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.

Keywords:

• Acetohydrazides
• isatin
• cytotoxicity
• caspase activation

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We acknowledge the principal financial supports from the National Foundation for Science and Technology of Vietnam [NAFOSTED, Grant number 104.01-2018.01]. The work was also supported by a grant funded by the Korean Government [NRF, Grant number 2017R1A5A2015541] for indepth bioevaluation that was not supported by Nafosted Grant.