Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First InVivo{In Vivo} Experiments

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex $\textbf{Pt1}$ significantly reduces fungal load in an in vivoG. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases

(E)-(1-(4-ethoxycarbonylphenyl)-5-(3,4-dimethoxyphe nyl)-3-(3,4-dimethoxystyryl)-2-pyrazoline: Synthesis, characterization, dna-interaction, and evaluation of activity against drug-resistant cell lines

(E)-1-(4-Ethoxycarbonylphenyl)-5-(3,4-dimethoxyphenyl)-3-(3,4-dimethoxystyryl)-2-pyrazoline was synthesized via the cyclization reaction between the monocarbonyl curcuminoid (2E,6E)-2,6-bis(3,4-dimethoxybenzylidene)acetone and ethyl hydrazinobenzoate in high yield and purity (>95% by High-performance liquid chromatography (HPLC)). The compound has been fully characterized by1H,13C NMR, FTIR, UV-Vis and HRMS and its activity was evaluated in terms of its potential interaction with DNA as well as its cytotoxicity against resistant and non-resistant tumor cells. Both DNA thermal denaturation and DNA viscosity measurements revealed that a significant intercalation binding takes place upon treatment of the DNA with the synthesized pyrazoline, causing an increase in melting temperature by 3.53 ± 0.11 °C and considerable DNA lengthening and viscosity increase. However, neither re-sensitisation of Doxorubicin (DO X)-resistant breast cancer and multidrug resistance (MDR) reversal nor synergistic activity with DOX by potentially increasing the DOX cell killing ability was observed. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Palladium(II) and platinum(II) complexes of derivatives of 2-(4′-aminophenyl)benzothiazole as potential anticancer agents

The synthesis, structural characterization and in vitro biological evaluation of two 2-(4′-aminophenyl)benzothiazole based ligands and their corresponding Pd(II) and Pt(II) complexes is reported. Their design was based on the selective anticancer action of phenylbenzothiazole in conjunction with the cytotoxicity of the metallic center, aiming at targeted and synergistic effectiveness of the complexes as anticancer agents. All compounds were fully characterized with IR, NMR and MS analysis and their binding to CT-DNA was investigated by UV–Vis spectroscopy, fluorescence, circular dichroism, viscometry, and thermal denaturation. The data indicate that both ligands interact with CT-DNA via a combined mode of action involving both groove binding and non-classical intercalation, while in the case of the complexes covalent bond formation takes place as well. The in vitro cytotoxicity and cell uptake studies in human breast carcinoma cell line (MCF-7 and MDA-MB-231) as well as in healthy human skin fibroblasts (DSF) show uptake of the intact complexes by cancer cells and increased activity against cancer cell lines. © 2016 Elsevier B.V

Oleuropein, an anti-oxidant polyphenol constituent of olive promotes α-Secretase cleavage of the amyloid precursor protein (AβPP)

Over the past decade, intense focus has been dedicated on investigating processes involved in the proteolysis of amyloid precursor protein (AβPP) and β-amyloid (Aβ) peptide metabolism, as possible targets for Alzheimer's disease (AD) therapy. To this goal, considerable research has been targeted on potential therapeutic use of compounds promoting non-amyloidogenic processing of AβPP. One of these compounds, oleuropein, a polyphenol constituent of extra virgin olive oil exhibiting a wide range of pharmacological properties, was shown to interact non-covalently with Aβ, an interaction that might be related to a potential protective role of oleuropein against Aβ aggregation. In the present study, it was demonstrated that oleuropein treatment of HEK293 cells stably transfected with the isoform 695 of human AβPP (APP695) leads to markedly elevated levels of sAPPα and to significant reduction of Aβ oligomers. These effects were associated with increased activity of matrix metalloproteinase 9 (MMP-9), whereas no significant alterations in the expression of secretases TACE, ADAM-10 or BACE-1 were observed. Similar results were obtained using the human neuroblastoma cell line SK-N-SH. The experimental data reveal an anti-amyloidogenic effect of oleuropein and suggest a possible protective role for oleuropein against AD, extending the spectrum of beneficial properties of this naturally occurring polyphenol. © 2012 Springer Science+Business Media New York

Synthesis of Novel Pyrazolo[3,4-b]pyridines with Affinity for β-Amyloid Plaques

Three novel pyrazolo[3,4-b]pyridines were synthesized via the cyclization of 5-amino-1-phenylpyrazole with the corresponding unsaturated ketone in the catalytic presence of ZrCl4. The ketones were afforded by modifying a stabilized ylide facilitated Wittig reaction in fairly high yields. The novel compounds exhibited exciting photophysical properties with the dimethylamine phenyl-bearing pyrazolopyridine showing exceptionally large Stoke’s shifts. Finally, both the dimethylamino-and the pyrene-substituted compounds demonstrated high and selective binding to amyloid plaques of Alzheimer’s disease (AD) patient brain slices upon fluorescent confocal microscopy observation. These results reveal the potential application of pyrazolo[3,4-b]pyridines in the development of AD amyloid plaque probes of various modalities for AD diagnosis. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Synthesis and structural characterization of neutral "3+2" oxorhenium and oxotechnetium complexes of the 2-mercaptoethyl-N-glycine (SNO)/2,2 '-bipyridine (NN) mixed ligand system

Neutral. hexacoordinated "3 + 2" mixed ligand oxorhenium (1) and oxotechnetium (2) complexes of the general formula MO [SNO][NN]. where M = Re or Tc-99, SNO is 2-mercaptoethyl-N-glycine and NN is 2,2'-bipyridine (bpy), were synthesized by simultaneous action of the tridentate SNO and the bidentate NN ligand on ReOCl3(PPh3)(2) or (TcO)-Tc-99-gluconate precursors in a 1: 1: 1 molar ratio. Both complexes were characterized by elemental analysis, IR and NMR spectroscopy. X-ray structure determination of rhenium complex I revealed a distorted octahedral coordination geometry where the SNO donor atoms of the tridentate ligand and one bpy nitrogen atom occupy the equatorial positions of the octahedron, whereas the second bpy nitrogen atom and the oxo-group fill the apical positions. (c) 2007 Elsevier B.V. All rights reserved

Curcumin derivatives as potential mosquito larvicidal agents against two mosquito vectors, culex pipiens and aedes albopictus

Vector-borne diseases have appeared or re-emerged in many Southern Europe countries making the transmission of infectious diseases by mosquitoes (vectors) one of the greatest worldwide health threats. Larvicides have been used extensively for the control of Aedes (Stegomyia) albopictus (Skuse, 1895) (Diptera: Culicidae) and Culex pipiens Linnaeus, 1758 (Diptera: Culicidae) mosquitoes in urban and semi-urban environments, causing the increasing resistance of mosquitoes to commercial insecticides. In this study, 27 curcuminoids and monocarbonyl curcumin derivatives were synthesised and evaluated as potential larvicidal agents against Cx. pipiens and Ae. albopictus. Most of the compounds were more effective against larvae of both mosquito species. Four of the tested compounds, curcumin, demethoxycurcumin, curcumin-BF2 complex and a monocarbonyl tetramethoxy curcumin derivative exhibited high activity against both species. In Cx. pipiens the recorded LC50 values were 6.0, 9.4, 5.0 and 32.5 ppm, respectively, whereas in Ae. albopictus they exhibited LC50 values of 9.2, 36.0, 5.5 and 23.6 ppm, respectively. No conclusive structure activity relationship was evident from the results and the variety of descriptors values generated in silico provided some insight to this end. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

New labeled derivatives of the neuroprotective peptide colivelin: Synthesis, characterization, and first in vitro and in vivo applications

Colivelin (CL), first reported in 2005, is the most potent member of the humanin family of neuroprotective peptides with in vitro and in vivo rescuing action against insults associated with Alzheimer's disease (AD). The objective of the present work is the design, synthesis and characterization of specific CL derivatives that can be used as molecular probes in the investigation of the unknown mechanism of CL action. Within this framework, three CL derivatives bearing suitable tags, i.e., the fluorescent moiety FITC, the streptavidin-counterpart biotinyl-group, and the 99mTc-radiometal chelating unit dimethylGly-Ser-Cys, were developed and subsequently applied in biological evaluation experiments. Specifically, the FITC-labeled derivative of CL was used in confocal microscopy, where specific binding at the periphery of F11 cells was observed; the biotin-labeled derivative of CL was used in an in-house developed ELISA-type assay, where specific and concentration-dependent binding with the β-amyloid peptide of AD was shown; finally, the 99mTc-radiolabeled derivative of CL was used in in vivo biodistribution studies in healthy Swiss Albino mice, where 0.58% of the radioactivity administered was measured in the mouse brain 2 min after injection. The above first successful applications of the CL probes demonstrate their potential to contribute in the field of neuroprotective peptides. © 2015 Elsevier Inc. All rights reserved

Synthesis of hydroxyapatite, β-Tricalcium phosphate and biphasic calcium phosphate particles to act as local delivery carriers of curcumin: Loading, release and in vitro studies

The successful synthesis of hydroxyapatite (HA), β-Tricalcium phosphate (β-TCP) and two biphasic mixtures (BCPs) of the two was performed by means of wet precipitation. The resulting crystals were characterized and the BCP composition was analyzed and identified as 13% HA-87% TCP and 41% HA-59% TCP. All samples were treated with curcumin solutions, and the degree of curcumin loading and release was found to be proportional to the TCP content of the ceramic. No further cytotoxicity was observed upon MG-63 treatment with the curcumin-loaded ceramics. Finally, the alkaline phosphatase activity of the cells was found to increase with increasing content of TCP, which provides an encouraging proof of concept for the use of curcumin-loaded synthetic biomaterials in bone remodeling. © 2018 by the authors