What question did this study set out to answer?

The study aims to synthesize and evaluate indirubin derivatives for their physicochemical properties and biological activity against EGFR and HIV targets.

March 10, 2026

Indirubin Derivatives: Synthesis, Physicochemical Profiling, Toxicity Assessment, and Molecular Docking Investigations Against EGFR and HIV Target Substrates

Key Points

The study aims to synthesize and evaluate indirubin derivatives for their physicochemical properties and biological activity against EGFR and HIV targets.
Synthesis of indirubin derivatives using a cascade alkylation strategy with alkylating agents.
Evaluation of physicochemical properties, ADMET behavior, and toxicity endpoints using in silico analyses.
Molecular docking studies to assess binding affinity to EGFR and HIV protease.
Comparison of binding scores with existing drugs gefitinib and lopinavir.
Several indirubin derivatives showed good drug-likeness and safety profiles in toxicity assessments.
Molecular docking revealed stronger binding affinities for select derivatives compared to gefitinib and lopinavir.
Derivatives I18 demonstrated the strongest binding score in both EGFR and HIV-2 protease simulations.

Abstract

ABSTRACT Indirubin‐based alkaloids constitute an important chemotype with documented anticancer and antiviral potential. In this study, a concise cascade alkylation strategy was employed to generate a diverse library of indirubinoid derivatives from the parent indirubin scaffold using alkylating agents in the presence of cesium carbonate, affording the targeted molecules in good to excellent yields. Comprehensive in silico analyses were performed to evaluate physicochemical suitability, ADMET behavior, predicted metabolites, and TOX21 toxicity endpoints, collectively indicating that several derivatives meet key drug‐likeness and safety criteria. Molecular docking further highlighted them as good candidates for binding with the extracellular domain of EGFR (PDB: 1NQL), as compounds I16 (−8.06 kcal/mol), I18 (−8.83 kcal/mol), I21 (−8.09 kcal/mol), and I23 (−7.61 kcal/mol) demonstrated substantially stronger binding affinities than the reference gefitinib (−6.74 kcal/mol) during the simulation experiments. Similarly, against HIV‐II protease (PDB: 1HSG), derivatives I16 , I18 , I20 , and I21 exhibited more favorable predicted docking scores than lopinavir under the same computational protocol, with I18 showing the strongest calculated binding within this compound set. These synergistic synthetic and computational findings identify indirubinoids as strong candidates for future development of anticancer and anti‐HIV drug leads.

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