Synthesis, In Silico Analysis, and In Vitro Cytotoxic Activity of Novel Benzocamalexins
Year: 2026
Type: article
Abstract: Cancer treatment remains a major challenge in medicine due to high toxicity and drug resistance, motivating the application of novel selective cytotoxic agents based on natural compounds. In this study, ten novel benzocamalexin analogues 5a–e with variously substituted indoles were designed, synthesized, and evaluated for anticancer activity. An efficient two-step strategy was applied, involving regioselective α-amidoalkylation at C3 of indoles, followed by oxidative rearomatization of 2-(3-indolyl)-N-acylbenzothiazolines 4a–f. The use of the mild oxidant o-Chloranil in the second step enables the formation of target benzocamalexins (73–93% yield). In silico toxicological screening classified all compounds as non-mutagenic, with analogues 5b–e showing high predicted acute oral safety (LD50 = 2447.55–2486.05 mg/kg). In vitro MTT assays across human lung (A549), cervical (HeLa), and colorectal (LS180) adenocarcinoma cells, alongside normal fibroblasts (HFFC), demonstrated selective cytotoxicity. Thus, analogues 5b, 5c, and 5e displayed superior cytotoxic potency against cancer cells compared to benzocamalexin, while 4d, 5a, 5c, and 5d showed lower toxicity toward normal fibroblasts. Molecular docking with the aryl hydrocarbon receptor (AhR) predicted strong binding affinities for 5b–e (−10.1 to −10.3 kcal/mol). The AhR interaction for camalexin (−9.4 kcal/mol) and benzocamalexin (−10.0 kcal/mol) was recognized as a potential mechanism for their selective antitumour efficacy.
Source: Biomolecules
DOI: 10.3390/biom16111651
Institution: Plovdiv University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7225908936