Etikyala, U.Reddyrajula, R.Udayakumar, U.Kokku, P.Vijjulatha, V.2026-02-032025ChemMedChem, 2025, 20, 22, pp. -18607179https://doi.org/10.1002/cmdc.202500231https://idr.nitk.ac.in/handle/123456789/19985Cancer 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.1 (1h indol 3 yl) n (5 methyl 1,3,4 thiadiazol 2 yl)methanimine1 (1h indol 3 yl) n (5 phenyl 1,3,4 thiadiazol 2 yl)methanimine1 (1h indol 3 yl) n (5 propyl 1,3,4 thiadiazol 2 yl)methanimine1 (1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine1 (1h indol 3 yl) n [5 (5 methylthiophen 2 yl) 1,3,4 thiadiazol 2 yl]methanimine1 (1h indol 3 yl) n [5 (thiophen 2 yl) 1,3,4 thiadiazol 2 yl]methanimine1 (1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 bromo 1h indol 3 yl) n (5 methyl 1,3,4 thiadiazol 2 yl)methanimine1 (5 bromo 1h indol 3 yl) n [5 (2 chlorophenyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 bromo 1h indol 3 yl) n [5 (4 chloro 2 nitrophenyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 bromo 1h indol 3 yl) n [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl)methanimine1 (5 bromo 1h indol 3 yl) n [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl)methanimine1 (5 bromo 1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 bromo 1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 fluoro 1h indol 3 yl) n [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 fluoro 1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 fluoro 1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl)methanimine1 (5 methoxy 1h indol 3 yl) n (5 propyl 1,3,4 thiadiazol 2 yl)methanimine1 (5 methoxy 1h indol 3 yl) n [5 (4 tolyl) 1,3,4 thiadiazol 2 yl]methanimine1 (5 methoxy 1h indol 3 yl) n [5 (trifluoromethyl) 1,3,4 thiadiazol 2 yl]methanimine1,3,4 thiadiazole derivative5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 amine5 (4 fluorophenyl) 1,3,4 thiadiazol 2 amine5 (thiophen 2 yl) 1,3,4 thiadiazol 2 amine5 (trifluoromethyl) 1,3,4 thiadiazol 2 amine5 amino 2 methyl 1,3,4 thiadiazole5 bromo 1h indole 3 carbaldehyde5 fluoro 1h indole 3 carbaldehyde5 methoxy 1h indole 3 carbaldehyde5 phenyl 1,3,4 thiadiazol 2 amine5 propyl 1,3,4 thiadiazol 2 amineantineoplastic agentdactolisibdoxorubicinG protein coupled receptorindole 1,3,4 thiadiazoleindole derivativen [5 (2 chlorophenyl) 1,3,4 thiadiazol 2 yl] 1 (5 methoxy 1h indol 3 yl)methaniminen [5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methaniminen [5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 yl] 1 (5 fluoro 1h indol 3 yl)methaniminen [5 (3,4 dimethoxyphenyl) 1,3,4 thiadiazol 2 yl] 1 (5 methoxy 1h indol 3 yl)methaniminen [5 (4 chloro 2 nitrophenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methaninen [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl) 1 (5 methoxy 1h indol 3 yl)methaniminen [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methaniminen [5 (4 chlorophenyl) 1,3,4 thiadiazol 2 yl] 1 (5 fluoro 1h indol 3 yl)methaniminen [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl) 1 (5 methoxy 1h indol 3 yl)methaniminen [5 (4 fluorophenyl) 1,3,4 thiadiazol 2 yl] 1 (1h indol 3 yl)methaniminephosphatidylinositol 3 kinasephosphatidylinositol 4,5 bisphosphateprotein kinase Bprotein tyrosine kinaseSchiff baseunclassified drug1,3,4-thiadiazolethiadiazole derivativeantineoplastic activityArticlebinding affinitybinding sitecancer inhibitionchemical interactionclinical evaluationcomparative studycomputer modelconformational transitioncontrolled studycytotoxicitydensity functional theorydrug designdrug efficacydrug potencydrug synthesisHeLa cell linehumanhuman cellin vitro studyMCF-7 cell lineMDA-MB-231 cell linemolecular dockingmolecular dynamicsmultiple cancerSiHa cell linestructure activity relationcell proliferationchemical structurechemistrydose responsedrug effectdrug screeningmetabolismsynthesistumor cell lineAntineoplastic AgentsCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorHumansIndolesMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructurePhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktSchiff BasesStructure-Activity RelationshipThiadiazoles