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. 2025 Nov 24;15(1):41821.
doi: 10.1038/s41598-025-27006-9.

Synthesis, antiproliferative screening, and molecular docking of some heterocycles derived from N-(1-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-hydrazineyl-3-oxoprop-1-en-2-yl)benzamide

Eman A E El-Helw  1 , Youssef M Youssef  2 , Galal A Elsayed  2 , Amira A El-Sayed  2 , Aya I Hassaballah  2 , Ashraf M Mohamed  3 , Mohammad E Azab  2
Affiliations

Synthesis, antiproliferative screening, and molecular docking of some heterocycles derived from N-(1-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-hydrazineyl-3-oxoprop-1-en-2-yl)benzamide

Eman A E El-Helw et al. Sci Rep. .

Abstract

The hydrazide derivative synthesized from oxazolone was employed as a key building block for the preparation of various N-acetyl, N-benzoyl, imidazole, tetrazine, pyrazole, and pyrazolopyrazole compounds. These target heterocycles were obtained by reacting the hydrazide with several carbon-based electrophilic reagents, including chloroacetyl chloride, benzoyl chloride, acetic anhydride, carbon disulfide, and pyrazole aldehyde. The synthesized compounds were evaluated for their antiproliferative activity against colon (HCT-116) and breast (MCF-7) cancer cell lines, which implied the more selective toxicity of these derivatives toward cancer cell lines rather than normal cell line (WI-38), signifying the safety of the tested compounds. Biological screening results demonstrated that compounds 5, 8, 9, and 10 exhibited significant cytotoxic activity against both cell lines. Among molecular docking simulation, the ligand binding energies were like those of doxorubicin (as an anticancer drug) and RRC (as a CDK2 inhibitor), as the most interacting amino acids were common, proposing being CDK2 inhibitor. The superlative docking score was given by compound 9 (S= -9.5080 kcal/mol), which was higher than that of doxorubicin and co-crystallized ligand (RRC). This work may develop the innovative, highly effective agents against cancer in the future.

Keywords: Antiproliferative; Imidazole; Pyrazole; Pyrazolopyrazole; Tetrazine.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Some drugs bearing pyrazole, imidazoline, oxadiazole, thiadiazole, and thiazolidinone moieties.
Scheme 1
Scheme 1
Synthesis of acid hydrazide 2 and its acylation with acetic anhydride.
Scheme 2
Scheme 2
Reactions of hydrazide 2 with acid chlorides and synthesis of oxadiazole 7.
Scheme 3
Scheme 3
A suggested pathway for the formation of oxadiazole 7.
Scheme 4
Scheme 4
Synthesis of compounds 8–11.
Scheme 5
Scheme 5
A plausible mechanism for the formation of tetrazinethione 11.
Scheme 6
Scheme 6
Condensation of hydrazide 2 with N-phenyl-5-chloro-4-formyl-3-methylpyrazole.
Scheme 7
Scheme 7
Reactions of thiosemicarbazide derivative 9 with diethyl acetylenedicarboxylate and ethyl chloroacetate.
Fig. 2
Fig. 2
SAR of the potent compounds.
Fig. 3
Fig. 3
2D diagrams of the superimposition of the native and redocked co-crystallized ligand (RRC) structures at CDK2 protein target (PDB ID: 2A4L) with RMSD value of 1.4404 Å.
See this image and copyright information in PMC

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