Potassium Hydrogen Sulfate Promoted One-pot Synthesis of Bis(indolyl)alkane Esters from α-Keto Carboxylic Acids: In Silico and In Vitro Anticancer Studies

Abstract

Sustainable and efficient synthetic strategies for bioactive bis and tris(indolyl) alkane (BIM and TIM) derivatives remain a central challenge because of their acid sensitivity. Herein, we demonstrate an eco-friendly synthesis of 3,3′-bisindolylalkane esters from α-keto carboxylic acids and indoles employing potassium hydrogen sulfate as a green promoter, with methanol acting as both reagent and solvent, in excellent yields. Beyond that, the methodology was further extended to the esterification of α-keto carboxylic acids and N-protected L-amino acid derivatives. Synthetic applications of the developed methodology were demonstrated in the concise total synthesis of Streptindole and Arsindoline B, bioactive natural products. Complementary computational investigations, including SwissADME analyses, DFT, MEP, molecular docking, and MD simulations, demonstrated promising pharmacokinetic profiles, favourable electronic properties, and strong EGFR binding affinities, highlighting the potential of selected novel compounds as effective anticancer agents. Guided by these in silico predictions, experimental anticancer evaluation using in vitro MTT assays identified compound C26 as the most potent and selective derivative against A549 and T24 cancer cell lines, with reduced toxicity toward normal MCF-10a cells, underscoring its potential as a promising anticancer lead.