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Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluationsopen access
- Authors
- Al-Karmalawy, Ahmed A.; Nafie, Mohamed S.; Shaldam, Moataz A.; Elmaaty, Ayman Abo; Antar, Samar A.; El-Hamaky, Anwar A.; Saleh, Mohamed A.; Elkamhawy, Ahmed; Tawfik, Haytham O.
- Issue Date
- Jan-2023
- Publisher
- American Chemical Society
- Keywords
- Doxorubicin; Human Immunodeficiency Virus Reverse Transcriptase; Rna Directed Dna Polymerase; Staurosporine; Telomerase; Antineoplastic Agents; Bibr 1532; Enzyme Inhibitors; Ligands; Telomerase; Bibr 1532; Benzothiophene Derivative; Bibr 1532; Doxorubicin; Ligand; N (3 Cyano 4,5,6,7 Tetrahydro 1 Benzothiophen 2 Yl) 2 [(6 Phenylpyridazin 3 Yl)sulfanyl]acetamide; N (3 Cyano 4,5,6,7 Tetrahydro 1 Benzothiophen 2 Yl) 2 [[6 (4 Bromophenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4,5,6,7 Tetrahydro 1 Benzothiophen 2 Yl) 2 [[6 (4 Chlorophenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4,5,6,7 Tetrahydro 1 Benzothiophen 2 Yl) 2 [[6 (4 Fluorophenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4,5,6,7 Tetrahydro 1 Benzothiophen 2 Yl) 2 [[6 (4 Methoxyphenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4,5,6,7 Tetrahydro 1 Benzothiophen 2 Yl) 2 [[6 (4 Methylphenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4h,5h,6h Cyclopenta[b]thiophen 2 Yl) 2 [(6 Phenylpyridazin 3 Yl)sulfanyl]acetamide; N (3 Cyano 4h,5h,6h Cyclopenta[b]thiophen 2 Yl) 2 [[6 (4 Bromophenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4h,5h,6h Cyclopenta[b]thiophen 2 Yl) 2 [[6 (4 Chlorophenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4h,5h,6h Cyclopenta[b]thiophen 2 Yl) 2 [[6 (4 Fluorophenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4h,5h,6h Cyclopenta[b]thiophen 2 Yl) 2 [[6 (4 Methoxyphenyl)pyridazin 3 Yl]sulfanyl]acetamide; N (3 Cyano 4h,5h,6h Cyclopenta[b]thiophen 2 Yl) 2 [[6 (4 Methylphenyl)pyridazin 3 Yl]sulfanyl]acetamide; Pyridazine Derivative; Staurosporine; Telomerase; Telomerase Inhibitor; Unclassified Drug; Antineoplastic Agent; Bibr 1532; Enzyme Inhibitor; A-549 Cell Line; Animal Cell; Animal Experiment; Animal Model; Animal Tissue; Antineoplastic Activity; Apoptosis; Article; Cancer Inhibition; Cell Cycle; Controlled Study; Drug Design; Drug Screening; Drug Synthesis; Ehrlich Ascites Tumor; Enzyme Inhibition; Female; Ic50; In Vitro Study; In Vivo Study; Mcf-7 Cell Line; Molecular Docking; Mouse; Nonhuman; Pharmacophore; Real Time Polymerase Chain Reaction; Structure Activity Relation; Animal; Cell Proliferation; Chemical Structure; Dog; Tumor Cell Line; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dogs; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Ligands; Molecular Docking Simulation; Molecular Structure; Telomerase
- Citation
- Journal of Medicinal Chemistry, v.66, no.1, pp 777 - 792
- Pages
- 16
- Indexed
- SCIE
SCOPUS
- Journal Title
- Journal of Medicinal Chemistry
- Volume
- 66
- Number
- 1
- Start Page
- 777
- End Page
- 792
- ISSN
- 0022-2623
1520-4804
- Abstract
- Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmaco-kinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of 8e on the cell cycle and apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.
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