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    In-silico pharmacokinetic and affinity studies of piperazine/morpholine substituted quinolines in complex with GAK as promising anti-HCV agent
    (WORLD SCIENTIFIC PUBL CO PTE LTD, 2021) Andaç, Ahmet Cenk; Çakmak, Osman; Ökten, Salih; Çağlar-Andaç, Sena; Işıldak, İbrahim
    Piperazine/morpholine derivatives of quinoline substituted at positions C-3, C-6 and C-8 has been previously prepared by SNAr reactions of 3,6,8-tribromoquinoline (1) under microwave or conventional heating reaction conditions. In this study, we evaluated binding interactions between the piperazine/morpholine substituted quinolines and its highly-likely receptor, Cyclin G associated kinase (GAK) involved in hepatitis C virus (HCV) entry into host cells, via docking, molecular dynamics (MD), thermodynamic and pharmacokinetics computations in order to select a possible lead compound, which may be used for lead-optimization in our future studies to develop novel drug candidates against HCV infections. 372 nsec MD simulations followed by MM-PBSA thermodynamic computations revealed that compound 23 (K-d= 0.08nM) possesses the greatest potential to inhibit GAK. Pharmacokinetics computations suggest that compound 23 is a drug-like molecule as it conforms to the Lipinski filter. We determined that compound 23 could be a lead-like molecule for peripheric and cerebral HCV infections.
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    Quinoline-based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors
    (Wiley-VCH Verlag, 2020) Ökten, Salih; Aydın, Ali; Koçyiğit, Ümit Muhammet; Çakmak, Osman; Erkan, Sultan; Andaç, Ahmet Cenk; Taslimi, Parham; Gülçin, İlhami
    A series of substituted quinolines was screened for their antiproliferative, cytotoxic, antibacterial activities, DNA/protein binding affinity, and anticholinergic properties by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation, lactate dehydrogenase cytotoxicity, and microdilution assays, the Wolfe–Shimmer equality method, the Ellman method, and the esterase assay, respectively. The results of the cytotoxic and anticancer activities of the compounds displayed that 6-bromotetrahydroquinoline (2), 6,8-dibromotetrahydroquinoline (3), 8-bromo-6-cyanoquinoline (10), 5-bromo-6,8-dimethoxyquinoline (12), the novel N-nitrated 6,8-dimethoxyquinoline (13), and 5,7-dibromo-8-hydroxyquinoline (17) showed a significant antiproliferative potency against the A549, HeLa, HT29, Hep3B, and MCF7 cancer cell lines (IC50 = 2–50 ?g/ml) and low cytotoxicity (?7–35%) as the controls, 5-fluorouracil and cisplatin. The compound–DNA linkages are hyperchromic or hypochromic, causing variations in their spectra. This situation shows that they can be bound to DNA with the groove-binding mode, with Kb value in the range of 2.0 × 103–2.2 × 105 M–1. Studies on human Gram(+) and Gram(?) pathogenic bacteria showed that the substituted quinolines exhibited selective antimicrobial activities with MIC values of 62.50–250 ?g/ml. All tested quinoline derivatives were found to be effective inhibitors of acetylcholinesterase (AChE) and the human carbonic anhydrase I and II isoforms (hCA I and II), with Ki values of 46.04–956.82 nM for hCA I, 54.95–976.93 nM for hCA II, and 5.51–155.22 nM for AChE. As a result, the preliminary data showed that substituted quinolines displayed effective pharmacological features. Molecular docking studies were performed to investigate the binding modes and interaction energies for compounds 2–17 with AChE (PDB ID: 4EY6), hCA I (PDB ID: 1BMZ), and hCA II (PDB ID: 2ABE).