New2-((2-(2,4-dinitrophenyl)hydrazineeylidene) derivatives: design, synthesis, in silico, and in vitro anticancer studies

Abstract

A series of novel hydrazone compounds have been synthesized by the condensation of hydrazines and different substituted salicylaldehydes at a molar ratio of 1:1 in one step reaction and characterized by FT-IR, ESI-MS, ¹H NMR, and single crystal x-ray diffraction. The crystal structure of the compound shows a trans configuration around the C = N bond and triclinic system with P −1/-p 1. Synthesized compounds were screened for cytotoxicity activities against A375 (melanoma), HT-29 (Colon), and A549 (lung) cancer cell lines. Among them, compound 2 exhibited the highest cytotoxic effect against the A375 cell line (IC₅₀ = 0.30 µM) and HT-29 cell line (1.68 µM), compared to those of apatinib as a reference standard drug (0.28, 1.49 µM, respectively). The cytocompatibility assay on the L929 normal cell line and the hemolysis assay on human RBC were used to validate the non-toxic action. From DFT calculation, the various parameters such as HOMO-LUMO energies, Hirshfeld, and MEP have been studied. Furthermore, in silico molecular docking with three receptors was studied. Among four compounds, compound 2 has the lowest binding energy against cyclin dependent kinase (ΔGb = −9.3 kcal/mol). In addition to this, molecular dynamics (MD) simulation was also performed. Based on this study, these novel hydrazones can be considered a promising anticancer agent due to their potent cytotoxicity activities and computational analysis.

Communicated by Ramaswamy H. Sarma

KEYWORDS:

• Hydrazone
• cytotoxicity activity
• crystal structure
• density functional theory
• molecular docking

Acknowledgements

Authors thank Dr. Vijay Kumbar, KLE Academy of Higher Education and Research, Belagavi for his valuable suggestions. VPS thanks, Karnataka University, Dharwad for NMR analysis and KLE Academy of Higher Education and Research, Belagavi for their help in cytotoxicity and biocompatibility studies.

Disclosure statement

The authors declare that there is no conflict of interest regarding publication of this article.

Scheme 1. Synthetic route of hydrazone compounds 1–4.

Additional information

Funding

PMG is thankful to VGST, Govt. of Karnataka for VGST-SMYSR (GRD 503), VGST KFIST L-1 (GRD 952), RCU for Minor Research Project (2020 &2021) and DST for DST-FIST grant. The molecular dynamics calculations reported in this article were partially performed at TUBITAK ULAKBIM in TURKEY, High Performance and Grid Computing Center (TRUBA resources).