Redox-triggered electronic modulation and ligand dissociation in cobalt(iii) bipyridine prodrugs for urease inhibition in Helicobacter pylori.

Abstract

Helicobacter pylori infection is one of the most significant health problems on a global scale, and the treatment has become, more than ever, less effective due to antibiotic resistance and low drug specificity. This work describes a redox-responsive cobalt-based prodrug system to specifically deliver acetohydroxamic acid (AHA) to urease for its inhibition. A cobalt(iii)-bipyridine coordination complex was designed to stabilize AHA during its systemic delivery and release it under reductive conditions typical of the infected gastric microenvironment. Density functional theory computations show that the oxidized Co(iii) form is strongly bonded to the metal, and structurally, the form is kinetically stable, but reduction to Co(ii) causes elongation of the bonds and a marked reduction in ligand-exchange energy. Molecular docking and replicated molecular dynamics simulations, comprising a total of 3.3 µs of production dynamics across H. pylori urease, a comparative Bifidobacterium infantis urease model, and human carbonic anhydrase I, are used to evaluate target-site access and off-target metal accessibility. Across both urease systems, free AHA remains metal-proximal, while the intact cobalt cage shows restricted access to the dinuclear nickel center. A human carbonic-anhydrase I comparison similarly supports reduced direct metal access by the intact prodrug. The redox potential, activation energetics, and lipophilicity of the bipyridine ligand can be systematically tuned by the substituent modification of the ligand. Altogether, we create a defined, tunable platform to design redox-activated antimicrobial prodrugs, connecting coordination chemistry and targeted therapeutic activation for future applications.

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