Editorial: New Developments in Bioinorganic and Bioorganic Chemistry

Isabel Correia^1*Sylvia Mary Draper²

• ¹Center for Structural Chemistry, Department of Chemical Engineering, Higher Technical Institute, University of Lisbon, Lisboa, Portugal
• ²School of Chemistry, Trinity College Dublin, Dublin, Ireland

The research topic exemplifies this progress, focusing on innovative strategies to address cancer, bacterial and fungal infections, and parasitic diseases, most of which demonstrate the shared role of metal-based compounds and redox modulation, in advancing therapeutic approaches in bioinorganic and bioorganic chemistry. Such developments highlight the critical role of interdisciplinary approaches in shaping and reshaping the landscape of medicinal chemistry. In this editorial we will briefly describe the area before focusing on the advances reported in the manuscripts included in this special issue. Additionally, the review highlights recent studies on the antifungal activity of Mn complexes, further showcasing their versatility as therapeutic agents.Parasitic diseases such as Chagas disease and Leishmaniasis are caused by closely related trypanosomatid protozoan parasites. These rely on insect vectors for transmission and predominantly affect marginalized population where they pose significant public health challenges and may be co-endemic in regions. The World Health Organization classifies them as neglected tropical diseases, largely due to socio-economic factors that limit pharmaceutical interest.The work of Dinorah Gambino and co-workers (ttps://doi.org/10.3389/fchbi.2023.1304571) stems from their ongoing search for metallodrugs based on vanadium for the treatment of Chagas disease and Leishmaniasis. In this work, the team presents heteroleptic oxidovanadium(IV) complexes containing two bidentate bioactive ligands: an 8hydroxyquinoline derivative and 2-mercaptopyridine N-oxide (mpo). Among them, [V IV O(L2-H)(mpo)], featuring a 5-chloro-7-iodo-8-hydroxyquinoline ligand, demonstrated selective activity against Trypanosoma cruzi trypomastigotes. The compound's mechanism of actionincluding oxidative stress induction and NADH-fumarate reductase inhibition -highlights its potential as a targeted antiparasitic agent. Metallomic analysis revealed preferential accumulation of the compound in the soluble protein fraction, with only small amounts localized in the DNA fraction, thereby excluding DNA as a primary target. The study underscores its promise for further development by elucidating the selective toxicity and vanadium uptake of this compound in mammalian cells.The study by Stefano Ciurli and colleagues. (https://doi.org/10.3389/fchbi.2023.1243564) delves into the activation mechanism of urease in Helicobacter pylori. This is a bacterium that uses a nickel-dependent enzyme to colonize the acidic environment of the human stomach.Urease activation requires the incorporation of Ni ions into its active site, a process facilitated by accessory proteins including UreD. The researchers employed an integrated approach combining evolutionary coupling analysis, site-directed mutagenesis, in-cell enzymatic assays, and computational docking to elucidate the interaction surface between urease and UreD.Their findings provide a detailed map of functional contacts essential for urease activation, offering potential targets for antimicrobial strategies aimed at inhibiting urease activity by disrupting these critical protein-protein interactions.The study demonstrates the power of combining computational prediction with experimental validation. By identifying key interaction sites between urease and its accessory protein UreD, the researchers successfully provide molecular insight into the molecular features that hamper H. pylori colonization by targeting urease activation. Such targeted interventions could be instrumental in treating infections caused by ureolytic pathogens, thereby addressing a significant public health concern. The work further demonstrates the importance of understanding metalloenzyme activation mechanisms and highlights how detailed molecular insights can help in the design of inhibitors that disrupt essential protein interactions, paving the way for innovative treatments against persistent bacterial infections.In summary these four articles highlight the strategic use of redox dynamics, metalloenzyme inhibition, and metal-based chemistry. They show how disrupting Trx in cancer cells, harnessing Mn's redox versatility, inducing oxidative stress in parasitic pathogens, and targeting urease activation in H. pylori can enhance therapeutic efficacy. The versatility of metal complex design in these examples provides opportunities to tune biological activity and highlights the importance of bioinorganic and bioorganic chemistry in modern drug discovery.Building on these findings, future research should focus on optimizing the pharmacological profiles of new and modified molecules. Expanding preclinical evaluations will be crucial to validate their efficacy and safety. Additionally, exploring synergies between redox modulation, metalloenzyme inhibition, and other therapeutic strategies will open new frontiers in disease management.