Design, synthesis, and evaluation of novel N'-substituted-1-(4-chlorobenzyl)-1H-indol-3-carbohydrazides as antitumor agents

Abstract

In continuity of our search for novel anticancer agents acting as procaspase activators, we have designed and synthesised two series of (E)-N′-benzylidene-carbohydrazides (4a–m) and (Z)-N'-(2-oxoindolin-3-ylidene)carbohydrazides (5a–g) incorporating 1-(4-chlorobenzyl)-1H-indole core. Bioevaluation showed that the compounds, especially compounds in series 4a–m, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Within series 4a–m, compounds with 2-OH substituent (4g–i) exhibited very strong cytotoxicity in three human cancer cell lines assayed with IC₅₀ values in the range of 0.56–0.83 µM. In particular, two compounds 4d and 4f bearing 4-Cl and 4-NO₂ substituents, respectively, were the most potent in term of cytotoxicity with IC₅₀ values of 0.011–0.001 µM. In caspase activation assay, compounds 4b and 4f were found to activate caspase activity by 314.3 and 270.7% relative to PAC-1. This investigation has demonstrated the potential of these simple acetohydrazides, especially compounds 4b, 4d, and 4f, as anticancer agents.