Structure–Property Relationship of Rationally Designed α-Mercurated Curcumin Derivatives: Quantum-Chemical Insights for Aqueous Compatibility and Pharmacological Activity

<jats:p> α-Mercurin ( <jats:bold>1</jats:bold> ), an organomercury derivative of curcumin containing a direct Hg–C <jats:sub>α</jats:sub> bond and distal coordination with β-keto oxygens, has shown promising anti-leukemic efficacy and favourable safety profile in our previous study. In continuation, the current study is performed to explore for further improved formulation in terms of overall efficacy and pharmacological property. In this study, we used rational computational strategy to design derivatives having improved aqueous compatibility, preserving core organomercury pharmacophore. We designed five analogues by modifying the peripheral methoxy groups/aromatic rings to generate catechol ( <jats:bold>1a</jats:bold> ), hydroxyethyl ether ( <jats:bold>1b</jats:bold> ), carboxymethyl ether ( <jats:bold>1c</jats:bold> ), sulfonate ( <jats:bold>1d</jats:bold> ), and morpholine ( <jats:bold>1e</jats:bold> ) derivatives. Using density functional theory, we evaluated their solvation behaviour, electrostatic potential, frontier molecular orbitals, Fukui functions, Mayer bond orders, physicochemical properties, ionization, and natural bond orbital interactions. We found that peripheral functionalization may improve polarity and aqueous-solvation, preserving the C <jats:sub>α</jats:sub> –Hg···O <jats:sub>β</jats:sub> ,O <jats:sub>β’</jats:sub> core electronic structure along with sp <jats:sup>2</jats:sup> hybridized framework. Among them, <jats:bold>1b</jats:bold> showed the most balanced profile, combining improved aqueous compatibility with moderate lipophilicity and preservation of characteristic electronic as well as bonding features. Overall, our findings identify <jats:bold>1b</jats:bold> as a promising candidate for further experimental validation, and demonstrate a rational strategy for improving the pharmacological properties of α-Mercurin. </jats:p>