Design, Synthesis, and Evaluation of Novel Adenine-Based Hydrazones as Potential Anticancer Agents: Cytotoxicity Against A549 and MRC-5 Cell Lines with In Silico Insights.

Authors

Emre Menteşe, Nedime Çalışkan, Mustafa Emirik, Adem Güner

Published in

Pharmaceuticals (Basel, Switzerland). Volume 19. Issue 10. Oct 19, 2026. Epub Oct 19, 2026.

Abstract

Background/Objectives: Lung cancer remains a leading cause of global cancer-related mortality, necessitating the development of new therapeutic candidates. In this study, we aimed to design, synthesize, and biologically evaluate novel adenine-based hydrazone derivatives as potential anticancer candidates. Methods: A series of novel adenine-hydrazones were synthesized via the condensation of 2-(6-amino-9H-purin-9-yl)acetohydrazide with various aldehydes and isatin derivatives. Their antiproliferative activities against human lung adenocarcinoma (A549) and normal lung fibroblast (MRC-5) cell lines were evaluated using the MTT assay. Mechanistic investigations-including cell membrane damage (LDH release), oxidative stress (TOS, iROS), mitochondrial membrane potential (MMP, ΔΨm), cell cycle distribution, and apoptosis (Annexin V/PI)-were conducted for the lead derivatives, complemented by multi-target in silico molecular docking against PLK1, TrxR1, and MDM2. Results: Compounds 3d, 3c, and 4j showed the strongest antiproliferative activity within the synthesized series against A549 cells, with IC₅₀ values of 37.2 ± 1.8 µM, 41.8 ± 1.9 µM, and 42.9 ± 1.7 µM, respectively, together with comparatively more favorable A549/MRC-5 activity profiles than several other derivatives. These compounds induced oxidative stress-associated cellular injury, accompanied by mitochondrial depolarization, G2/M phase accumulation, and Annexin V-confirmed apoptotic cell death. Complementary multi-target in silico molecular docking provided theoretical insights into potential binding interactions with PLK1, TrxR1, and MDM2. Conclusions: Adenine-hydrazone hybrids, particularly 5-halogenated isatin derivatives such as compound 3d, provide preliminary lead scaffolds with moderate in vitro cytotoxicity against lung cancer cells, serving as a platform for future structural optimization to enhance potency and selectivity.

PMID:
42943349
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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