Exploring Indole-1,3,4-Thiadiazole Schiff Base Derivatives as Anticancer Agents: Design, Synthesis, In Vitro and In Silico Evaluation
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Date
2025
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John Wiley and Sons Ltd
Abstract
Cancer remains a major global health challenge, with resistance to existing therapeutic regimens underscoring the development of novel agents with improved efficacy and reduced toxicity. The indole and 1,3,4-thiadiazole scaffolds are distinguished for their broad-spectrum bioactivities, including anticancer properties. In this study, the synthesis and biological evaluation of a new series of indole-1,3,4-thiadiazole Schiff bases (U1-U31) designed to enhance anticancer efficacy is explored. In vitro evaluation demonstrates potent and selective cytotoxicity of several compounds, particularly U19 and U24, against multiple cancer cell lines, with minimal toxicity to normal cells. Molecular docking and density functional theory studies demonstrate that these hybrid compounds effectively occupy the ATP-binding sites of Pi3K and Akt proteins, exhibiting notable binding interactions comparable to the respective standard inhibitors. In addition, molecular dynamics simulation is performed to understand the conformational changes of the protein–ligand complex. Overall, the findings indicate that these novel indole-1,3,4-thiadiazole derivatives have selective inhibitory potency, making them promising leads for further anticancer drug development. © 2025 Wiley-VCH GmbH.
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1 (1h indol 3 yl) n (5 methyl 1,3,4 thiadiazol 2 yl)methanimine, 1 (1h indol 3 yl) n (5 phenyl 1,3,4 thiadiazol 2 yl)methanimine, 1 (1h indol 3 yl) n (5 propyl 1,3,4 thiadiazol 2 yl)methanimine, 1 (1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (1h indol 3 yl) n [5 (5 methylthiophen 2 yl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (1h indol 3 yl) n [5 (thiophen 2 yl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 bromo 1h indol 3 yl) n (5 methyl 1,3,4 thiadiazol 2 yl)methanimine, 1 (5 bromo 1h indol 3 yl) n [5 (2 chlorophenyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 bromo 1h indol 3 yl) n [5 (4 chloro 2 nitrophenyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 bromo 1h indol 3 yl) n [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl)methanimine, 1 (5 bromo 1h indol 3 yl) n [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl)methanimine, 1 (5 bromo 1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 bromo 1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 fluoro 1h indol 3 yl) n [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 fluoro 1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 fluoro 1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl)methanimine, 1 (5 methoxy 1h indol 3 yl) n (5 propyl 1,3,4 thiadiazol 2 yl)methanimine, 1 (5 methoxy 1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine, 1 (5 methoxy 1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl]methanimine, 1,3,4 thiadiazole derivative, 5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 amine, 5 (4 fluorophenyl) 1,3,4 thiadiazol 2 amine, 5 (thiophen 2 yl) 1,3,4 thiadiazol 2 amine, 5 (trifluoromethyl) 1,3,4 thiadiazol 2 amine, 5 amino 2 methyl 1,3,4 thiadiazole, 5 bromo 1h indole 3 carbaldehyde, 5 fluoro 1h indole 3 carbaldehyde, 5 methoxy 1h indole 3 carbaldehyde, 5 phenyl 1,3,4 thiadiazol 2 amine, 5 propyl 1,3,4 thiadiazol 2 amine, antineoplastic agent, dactolisib, doxorubicin, G protein coupled receptor, indole 1,3,4 thiadiazole, indole derivative, n [5 (2 chlorophenyl) 1,3,4 thiadiazol 2 yl] 1 (5 methoxy 1h indol 3 yl)methanimine, n [5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methanimine, n [5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 yl] 1 (5 fluoro 1h indol 3 yl)methanimine, n [5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 yl] 1 (5 methoxy 1h indol 3 yl)methanimine, n [5 (4 chloro 2 nitrophenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methanine, n [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl) 1 (5 methoxy 1h indol 3 yl)methanimine, n [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methanimine, n [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl] 1 (5 fluoro 1h indol 3 yl)methanimine, n [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl) 1 (5 methoxy 1h indol 3 yl)methanimine, n [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methanimine, phosphatidylinositol 3 kinase, phosphatidylinositol 4,5 bisphosphate, protein kinase B, protein tyrosine kinase, Schiff base, unclassified drug, 1,3,4-thiadiazole, thiadiazole derivative, antineoplastic activity, Article, binding affinity, binding site, cancer inhibition, chemical interaction, clinical evaluation, comparative study, computer model, conformational transition, controlled study, cytotoxicity, density functional theory, drug design, drug efficacy, drug potency, drug synthesis, HeLa cell line, human, human cell, in vitro study, MCF-7 cell line, MDA-MB-231 cell line, molecular docking, molecular dynamics, multiple cancer, SiHa cell line, structure activity relation, cell proliferation, chemical structure, chemistry, dose response, drug effect, drug screening, metabolism, synthesis, tumor cell line, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Humans, Indoles, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Schiff Bases, Structure-Activity Relationship, Thiadiazoles
Citation
ChemMedChem, 2025, 20, 22, pp. -