A multilayered supramolecular chelate of diclofenac-appended AgI-hydrazide as an efficient anti-inflammatory, anticancer, and nanometal dispersing material, in comparison to analogous ZnII-hydrazide

Abstract

We herein present new Ag^I and Zn^II chelating materials based on diclofenac (dicf)-appended hydrazide (dh), along with their comparative structural, crystal, solution, anti-inflammatory, and cytotoxic properties. The spectral (FT-IR, NMR, FAB-MS, and UV-vis), physicochemical, SEM, and single-crystal X-ray studies ensure the Ag^I complex as [Ag(dh)NO₃] (1), where neutral dh is a bidentate N,O donor, while nitrate is a monodentate O donor. Chelate 1 bears a distorted trigonal planar geometry and a triclinic (P) crystal. It assembles into a unique supramolecular multilayered (sheet) framework stabilized by N–H⋯O, C–H⋯O, X–H⋯π, Ag⋯π/O/N, and Cl⋯O/H contacts, evidenced by Hirshfeld surface, QTAIM and NCI analyses. Zn^II forms a microcrystalline stable tetrahedral complex [Zn(dh)SO₄] (2) with two chelate rings from bidentately attached dh and sulfate. Intracellular oxidative burst (ROS) suppression-based anti-inflammatory studies manifest chelate 1 as the strongest ROS inhibitor (IC₅₀ = 2.6 μg mL⁻¹), with the cumulative effect of precursors that makes chelate 1 3-fold superior to reference drugs, dicf and ibuprofen (ibup). Molecular docking validates empirical results and cyclooxygenase-2 (COX-2) inhibition by these compounds as a dominant anti-inflammatory mechanism. The stabilization based on the number of H-bonding/hydrophobic/ionic interactions within the COX-2 binding pocket exhibits the following order: chelate 1 > dh > chelate 2 > dicf > ibup. Chelate 1 shows a high selectivity towards COX-2 comparable to celecoxib, while chelate 2 shows non-selective non-competitive COX-2 inhibition. Replacing nitrate in chelate 1 with bio-anions (Cl⁻, HCO₃⁻, H₂PO₄⁻, and HSO₄⁻) does not significantly alter its COX-2 inhibitory mechanism. Chelate 1 exhibits strong cytotoxicity on cancer cells (PC3 and H460) compared to that on normal BJ fibroblasts, being most selective against PC3 (IC₅₀ = 3.5 μg mL⁻¹, twelve-fold better than cisplatin), while chelate 2 shows low cytotoxicity overall. Chelate 1 also acts as a precursor for the controlled production of stable silver colloids (AgNPs) and uniform thin reflective films (TRFs) in methanol through concentration-dependent selective intramolecular chemical reduction and deposition, not shown by chelate 2 for zinc. This study indicates chelate 1 as a promising future anti-inflammatory/anticancer drug candidate and a plausible single-molecule source for AgNPs and TRFs.