Facile synthesis of new N1-alkylated 1H-indazole-3-carboxamide derivatives as potential anticancer agents: In vitro, ADMET prediction, and SAR studies

• A series of 36 novel N1-alkylated 1 H -indazole-3-carboxamide analogs SN-1.1 to SN - 9.3 were designed and synthesized. • Newly synthesized analogs were evaluated via in vitro MTT assay against MDAMB-231, A-549 , and MCF-7 along with in-silico ADMET prediction. • Compound SN-1.1 displayed the most potent anticancer activity against the MCF-7 cell line with a GI 50 : 2.34µM. • In vitro results were validated with an in silico ADMET property. This work is focused on the synthesis and characterization by spectroscopic methods of new indazole compounds containing carboxamide and acetamido N-substituted moieties on C3 and N1 atoms, respectively, where acetamido moiety has been considered a linker essential for different biological activities including anticancer activity. In this context, the antiproliferative activity of all these compounds was investigated over MDAMB-231, A-549, and MCF-7 cancer cell lines and their cytotoxicity activity over normal fibroblast cell lines (NIH-3T3). The result showed that compounds SN-1.1, SN-2.1 , and SN 3.2 bearing electron-withdrawing group at the fourth position on phenyl rings exhibited the most potent activity against MCF-7 cell line with GI 50 value 2.34±0.036, 3.21±0.033, and 4.93±0.038 μM respectively. Further synthesized compounds were evaluated by various in silico screening technologies to better understand the drug-likeness features. All the compounds displayed optimal physicochemical features as excellent lead molecules. In the toxicity profiling study, all compounds were predicted to lack mutagenicity and cytotoxicity. This work provides a new class of safer indazole molecules with anticancer potential.