Isoindole-1 3-dione derivatives as potent anticancer agents: in silico, in vitro, and in vivo insight

Cancer remains the second leading cause of mortality worldwide, largely due to limitations of current therapies such as drug resistance, metastasis, and poor pharmacokinetic profiles. In search of more effective alternatives, Isoindole-1 3-dione a well-established anticancer scaffold was employed to design a new series of 1,3,4-oxadiazole-linked Isoindole-1 3-dione derivatives. A validated 3D-QSAR pharmacophore model was developed to identify essential structural features associated with anticancer potency and to design and predict inhibitory activity (IC??) values. Guided by this model, a series of novel derivatives were synthesized and structurally confirmed using FT-IR, ¹H NMR, ¹³C NMR, LCMS, and elemental analysis.

In vitro cytotoxicity screening against MCF-7 (breast cancer) and HCT-116 (colon cancer) cell lines demonstrated that all compounds possessed moderate to potent activity, with three derivatives (4B, 6B, and 10B) exhibiting IC?? values below 10 μM. Among them, compound 6B emerged as the most promising candidate, showing IC?? values of 7.03 μM (MCF-7) and 6.81 μM (HCT-116). In vivo studies using Ehrlich ascites carcinoma (EAC) tumor-bearing mice further validated its potency, as 6B significantly reduced tumor volume, inhibited tumor weight by 70.06%, suppressed tumor cell proliferation by 69.26%, and extended the lifespan of treated animals compared to controls.

Molecular docking and binding free energy studies revealed strong binding affinities, energies, and favorable interactions towards tyrosine kinase receptors (EGFR and VEGFR). Molecular dynamics (MD) simulations over a 100 ns trajectory further confirmed the stability of compound 6B within the receptor binding pocket. Additionally, ADMET profiling suggested desirable drug-like properties, favorable pharmacokinetics, and a non-toxic, non-carcinogenic profile.

Overall, this study successfully integrates computational, synthetic, and biological approaches to yield potent anticancer candidates. Compound 6B demonstrated consistent efficacy across in silico, in vitro, and in vivo platforms, highlighting its potential as a promising lead for further development in anticancer therapy.

He is a pharmaceutical chemist specializing in in-silico drug design and synthesis of novel small molecules for Cancer and Alzheimer’s disease. He completed his Master’s in Pharmaceutical Chemistry with a GPAT fellowship from AICTE, New Delhi, and worked as a Junior Research Fellow on a DST-SERB project. Currently, he is pursuing his PhD and completed PhD pre-submission at Guru Ghasidas University, Bilaspur, supported by the MJPRF-2022 fellowship from MAHAJYOTI, Nagpur. With over five years of research experience, he has published more than 30 research and review articles in peer-reviewed journals