The guanidine core has been one of the most studied functional groups in medicinal chemistry, and guanylation reactions are powerful tools for synthesizing this kind of compound. In this study, a series of five guanidine-core small molecules were obtained through guanylation reactions. These compounds were then evaluated against three different strains of Escherichia coli, one collection strain from the American Type Culture Collection (ATCC) of E. coli ATCC 35218, and two clinical extended-spectrum beta-lactamase (ESBL)-producing E. coli isolates (ESBL1 and ESBL2). Moreover, three different strains of Pseudomonas aeruginosa were studied, one collection strain of P. aeruginosa ATCC 27853, and two clinical multidrug-resistant isolates (PA24 and PA35). Among Gram-positive strains, three different strains of Staphylococcus aureus, one collection strain of S. aureus ATCC 29213, and two clinical methicillin-resistant S. aureus (MRSA1 and MRSA2) were evaluated. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) experiments were reported, and the drop plate (DP) method was used to determine the number of viable suspended bacteria in a known beaker volume. The results from this assessment suggest that guanidine-core small molecules hold promise as therapeutic alternatives for treating infections caused by clinical Gram-negative and Gram-positive bacteria, highlighting the need for further studies to explore their potential. The results from this assessment suggest that the chemical structure of CAPP4 might serve as the basis for designing more active guanidine-based antimicrobial compounds, highlighting the need for further studies to explore their potential.

The modular synthesis of the guanidine core by guanylation reactions using commercially available ZnEt₂ as a catalyst has been exploited as a tool for the rapid development of antitumoral guanidine candidates. Therefore, a series of phenyl-guanidines were straightforwardly obtained in very high yields. From the in vitro assessment of the antitumoral activity of such structurally diverse guanidines, the guanidine termed ACB3 has been identified as the lead compound of the series. Several biological assays, an estimation of AMDE values, and an uptake study using Fluorescence Lifetime Imaging Microscopy were conducted to gain insight into the mechanism of action. Cell death apoptosis, induction of cell cycle arrest, and reduction in cell adhesion and colony formation have been demonstrated for the lead compound in the series. In this work, and as a proof of concept, we discuss the potential of the catalytic guanylation reactions for high-throughput testing and the rational design of guanidine-based cancer therapeutic agents.

Guanidine‐containing molecules represent a versatile class of nitrogen‐rich compounds whose unique structural and physicochemical features underpin a rich and tunable coordination chemistry. Their capacity to act as strong donor ligands, stabilize a variety of metal centers in different oxidation states, and access multiple coordination modes has established guanidine and guanidine‐like cores as pivotal components in medicinal inorganic chemistry. This review provides a focused overview of metallodrugs for antitumor applications in which guanidine or guanidine‐like ligands play a central role in metal coordination, highlighting how the coordination modes of the guanidine core translate into their application as anticancer metallodrugs. By correlating coordination mode, metal center, and ligand design with anticancer performance, this work underscores the potential of guanidine‐based ligand platforms for the development of next‐generation metal‐based therapeutics.

Head and neck squamous cell carcinoma (HNSCC) is a major oncological challenge due to its high recurrence rates, biological heterogeneity, and poor long-term survival outcomes. Despite advances in surgery and radiotherapy, chemotherapeutic options are limited. Cisplatin (CDDP) remains the mainstay, while small molecule inhibitors, such as the selective PI3K3CA; inhibitor Alpelisib, are still under clinical evaluation. However, systemic side effects and suboptimal tumor specificity hamper the clinical utility of both standard and novel specific therapies. In this study, we developed passive- and active-targeting liposomes encapsulating Cisplatin (CDDP) and Alpelisib. To achieve active targeting, the anti-epidermal growth factor receptor (EGFR) antibody Cetuximab was conjugated to the liposome surface. All formulations were characterized based on size, morphology, encapsulation efficiency, and drug release profiles. In vitro assays demonstrated that liposomal encapsulation preserved the cytotoxic effects of both CDDP and Alpelisib in HNSCC cell lines, with CDDP showing adequate encapsulation efficiency for in vivo evaluation. In vivo near-infrared fluorescence imaging demonstrated that active-targeting liposomes achieved greater tumor accumulation and a better tumor-to-spleen ratio compared to passive formulations. Tumor growth by CDDP-loaded active-targeting liposomes was comparable to that of the free drug, likely due to the hydrophilic nature and rapid release of CDDP from liposomes in physiological conditions. Importantly, blood chemistry analysis indicated a favorable toxicity profile for the targeted liposomal formulation. These findings highlight the potential of liposome-based targeted strategies to improve therapeutic outcomes in HNSCC and underscore the value of nanotechnology in the development of next-generation oncological therapies.

The straightforward catalytic synthesis of guanidine ligands has been evaluated as a strategy for rapidly developing ruthenium metallodrugs as antitumor agents. A series of structurally guanidine ligands, obtained via guanylation reactions, were used as scaffolds for generating RAPTA‐C derivatives. Consequently, a novel family of guanidine–ruthenium derivatives was synthesized, fully characterized, and assessed as potential alternatives to platinum‐based chemotherapy. Their antitumor activity was evaluated in vitro across various cancer cell lines, using RAPTA‐C and cisplatin as metallodrug controls. Two ruthenium–guanidine derivatives were identified as the most promising candidates, exhibiting IC ₅₀ values between 3 and 5 μM across multiple cancer cell lines. These compounds were selected for further investigation. Notably, their significant cytotoxicity in triple‐negative breast cancer (TNBC) cells suggests a mechanism of action independent of receptor status. In vitro experiments, such as cell cycle assessment, apoptosis detection, Matrigel invasion tests, and measurement of ROS production, corroborated this hypothesis. Compared to cisplatin and RAPTA‐C, the most promising ruthenium complexes, RuG3 and RuG8, demonstrated enhanced cytotoxicity across various cancer cell lines. As a proof of concept, fluorescence lifetime imaging microscopy (FLIM) was used to visualize the intracellular distribution of a luminescent derivative in MCF7 breast cancer cells. The results showed homogeneous cytoplasmic distribution, while the guanidine ligand contributed to increased stability. Furthermore, photophysical studies showed that in aqueous solution, the protonation of the guanidine group triggers the isomerization of the luminescent complex, yielding the active and more symmetrical species. Finally, in vivo safety studies in mice highlighted the potential of the selected compound as a promising candidate for further preclinical development in MIC. Overall, these findings provide valuable insights into the use of guanidines as ancillary ligands for designing new ruthenium‐based antitumor agents as an alternative to platinum‐based chemotherapy.