ABSTRACT: Four platinum(II) rollover cyclometalated complexes derived from 2,2’-bipyridine N-oxide (bpyNO), [Pt(bpyNOH)(DMSO)Me] (1a), [Pt(bpyNO-H)(PPh3)Me] (2a), [Pt(bpyNOH)(DMSO)Cl] (3a), and [Pt(bpyNO-H)(PPh3)Cl] (4a), were synthesized, characterized, and evaluated for their antimicrobial and cytotoxic activities. The electron-poor nature of bpyNO enables rollover C−H bond activation at room temperature. NMR and Xray analysis (4a) revealed distinctive features, including an intramolecular interaction between the H3′ hydrogen and the Noxide oxygen. A correlation between the direct 195Pt−31P coupling constant and the donating properties of cyclometalated ligands has been found, allowing a useful scale of donor properties. A preliminary screening of antimicrobial activity against E. coli, K. pneumoniae, S. aureus multidrug resistant (MDR), S. pyogenes, P. aeruginosa, and C. albicans demonstrated selective activity. Complex 3a showed the most promising results against E. coli and multidrug-resistant S. aureus. Significantly, the complexes also exhibited biofilm inhibitory behavior; notably, complex 1a showed activity against K. pneumoniae. Additionally, preliminary cytotoxicity tests on human tumor (HT29) cells and normal (CCD 841 CoN) cells were performed. Among the investigated compounds, 1a, 2a, and 3a exhibited a significant reduction in tumor cell viability, whereas complex 4a displayed moderate activity. These results establish 2,2’-bipyridine N-oxide as a promising ligand scaffold for developing platinum complexes. ■ INTRODUCTION Over recent decades, coordination compounds of transition metals have assumed a key role in several scientific and industrial fields.1 Based on the knowledge gained in this area, it is often possible, by adapting the stereoelectronic properties of coordinated ligands, to fine-tune the chemical and physical properties of a complex to target a specific functionality or application. Because of their high tunability, transition-metal complexes are used as advanced materials,2,3 in catalysis,4 and in medicinal chemistry.5,6 In the latter context, metal complexes are currently in clinical development for the treatment of cancer, malaria, and neurodegenerative diseases, while less attention has been paid to their application as antimicrobial agents.7 However, this field of application is gaining increasing attention due to the emerging global health threat of antimicrobial resistance (AMR) and multidrug resistance (MDR). As evidenced by the WHO, due to the use and overuse of antimicrobial drugs over the last century, several classes of microorganisms have evolved, developing resistance to commonly used antimicrobial drugs, so that the return to a preantibiotic era has become a realistic scenario.8 Most of the molecules currently under clinical development are merely derivatives of commercial antibiotics, with the consequence that they will likely be rendered ineffective by existing resistance mechanisms. Transition-metal complexes are extensively investigated for both antimicrobial and anticancer applications. This dual screening approach is often employed to probe how the electronic and structural properties of metal centers can be tuned to interact with distinct biological targets. While the challenge of achieving selectivity between bacterial and cancer cells is significant, understanding the fundamental mechanisms of metal-based cytotoxicity in these different systems is a critical step in the rational design of more specific and potent therapeutic agents.9 The rollover cyclometalated Pt(II) Received: March 30, 2026 Revised: June 26, 2026 Accepted: June 30, 2026 Published: July 14, 2026 pubs.acs.org/Organometallics Article © 2026 The Authors. Published by American Chemical Society 1698 https://doi.org/10.1021/acs.organomet.6c00114 Organometallics 2026, 45, 1698−1711 This article is licensed under CC-BY 4.0 Downloaded from http://pubs.acs.org/orgnd7/article-pdf/45/14/1698/65920804/acs.organo
Pt(II) Rollover Cyclometalated Complexes Supported by 2,2’-Bipyridine N-Oxide: Synthesis, Characterization, and Biological Evaluation
Germano Orru;Sara FaisPenultimo
;Alessandra Scano
Ultimo
2026-01-01
Abstract
ABSTRACT: Four platinum(II) rollover cyclometalated complexes derived from 2,2’-bipyridine N-oxide (bpyNO), [Pt(bpyNOH)(DMSO)Me] (1a), [Pt(bpyNO-H)(PPh3)Me] (2a), [Pt(bpyNOH)(DMSO)Cl] (3a), and [Pt(bpyNO-H)(PPh3)Cl] (4a), were synthesized, characterized, and evaluated for their antimicrobial and cytotoxic activities. The electron-poor nature of bpyNO enables rollover C−H bond activation at room temperature. NMR and Xray analysis (4a) revealed distinctive features, including an intramolecular interaction between the H3′ hydrogen and the Noxide oxygen. A correlation between the direct 195Pt−31P coupling constant and the donating properties of cyclometalated ligands has been found, allowing a useful scale of donor properties. A preliminary screening of antimicrobial activity against E. coli, K. pneumoniae, S. aureus multidrug resistant (MDR), S. pyogenes, P. aeruginosa, and C. albicans demonstrated selective activity. Complex 3a showed the most promising results against E. coli and multidrug-resistant S. aureus. Significantly, the complexes also exhibited biofilm inhibitory behavior; notably, complex 1a showed activity against K. pneumoniae. Additionally, preliminary cytotoxicity tests on human tumor (HT29) cells and normal (CCD 841 CoN) cells were performed. Among the investigated compounds, 1a, 2a, and 3a exhibited a significant reduction in tumor cell viability, whereas complex 4a displayed moderate activity. These results establish 2,2’-bipyridine N-oxide as a promising ligand scaffold for developing platinum complexes. ■ INTRODUCTION Over recent decades, coordination compounds of transition metals have assumed a key role in several scientific and industrial fields.1 Based on the knowledge gained in this area, it is often possible, by adapting the stereoelectronic properties of coordinated ligands, to fine-tune the chemical and physical properties of a complex to target a specific functionality or application. Because of their high tunability, transition-metal complexes are used as advanced materials,2,3 in catalysis,4 and in medicinal chemistry.5,6 In the latter context, metal complexes are currently in clinical development for the treatment of cancer, malaria, and neurodegenerative diseases, while less attention has been paid to their application as antimicrobial agents.7 However, this field of application is gaining increasing attention due to the emerging global health threat of antimicrobial resistance (AMR) and multidrug resistance (MDR). As evidenced by the WHO, due to the use and overuse of antimicrobial drugs over the last century, several classes of microorganisms have evolved, developing resistance to commonly used antimicrobial drugs, so that the return to a preantibiotic era has become a realistic scenario.8 Most of the molecules currently under clinical development are merely derivatives of commercial antibiotics, with the consequence that they will likely be rendered ineffective by existing resistance mechanisms. Transition-metal complexes are extensively investigated for both antimicrobial and anticancer applications. This dual screening approach is often employed to probe how the electronic and structural properties of metal centers can be tuned to interact with distinct biological targets. While the challenge of achieving selectivity between bacterial and cancer cells is significant, understanding the fundamental mechanisms of metal-based cytotoxicity in these different systems is a critical step in the rational design of more specific and potent therapeutic agents.9 The rollover cyclometalated Pt(II) Received: March 30, 2026 Revised: June 26, 2026 Accepted: June 30, 2026 Published: July 14, 2026 pubs.acs.org/Organometallics Article © 2026 The Authors. Published by American Chemical Society 1698 https://doi.org/10.1021/acs.organomet.6c00114 Organometallics 2026, 45, 1698−1711 This article is licensed under CC-BY 4.0 Downloaded from http://pubs.acs.org/orgnd7/article-pdf/45/14/1698/65920804/acs.organo
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