Alberto Aragón-Muriel

Background/Objectives: The development of new metallodrugs has represented an important milestone in recent years for their potential application in different therapeutic approaches. Therefore, the objective of this study was to synthesize a series of P^N iminophosphine Pd(II) complexes (1Pd–3Pd) incorporating different aliphatic amines. Methods: All complexes were characterized using several spectroscopic and analytical techniques, including ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectroscopy, mass spectrometry, FT-IR spectroscopy, and elemental analysis. In addition, complex 3Pd was unambiguously characterized by single-crystal X-ray diffraction. Results: Supramolecular studies allowed the main noncovalent interactions responsible for stabilizing the crystal lattice of complex 3Pd to be identified. These interactions were analyzed using Hirshfeld surface analysis, which revealed that C-H···π and C-H···Cl interactions contributed most significantly to the stabilization of the crystal lattice. All complexes exhibited stability in different solvents and positive lipophilicity values, with complex 3Pd displaying the highest hydrophobicity. Through in vitro studies, the minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of all complexes were determined against different Gram-positive and Gram-negative bacterial strains, as well as fungal strains of Candida species. Complex 3Pd exhibited the highest activity, particularly against L. monocytogenes (1.17 µg/mL), P. aeruginosa (4.68 µg/mL), and all fungal strains (18.75 µg/mL), displaying both bactericidal and fungicidal activity. Furthermore, in silico studies enabled the identification of the potential modes of action of the complexes against different molecular targets present in the bacterial and fungal strains. Conclusions: These results demonstrate the efficacy of the three synthesized complexes against different virulent strains exhibiting resistance to broad-spectrum drugs. Furthermore, the presence of the metal center, together with the incorporation of increasingly longer aliphatic chains, appears to enhance the antibacterial and antifungal activity of the complexes.

The antimicrobial resistance of Acinetobacter baumannii necessitates the development of novel therapeutic strategies targeting essential enzymes such as Undecaprenyl Pyrophosphate Phosphatase (UppP). This study explored spider venom peptides in silico as potential allosteric inhibitors of A. baumannii UppP. A systematic literature review was conducted to select eight α-helical peptides with reported anti-A. baumannii activity, followed by their computational physicochemical characterization. Three-dimensional models of A. baumannii UppP and the candidate peptides were generated, and a putative allosteric binding site was validated through molecular docking of a known inhibitor of the BacA homolog. The eight peptides were subsequently docked to this validated site using HADDOCK. Results revealed variable binding affinities; peptides LC-AMP-I1, Lycosin-II, and GK37 exhibited the most favorable HADDOCK scores and extensive interaction networks, consistent with their reported high antimicrobial potency. Other candidates, notably Lt-MAP2, showed low binding affinity but high predicted synergistic potential. These findings identify promising spider venom peptide candidates, suggesting dual (membrane disruption/UppP inhibition) or synergistic mechanisms of action, and validate UppP as a viable pharmacological target for peptide-based inhibitors.

Background and Objectives: While nisin exhibits promising antitumor properties, its clinical utility is hindered by pharmacokinetic instability and rapid enzymatic degradation. This systematic review evaluates the critical role of advanced pharmaceutical formulations and targeted nanosystems in overcoming these limitations to enhance nisin’s cytotoxic and pro-apoptotic efficacy in vitro. Methods: Following PRISMA guidelines, a comprehensive search was conducted across six electronic databases (PubMed, ScienceDirect, Scopus, Web of Science, SpringerLink, and DOAJ). In vitro studies comparing free nisin against polymeric, metallic, and cyclodextrin-based nanocarriers across diverse neoplastic lineages were included. Methodological quality was assessed using the SciRAP 2.1 tool, and a within-line comparative analysis was performed for MDA-MB-231 and HT-29 models. Results: Twelve studies met the inclusion criteria. A definitive technological inflection point was identified: nisin-loaded nanosystems reduced effective concentrations by up to 2706-fold relative to the free peptide in MDA-MB-231 cells, and 71-fold in A549 lung cancer cells. Mechanistically, nanosystems facilitated membrane pore formation, mitochondrial-mediated apoptosis via Bax/Bcl-2 modulation, caspase 3/7/9 activation, and p53 reactivation. Three previously underreported mechanistic dimensions were identified: TWIST1 downregulation and FZD7 binding in hepatocellular carcinoma, and downregulation of CEA, CEAM6, MMP2F, and MMP9F in colorectal cancer lines. Conclusions: The therapeutic viability of nisin in oncology is strictly dependent on pharmaceutical engineering. Future research must prioritize in vivo pharmacokinetic validation, experimental confirmation of novel mechanistic targets, and standardized nisin purity reporting to consolidate its clinical translation.

Two heteroaromatic hybrid compounds were synthesized and characterized using various analytical techniques. The results indicate that the benzimidazole/oxadiazole (BZ/OZ) metal derivative exhibits a tridentate coordination mode, where the carbonyl, imidazole and oxadiazole groups participate in coordination with the metal, in a ratio of 2:1 of the ligand to the metal. The antibacterial activities of the organic ligand and its metal complex were determined by in vitro tests against both Gram-positive bacterial strains and Gram-negative bacterial strains using the broth microdilution method. The metal complex showed greater antibacterial activities compared to the precursor ligand against all evaluated microorganisms. The results obtained through in silico predictions revealed significant toxicological differences among the analyzed molecules, suggesting special attention in the use of the ligand due to its possible carcinogenicity in mice and a need for structural modifications in the complex to reduce its carcinogenicity and toxicity. Furthermore, a biophysical study of the interaction of the BZ/OZ derivatives with different model membranes was explored through differential scanning calorimetry (DSC), simultaneous small- and wide-angle X-ray diffraction (SAXD and WAXD) and infrared spectroscopy (FT-IR). The results indicate that the compounds influenced membrane properties without significantly altering the lamellar organization. The findings suggest potential applications in understanding lipid interactions, elucidating toxicology and developing antibacterial agents.

Their demonstrable bioactive characteristics, coupled with their wide structural diversity and coordination versatility, render Schiff bases and their coordination complexes biologically active compounds demonstrating outstanding properties. This research describes the synthesis and characterization of new Cu(II) and Ni(II) complexes with an NNO-donor hydrazone ligand (HL). The crystal structure of the HL ligand was determined through single-crystal X-ray diffraction studies. The in vitro antibacterial activities of the HL ligand and its metal(II) complexes against Gram-positive and Gram-negative bacteria demonstrated that the metal(II) complexes displayed greater antimicrobial activities compared to the free Schiff base ligand. Furthermore, the interaction of the ligand and the complexes with calf thymus DNA (CT-DNA) was explored through electronic absorption and viscosity measurements, suggesting intercalation as the most likely mode of binding. The compounds promoted oxidative DNA cleavage, as demonstrated by the strand breaks of the pmChery plasmid under oxidative stress conditions. Finally, fluorescence spectroscopy also revealed the strong binding affinity of these compounds for bovine serum albumin (BSA).

Background: Prostate cancer is the most common cancer in men, especially after the age of 50. It is a malignant disease that is increasing due to the increased life expectancy of the world population. Its development and progression are dependent on androgenic stimulation. Objectives: This study aimed to identify potential inhibitors with anti-prostate cancer activity through the application of chemoinformatics tools, exploring the Princeton (~1.2 million compounds) and Zinc Drug (~175 million compounds) databases. Methods: The methodology used several computational techniques, such as ROCS (Rapid Chemical Structure Superposition) and EON (Electrostatic Potential Screening), predictions of pharmacokinetic and toxicological properties, molecular docking, synthetic accessibility, biological activity, and molecular dynamics. Results: At the end of all these virtual screening steps, the study resulted in four promising potential candidates for the treatment of prostate cancer: the molecules ZINC34176694, ZINC03876158, ZINC04097308, and ZINC03977981, which exhibited all the desirable pharmacokinetic parameters (ADME/Tox) for a potential drug. Conclusions: Docking and molecular dynamics studies demonstrate stability and interaction with the androgen receptor of the selected compounds, showing them to be promising candidates for the development of new drugs.

Benzimidazoles are considered a promising class of bioactive heterocyclic compounds that show a wide variety of useful biological properties due to their structural similarities to nucleotides such as purines. Among these properties, great attention has been given to the antibacterial activity exhibited by molecules containing a benzimidazole nucleus in their structure since recent research results have shown the potential of such molecules as alternatives in the fight against bacterial resistance. When these compounds have phenylsubstituted groups in the 2-position of the imidazole ring, a series of molecules can be obtained with generally improved pharmacological activity. These types of compounds are suitable for the formation of stable complexes with several transition metals, including nickel and copper; such compounds have also exhibited many biological properties in different reports. Accordingly, this brief review focuses on recent work on the synthesis and characterization of metal complexes of Ni(II) and Cu(II) with ligands derived from 2-(phenylsubstituted) benzimidazole that were subsequently evaluated for antibacterial activity.

In recent years, metallodrugs have emerged as captivating and promising compounds in the fields of cancer therapy and antimicrobial agents. While noble metals have shown remarkable biological activity, increasing interest lies in utilizing more abundant and cost-effective metals in medicinal chemistry. This is primarily due to their pivotal role in biological processes and their lower cost compared to precious metals. Among these, copper(II) complexes have emerged with promising applications in medicine. Notably, copper compounds bearing Schiff bases stand out as innovative metallodrugs. They exhibit intriguing cytotoxic properties against a wide range of cancer cell lines, while also demonstrating inhibitory effects on prevalent bacterial and fungal strains. Nevertheless, research into Cu(II) complexes with Schiff bases remains of paramount interest. One strategic avenue to bolster their biological activity involves the introduction of fluorine groups into the ligands. This approach has demonstrated a significant augmentation in efficacy and selectivity, particularly in targeting cancer cells and microbial pathogens, because fluorine incorporation can improve metabolic stability and cellular uptake. This further reinforces the therapeutic potential of these metallodrugs. Thanks to these promising outcomes, research into the development of Cu(II) complexes with fluorinated Schiff bases is advancing significantly. This holds immense potential for progressing the field of medicinal chemistry, with the aim of addressing unmet clinical needs in both cancer therapy and antimicrobial treatment. This review comprehensively explores the latest advancements in Cu(II) complexes bearing fluorinated Schiff bases, encompassing diverse coordination modes. It delves into their scope and applications in cytotoxic evaluations, as well as their efficacy as antimicrobial and antifungal agents.

The synergistic combination of vanadium and pincer ligands produces complexes with potential antidiabetic, antibacterial, antiviral, antiparasitic, and anticancer activities with enhanced stability, improved bioavailability, and greater specificity.

Antimicrobial resistance threatens the effective prevention and treatment of an increasingly broad spectrum of infections caused by pathogenic microorganisms. This pressing challenge has intensified the search for alternative antibiotics with new pharmacological properties. Due to the chemical synergy between the biological activity of antimicrobial peptides (AMPs) and the different modes of action, catalytic properties, and redox chemistry of metal complexes, metallopeptides have emerged in recent years as an alternative to conventional antibiotics. In the present investigation, peptide ligands conjugated with 5-carboxy-1,10-phenanthroline (Phen) were prepared by solid-phase peptide synthesis (SPPS), and the corresponding copper(II) metallopeptides, Cu-PhenKG and Cu-PhenRG (where K = lysine, R = arginine, and G = glycine), were synthesized and characterized. The antimicrobial activities of these compounds toward Gram-positive and Gram-negative bacteria, evaluated by the broth microdilution technique, indicate that the metal center in the metallopeptides increases the antimicrobial activity of the complexes against the conjugated peptide ligands. Minimum inhibitory concentration (MIC) values of 0.5 μg/mL for S. aureus with the Cu-PhenKG complex and 0.63 μg/mL for S. typhimurium with the Cu-PhenRG complex were obtained. The MIC values found for the conjugated peptides in all microorganisms tested were greater than 1.5 μg/mL. The interactions of the conjugated peptides and their metallopeptides with plasmid DNA were evaluated by agarose gel electrophoresis. Alterations on the replication machinery were also studied by polymerase chain reaction (PCR). The results indicate that the complexes interact efficiently with pBR322 DNA from E. coli, delaying the band shift. Furthermore, the resulting DNA–metallopeptide complex is not a useful template DNA because it inhibits PCR, since no PCR product was detected. Finally, molecular dynamics and molecular docking simulations were performed to better understand the interactions of the obtained compounds with DNA. The Cu-PhenRG complex shows a significantly higher number of polar interactions with DNA, suggesting a higher binding affinity with the biopolymer.