Synthesis of (1H‐Indol‐6‐yl)methyl Benzoate Analogs as Mitochondrial Oxidative Phosphorylation Inhibitors

Targeting oxidative phosphorylation (OXPHOS) in cancer metabolism offers a promising alternative to glycolytic inhibition. Herein, the synthesis and in vitro biological evaluation of 30 6-indolyl ester derivatives as potential OXPHOS inhibitors are reported. Screening against a panel of 5 mammalian cancerous cell lines and 1 noncancerous cell line using galactose- and glucose-containing media identified 11 hits with strong activity under OXPHOS-dependent conditions. Selectivity index (SI) and OXPHOS inhibition index (OI) analyses using IC₅₀ values obtained across a panel of 8 cancerous and noncancerous cell lines confirm compound 28 as a standout inhibitor, with an OI value of >91 and a SI value of 9.88 against pancreatic cancer cell line MiaPaCa-2. Additional hits (e.g., compounds 13, 20, 37) also demonstrate strong OXPHOS-specific activity and moderate to good selectivity with breast cancer and pancreatic cancer cell lines. In silico assessment using OSIRIS and SwissADME tools validate their physicochemical properties and drug-likeness. These findings support further investigation of 6-indolyl esters, specifically compound 28, as a structurally simple and synthetically accessible scaffold for the development of novel OXPHOS-targeting anticancer agents.