H- and 13C-NMR, APT, DEPT 135), 2D NMR (HETCOR and HMBC), and elemental analysis (CHNS). Antiproliferative activity of the molecules was determined against cancer cell lines, namely, the human lung adenocarcinoma cell line (A549) and the colorectal adenocarcinoma cell line (DLD-1), using MTT method for both 48 and 72 h. Compounds (14–25) showed cytotoxic activities against A549 with IC50 values ranging from 9.98 to 81.83 μM, respectively, compared to cisplatin (6.65 μM). These compounds exhibited antiproliferative activities against DLD-1 cancer cells at concentrations ranging from 4.29 to 53.62 μM, respectively, compared to cisplatin (9.91 μM). Especially, compound 16 displayed significant cytotoxicity on A549 and DLD-1 cancer cells with IC50 values of 9.98 and 10.75 μM, respectively. Finally, molecular docking studies were performed with Bcl-2, VEGFR-2, EGFR, and HER2 targets using the Schrödinger 2021-2 Maestro Glide program. The binding energy values and binding interactions of compounds 16 and 22 were determined to be the result of their interactions with these targets. Schrödinger 2021-2 Qikprop wizard drug similarity ratios and ADME prediction of all compounds 14–25 were also calculated.

Somturk-Yilmaz, Burcu; Altiparmak, Ayşegül; Turkmenoglu, Burçin; Akkoc, Senem

In this study, organic–inorganic hybrid nanoflower (hNFs) synthesis was realized using 3,4-diaminobenzophenone and Cu(II) metal ions as organic and inorganic ingredients, respectively. The characterization of the synthesized hNFs was carried out using SEM, EDX, FT-IR, XRD, and elemental mapping. The cytotoxic effect of hNFs was investigated against A549 (lung) and MCF-7 (breast) cancer cell lines. Interactions of 3,4-diaminobenzophenone were also investigated via molecular docking studies at the binding site of the human estrogen receptor (PDB ID:3ERT) and epidermal growth factor receptor tyrosine kinase (PDB ID: 1M17). Physicochemical and pharmacokinetic parameters for ligands that could be potential anticancer drug candidates were determined by ADME prediction calculations from in silico approaches. In vitro results showed an increase in cell death when the synthesized hybrid nanoflowers were applied against both cell lines, depending on the concentrations tested. Additionally, it was determined that the synthesized nanoflower was more effective on the MCF-7 cell line.

Dadou, Said; Altay, Ahmet; Baydere, Cemile; Anouar, El Hassane; Türkmenoğlu, Burçin; Koudad, Mohammed; Dege, Necmi; Oussaid, Abdelouahad; Benchat, Noureddine; Karrouchi, Khalid

In this work, two novel chalcone-based imidazothiazole derivatives ITC-1 and ITC-2 were synthesized and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry with electrospray ionization, and chemical structure of ITC-1 was confirmed by single-crystal X-ray diffraction. Also, the anticancer activity of ITC-1 and ITC-2 was evaluated. First, antiproliferative activity tests were performed against cancer cells namely, human-derived breast adenocarcinoma (MCF-7), lung carcinoma (A-549), and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast healthy cell line (3T3-L1) by XTT assay. Afterward, mitochondrial membrane disruption (MMP), caspase activity, and apoptosis tests were performed on MCF-7 cells to elucidate the anticancer mechanism of action of the test compounds by flow cytometry analysis. XTT results revealed that both compounds exhibited a very high degree of antiproliferative effects on each tested cancer cell line with very low IC50 values while showing much lower antiproliferation on 3T3-L1 normal cells with much higher IC50 values. Besides, ITC-2 was determined to have a striking cytotoxic power competing with the chemotherapeutic drug carboplatin. Flow cytometry results demonstrated the mitochondrial-mediated apoptotic effects of both compounds through membrane disruption and multi-caspase activation in MCF-7 cells. Finally, molecular docking studies were performed to determine the structural understanding of the test compounds by their interactions on caspase-3 and DNA dodecamer enzymes, respectively. The interactions between the compound and the crystal structure were determined according to parameters such as free binding energies (ΔGBind), Glide score values, and determination of the active binding site. The obtained data suggest that ITC-1 and ITC-2 may be considered remarkable anticancer drug candidates. In addition to molecular docking via in silico approaches, the pharmacokinetic properties of compounds ITC-1 and ITC-2 were calculated using the Schrödinger 2021-2 Qikprop wizard. Communicated by Ramaswamy H. Sarma.

Dawbaa, Sam; Türkeş, Cüneyt; Nuha, Demokrat; Demir, Yeliz; Evren, Asaf Evrim; Yurttaş, Leyla; Beydemir, Şükrü

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure–activity relationship.

Akman, Ebru; Sirinzade, Hanif; Ozguven, Serap Yilmaz; Dilek, Esra; Suzen, Sibel

In this study, the in vitro effects of some indole Schiff bases on acetylcholinesterase and human carbonic anhydrase isoforms I and II were investigated. A series of N-methylindole hydrazide/hydrazone derivatives (1a-1t) were tested on these enzymes. The interactions of the synthesized indole derivatives with target enzymes were studied by molecular docking methodology. The results revealed that indole derivative Schiff base compounds inhibited the enzymes significantly. Ki values for hCAI isoenzyme were determined to be in the range of 36.18 ± 3.07–224.29 ± 5.78 nM; for the hCAII isoenzyme in the range of 31.30 ± 2.63–201.64 ± 7.25 nM; for acetylcholinesterase in the range of 6.82 ± 0.72–110.30 ± 9.26 nM. Compared to the control compound Acetazolamide (AZA), 1k and 1p were found to have the best inhibitory effect for hCAI; 1p was found to be the best inhibitory effect for hCAII. Compared to the control compound Tacrine (TAC), 1s showed the best inhibitory effect for AChE. In vitro results were verified with the results obtained by docking studies and interactions with enzymes were demonstrated. Communicated by Ramaswamy H. Sarma.

Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; Beydemir, Şükrü

In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a–l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with K Is in the low nanomolar range (66.60–278.40 nM) than the reference drug acetazolamide (AAZ), which had a K I of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d–g and 5l, with K Is of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, K I of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had K Is ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a K I of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski’s and Jorgensen’s rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents. Communicated by Ramaswamy H. Sarma.

Güngör, Seyit Ali; Köse, Muhammet; Tümer, Mehmet; Türkeş, Cüneyt; Beydemir, Şükrü

Carbonic Anhydrases (CAs) are an important family of metalloenzymes that contain zinc (Zn2+) ions in their active site and catalyze the conversion of carbon dioxide to bicarbonate and proton and found in all living organisms. Sulfonamides are well-known inhibitors of CAs isoenzymes. In this study, a series of benzenesulfonamide derivatives (9a–h) containing 1,2,3-triazole-moiety were designed, synthesized and their structures were characterized by spectroscopic methods. In addition, molecular structures of compounds 5a, 5 b, 9e and 9f were elucidated by X-ray diffraction technique. To investigate drug similarity of 9a–h compounds, Lipinski’s five rules (ADMET: absorption, distribution, metabolism, excretion and toxicity) were carried out by in silico studies. According to results, the compounds showed drug-like properties. Docking studies were applied to determine the scores, interactions and binding modes of compounds 9a–h against hCA I and hCA II enzymes. Compound 9c (-5.13 kcal/mol docking score) against hCA I enzyme and 9 h (-5.32 kcal/mol docking score) against hCA II enzyme showed potent inhibitory properties. The binding interactions of the compounds with the carbonic anhydrases were examined by docking studies. Communicated by Ramaswamy H. Sarma.

Türkeş, Cüneyt; Demir, Yeliz; Beydemir, Şükrü

Many drugs, which are used in clinical treatments, show pharmacological effects on enzyme activity with an essential role in the pathogenesis of various diseases. Paraoxonase-I (PON1) is a member of the mammalian lactonase enzyme family, serves to the prevention of blood vessel plaque formation by protecting high-density lipoprotein and low-density lipoprotein against oxidation. In the current study, we aimed to contribute to drug discovery and to determine the interaction of some calcium channel blockers (CCBs) with PON1. For this purpose, first, the PON1 enzyme was purified from fresh human serum by using different chromatographic techniques. Then, the various concentrations of CCBs were tested on the paraoxonase activity of PON1. IC 50 values were found as 41.00, 48.00, and 180 µM for nimodipine, cinnarizine, and nilvadipine, respectively. PON1 was effectively inhibited by these drugs (K is ranging between 22.13 ± 1.13 and 174.12 ± 20.52 µM). Of these drugs, only the inhibition mechanism of cinnarizine was competitive on PON1. Besides, the molecular docking analysis of cinnarizine was applied to detailed the binding interactions on the active site of PON1. The docking scores for the Glide standard-precision (SP), and Glide extra-precision (XP) modes for 1V04 receptor monitored to be −5.001, and −6.079, respectively. We determined that the CCBs reduced PON1 enzyme activity both in vitro and in silico conditions, significantly. Therefore, further biological studies such as gene expression and in vivo experiments should be done for these drugs. Communicated by Ramaswamy H. Sarma.

Demir, Yeliz; Ceylan, Hamid; Türkeş, Cüneyt; Beydemir, Şükrü

Aldose reductase (AR) and sorbitol dehydrogenase (SDH) are important enzymes of the polyol pathway. In the current study, inhibitory effects of vulpinic acid (VA) carnosic acid (CA) and usnic acid (UA) on purified AR and SDH enzymes were determined. These enzymes inhibition could be essential to prevent diabetic complications. AR and SDH enzymes were purified from sheep kidney. Then, VA, CA and UA were tested in various concentrations against these enzymes activity in vitro. K I values were found to be as 1.46 ± 0.04, 5.13 ± 0.25 and 11.71 ± 0.27 μΜ for VA, CA and UA, respectively, for AR. K I constants were found to be as 15.32 ± 0.34, 145.60 ± 2.17 and 213.40 ± 2.64 μΜ VA, CA and UA, respectively, for SDH. These findings indicate that VA, CA and UA could be useful in the treatment of diabetic complications. Communicated by Ramaswamy H. Sarma.