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Research Article

Design, synthesis, molecular modeling, and biological evaluations of novel chalcone based 4-Nitroacetophenone derivatives as potent anticancer agents targeting EGFR-TKD

, , , , , , & show all
Received 12 Oct 2023, Accepted 30 Dec 2023, Published online: 28 Jan 2024
 

Abstract

A series of chalcone-based 4-Nitroacetophenone derivatives were designed and synthesized by the single-step condensation method. These compounds were identified by 1H NMR,13C NMR, MS, and FTIR analysis. Further, the derivatives were evaluated against four cancer cell lines H1299, MCF-7, HepG2, and K526. The IC50 value of potent compounds NCH-2, NCH-4, NCH-5, NCH-6, NCH-8, and NCH-10 was 4.5–11.4 μM in H1299, 4.3–15.7 μM in MCF-7, 2.7–4.1 μM in HepG2 and 4.9–19.7 μM in K562. To assess the toxicity against healthy cells all potent molecules were evaluated against the HEK-293T cell line, and IC50 values exhibited by NCH-2, and NCH-3 were 77.8, 74.3, and other molecules showed IC50 values > 100 μM. The EGFR expression was determined by using rabbit anti-EGFR monoclonal antibody and significant EGFR expression was knocked down observed in H1299 treated with NCH-10 as well as erlotinib. The underlying mechanism behind cell death was investigated through bioinformatics. First, the molecules were optimized and docked to the binding site of the EGFR kinase domain. The best complexes were simulated for 100-ns and compounds NCH-2, NCH-4, and NCH-10 achieved stability similar to the erlotinib bound kinase domain. The free energy binding (ΔGbind) of NCH-10 was found to be more negative −226.616 ± 2.148 kJ/mol calculated by Molecular Mechanics Poisson Boltzmann’s Surface Area (MM-PBSA) method. Both in vitro and in silico results conclude that the present class of chalcone-based 4-Nitroacetophenone derivatives are potent anti-cancer agents targeting EGFR-TKD and are 39 folds more effective against H1299, MCF-7, HepG2, and K562 carcinoma cell lines than healthy HEK-293T cell lines.

Communicated by Ramaswamy H. Sarma

Author contributions

All authors contributed equally.

Acknowledgement

The authors thank the Office of the Dean, R&D, Integral University, for providing manuscript communication number (IU/R&D/2024-MCN0002370).

Disclosure statement

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

Additional information

Funding

This research work was funded by Institutional Fund Projects under grant no. (IFPIP-1206-130-1443). Therefore, the authors gratefully acknowledge the technical and financial support from the Ministry of Education and King Abdulaziz University, DSR Jeddah, Saudi Arabia.

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