Antimicrobial Activity of Copper(II), Nickel(II) and Zinc(II) Complexes with Semicarbazone and Thiosemicarbazone Ligands Derived from Substituted Salicylaldehydes

Antibiotic resistance is a problem repeatedly reported by health authorities. Metalloantibiotics, i.e., biologically active compounds containing one or more metal ions, can be an important resource in the fight against bacteria and fungi. Here, we report the results obtained with a panel of copper(II), nickel(II) and zinc(II) complexes with thiosemicarbazone, semicarbazone and acylhydrazone ligands on Staphylococcus aureus, Escherichia coli and Candida albicans, taken as model systems of human pathogens. To increase the solubility in water, the sulfonic group was introduced on some of the ligands, isolating them as sodium salts (NaH2L4-NaH2L7). Complexes 1–14 were isolated, fully characterized and the X-ray structures of 11, 12 and 13 were obtained. While all the ligands have no antimicrobial activity, the copper(II) complexes 1 and 4 and the nickel(II) complex 2, obtained from thiosemicarbazone ligands, showed good activity, in particular against S. aureus; these complexes were investigated in depth, calculating their respective IC50 values (4.2 μM, 3.5 μM and 61.8 μM, respectively). It should be noted that nickel(II) complex 2 does not show hemolytic activity and has a favorable SI value. While all the copper(II) complexes completely degraded the plasmid DNA in presence of H2O2, nickel(II) complex 2 cleaved the plasmid DNA leading to the formation of the relaxed nicked conformation, thus suggesting a different mechanism of action

Studies on the Effect of Diamine Elongation in Copper(II) Complexes with NNO Tridentate Schiff Base Ligands

The copper(II) complexes of general formula [Cu(GL2H,H)(Cl)] (A4–A6, G = NO2, H and OMe, respectively), bearing NNO tridentate Schiff base ligands (GL2H,H)− derived from the mono-condensation of 1,3-diaminopropane and G-substituted salicylaldehydes, are here reported. The elongation of the diamine with one additional carbon atom with respect to the triad derived from ethylenediamine [Cu(GL1H,H)(Cl)] (A1–A3, G = NO2, H and OMe, respectively) led to different synthetic procedures, with the difficult isolation of A6 that could be obtained only in few crystals suitable for X-ray diffractions. Operating in acidic conditions to promote the coordination of chloride and expulsion of pyridine from the complex [Cu(GL2H,H)(py)](ClO4) (G = NO2) allows for obtaining A4. On the other hand, structural rearrangement occurs when G = H, yielding the dinuclear species [Cu2(μ-saltn)(HL2H,H)](ClO4)⋅0.5MeOH (D5⋅0.5MeOH) instead of the desired A5, which can be obtained by avoiding the use of HCl and operating in the excess of LiCl. Finally, A4 and A5 were investigated as cytotoxic agents against malignant (MDA-MB-231 and 22-Rv1) and healthy (HaCaT) cell lines, and the ability of the most promising A5 to be internalized and interact with cellular targets was studied

Sisters in structure but different in character, some benzaldehyde and cinnamaldehyde derivatives differentially tune Aspergillus flavus secondary metabolism

Great are the expectations for a new generation of antimicrobials, and strenuous are the research efforts towards the exploration of diverse molecular scaffolds—possibly of natural origin – aimed at the synthesis of new compounds against the spread of hazardous fungi. Also high but winding are the paths leading to the definition of biological targets specifically fitting the drug’s structural characteristics. The present study is addressed to inspect differential biological behaviours of cinnamaldehyde and benzaldehyde thiosemicarbazone scaffolds, exploiting the secondary metabolism of the mycotoxigenic phytopathogen Aspergillus flavus. Interestingly, owing to modifications on the parent chemical scaffold, some thiosemicarbazones displayed an increased specificity against one or more developmental processes (conidia germination, aflatoxin biosynthesis, sclerotia production) of A. flavus biology. Through the comparative analysis of results, the ligand-based screening strategy here described has allowed us to delineate which modifications are more promising for distinct purposes: from the control of mycotoxins contamination in food and feed commodities, to the environmental management of microbial pathogens, to the investigation of specific structure–activity features for new generation drug discovery

Interaction Studies between Carbonic Anhydrase and a Sulfonamide Inhibitor by Experimental and Theoretical Approaches

The most used approaches in structure-based drug design possess peculiar characteristics with advantages and limitations, and thus the management of complementary data from various techniques is of particular interest to synergistically achieve the development of effective enzyme inhibitors. In this Letter, we describe the application of experimental and computational techniques to study the interactions between human carbonic anhydrases and sulfonamide inhibitors. In particular, a series of affinity-labeled carbonic anhydrase inhibitors containing sulfonamido photoprobes was designed and synthesized, and one of these compounds, a benzophenone derivative, was chosen as a model photoprobe/inhibitor. A photoaffinity labeling method followed by mass spectrometry analysis was then applied to elucidate the inhibitor binding site, and a comparison with X-ray crystallography and molecular dynamics simulation data was carried out, highlighting that to have a comprehensive view of the protein/inhibitor complex stabilization all three kinds of experiments are necessary

The aflatox® project: Approaching the development of new generation, natural‐based compounds for the containment of the mycotoxigenic phytopathogen Aspergillus flavus and aflatoxin contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre‐ and post‐harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox® Project was aimed at the development of new‐generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti‐aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi‐genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem

Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease

The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site

Conformational changes of retinal exchanger probed with flash photolysis of novel Ca-caged compounds

3noneMORIONDO A.; ROGOLINO D; RISPOLI GMoriondo, Andrea; Rogolino, D; Rispoli, G