Crystal engineering for enzymatic activity inhibition and antimicrobial applications

Crystal engineering offers strategies to guide solid-state modifications, enabling the rational design of materials with desired physical and chemical properties. When applied to biologically active compounds, it provides methods to modulate their solubility, stability, and bioavailability. This work explores crystal engineering as a tool for designing and controlling the solid-state organisation of compounds with biological and environmental relevance, articulated along three research lines: (1) enzymatic activity inhibition, (2) antimicrobial applications, and (3) chiral resolution of racemic active pharmaceutical ingredients (APIs). The first line focuses on the preparation of metal complexes and co-crystals of compounds known to inhibit urease, thereby mitigating nitrogen losses in agricultural and animal husbandry contexts. Bismuth(III) complexes were synthesised and structurally characterised. In vitro assays using Canavalia ensiformis urease and in vivo assays using cultures of Helicobacter pylori provided insight into their biological activity, suggesting that a reassessment of the mode of action of Bi(III) compounds is required. A urea-based co-crystal was designed to reduce water solubility and to inhibit urease. The co-crystal was then incorporated into electrospun polymeric mats to provide additional control on its release. Lastly, a urea∙proline cocrystal was proposed as a nutritional supplement for ruminants. The second line addresses antimicrobial resistance by enhancing drug efficacy through crystal engineering. In this context, metal complexes of metronidazole were synthesised and structurally characterised. Microbiological studies revealed an enhancement of antimicrobial activity upon complexation. These complexes were further embedded into hydroxyapatite, yielding bioactive composites with potential use in implant coatings. Lastly, structural investigations of APIs with antimicrobial properties, including rifaximin and allantoin, were conducted. The third line focuses on the chiral drug phenylpiracetam, a nootropic API whose enantiomers exhibit a pronounced tendency to form solid solutions that hinder chiral resolution. Co-crystallization was explored to test whether this behaviour could be altered through crystal engineering.