Synthesis, Biological Evaluation, and In Silico ADMET Screening of Indole Embedded Sulfonamides as Anticancer Agents

ABSTRACT Two new series of the indole‐based sulfonamide derivatives were synthesized by the reaction of various sulfonylhydrazides with N ‐substituted indole 3‐carboxaldehydes (4a–j) . Crystallographic parameters and intramolecular interactions of compound HS4 were examined through x‐ray crystallography to establish the structure of compound. The biological activity of the synthesized compounds was evaluated against breast cancer cell line 4T1 and rat adipose‐derived stem cells (rADSC). Among all the compounds, HS3 and MP3 possessed significant antiproliferative activity against 4T1 malignant cells inhibiting the cell growth with IC 50 values of 25 and 37.5 µM, respectively. Compounds HS3 and MP3 were toxic to rADSCs at 25 and 37.5 µM concentration, respectively. Further mechanistic studies revealed that compounds HS3 and MP3 induced effective autophagy to cause cell death, confirmed by the progressive conversion of LC3I to LC3II and enhanced expression of LC3A/B in 4T1 breast cancer cells. In addition, the in silico physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling validated the drug likeness properties of the synthesized compounds.