Coordination of azol(in)ium dithiocarboxylate ligands to Au(III): unexpected formation of a novel family of cyclometallated Au(III) complexes, DFT calculations and catalytic studies.

A series of cyclometallated gold(III) complexes 21-27 of general formula [Au(dppta)(azdtc)Cl] (dppta = N,N-diisopropyl-P,P-diphenylphosphinothioic amide-κ2C,S; azdtc = azol(in)ium-2-dithiocarboxylate-κ1S) were prepared and characterized by spectroscopic and diffractometric techniques. Treatment of [Au(dppta)(azdtc)Cl] complexes with methanol led to their quantitative transformation into a novel family of (C^S, S^S)-cyclometallated gold(III) complexes of general formula [Au(dppta)(azmtd)] (azmdt = azol(in)ium-2-(methoxy)methanedithiol-κ2S,S) 28-34. All the [Au(dppta)(azdtc)Cl] complexes 21-27 catalyzed the alkylation of indoles, whereas [Au(dppta)(azmtd)] complexes 28-34 were inactive. Among the synthesized derivatives, complex 22 displayed the highest catalytic activity, leading to a series of functionalized indoles in excellent yields.

Heteroleptic (S

Despite the increasingly widespread clinical impact of adenovirus (HAdV) infections in healthy individuals and the associated high morbidity in immunosuppressed patients, particularly among the paediatric population, a specific treatment for this virus has yet to be developed. In this study, we report the anti-HAdV activity of sub-micromolar concentrations of four heteroleptic (C^S)-cycloaurated complexes bearing a single thiophosphinamide [Au(dpta)Cl2, Au(dpta)(mrdtc), and Au(dpta)(dedtc)] or thiophosphonamide [Au(bpta)(dedtc)] chelating ligand and a dithiocarbamate moiety. In addition to their low cytotoxicity, the findings of mechanistic assays revealed that these molecules have antiviral activity by targeting stages of the viral replication cycle subsequent to DNA replication. Additionally, all four compounds showed a significant inhibition of human cytomegalovirus (HCMV) DNA replication, thereby providing evidence for potential broad-spectrum antiviral activity.

Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights.

Introduction: Antimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate. Methods and results: The Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity. Discussion: Overall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action.

Effect of culture conditions at lab-scale on metabolite composition and antibacterial and antibiofilm activities of Dunaliella tertiolecta.

Dunaliella tertiolecta RCC6 was cultivated indoors in glass bubble column photobioreactors operated under batch and semi-continuous regimens and using two different conditions of light and temperature. Biomass was harvested by centrifugation, frozen, and then lyophilized. The soluble material was obtained by sequential extraction of the lyophilized biomass with solvents with a gradient of polarity (hexane, ethyl acetate, and methanol) and its metabolic composition was investigated through nuclear magnetic resonance (NMR) spectroscopy. The effect of light on chlorophyll biosynthesis was clearly shown through the relative intensities of the 1 H NMR signals due to pheophytins. The highest signal intensity was observed for the biomasses obtained at lower light intensity, resulting in a lower light availability per cell. Under high temperature and light conditions, the 1 H NMR spectra of the hexane extracts showed an incipient accumulation of triacylglycerols. In these conditions and under semi-continuous regimen, an enhancement of ß-carotene and sterols production was observed. The antibacterial and antibiofilm activities of the extracts were also tested. Antibacterial activity was not detected, regardless of culture conditions. In contrast, the minimal biofilm inhibitory concentrations (MBICs) against Escherichia coli for the hexane extract obtained under semi-continuous regimen using high temperature and irradiance conditions was promising.

Gold(III) Complexes Activity against Multidrug-Resistant Bacteria of Veterinary Significance.

The emergence and spread of multidrug-resistant bacteria are a global concern. The lack of new antibiotics in the pipeline points to the need for developing new strategies. In this sense, gold(III) complexes (G3Cs) could be a promising alternative due to their recently described antibacterial activity. The aim of this study was to evaluate the antimicrobial activity of G3Cs alone and in combination with colistin against pathogenic bacteria from veterinary sources. Minimal inhibitory concentration (MIC) values were determined by broth microdilution and compared with clinically relevant antibiotics. Antibiofilm activity was determined by crystal violet staining. Combinations of selected G3Cs with colistin and cytotoxicity in commercial human cell lines were evaluated. Four and seven G3Cs showed antibacterial effect against Gram-negative and Gram-positive strains, respectively, with this activity being higher among Gram-positive strains. The G3Cs showed antibiofilm activity against Gram-negative species at concentrations similar or one to four folds higher than the corresponding MICs. Combination of G3Cs with colistin showed a potential synergistic antibacterial effect reducing concentrations and toxicity of both agents. The antimicrobial and antibiofilm activity, the synergistic effect when combined with colistin and the in vitro toxicity suggest that G3Cs would provide a new therapeutic alternative against multidrug-resistant bacteria from veterinary origin.

Synthesis of the cyanobacterial halometabolite Chlorosphaerolactylate B and demonstration of its antimicrobial effect in vitro and in vivo.

Chlorosphaerolactylate B, a newly discovered antimicrobial halometabolite from the cyanobacterium Sphaerospermopsis sp. LEGE 00249 has been synthesized in three steps by using 12-bromododecanoic acid as starting material. A total of 0.5 g was produced for in vitro and in vivo antimicrobial efficacy testing. In vitro, the minimal inhibitory concentration (MIC) was estimated to be 256 mg/L for Staphylococcus aureus, while the minimal biofilm inhibitory concentration (MBIC) was estimated to be 74 mg/L. The in vivo study utilized a porcine model of implant-associated osteomyelitis. In total, 12 female pigs were allocated into 3 groups based on inoculum (n = 4 in each group). An implant cavity (IC) was drilled in the right tibia and followed by inoculation and insertion of a steel implant. All pigs were inoculated with 10 µL containing either: 11.79 mg synthetic Chlorosphaerolactylate B + 104 CFU of S. aureus (Group A), 104 CFU of S. aureus (Group B), or pure saline (Group C), respectively. Pigs were euthanized five days after inoculation. All Group B animals showed macroscopic and microscopic signs of bone infection and both tissue and implant harbored S. aureus bacteria (mean CFU on implants = 1.9 × 105). In contrast, S. aureus could not be isolated from animals inoculated with saline. In Group A, two animals had a low number of S. aureus (CFU = 6.7 × 101 and 3.8 × 101, respectively) on the implants, otherwise all Group A animals were similar to Group C animals. In conclusion, synthetic Chlorosphaerolactylate B holds potential to be a novel antimicrobial and antibiofilm compound.

Synthesis of Optically Active syn- and anti-Chlorohydrins through a Bienzymatic Reductive Cascade.

A bienzymatic cascade has been designed and optimized to obtain enantiopure chlorohydrins starting from the corresponding 1-aryl-2-chlorobut-2-en-1-ones. For the synthesis of these α-chloroenones, a two-step sequence was developed consisting of the allylation of the corresponding aldehyde with 3-dichloroprop-1-ene, followed by oxidation and further isomerization. The selective cooperative catalytic system involving ene-reductases (EREDs) and alcohol dehydrogenases (ADHs) afforded the desired optically active chlorohydrins under mild reaction conditions in excellent conversions (up to >99%) and selectivities (up to >99:1 diastereomeric ratio (dr), >99% enantiomeric excess (ee)).

Gold-Derived Molecules as New Antimicrobial Agents.

Antimicrobial resistance is considered one of the three most important health problems by the World Health Organization. The emergence and spread of an increasing number of antimicrobial-resistant microorganisms make this a worldwide problem. Antibiotic-resistant bacteria are estimated to be the cause of 33,000 deaths in Europe and 700,000 worldwide each year. It is estimated that in 2050 bacterial infections will cause 10 million deaths across the globe. This problem is concomitant with a decrease in the investment and, therefore, the discovery and marketing of new antibiotics. Recently, there have been tremendous efforts to find new effective antimicrobial agents. Gold complexes, with their broad-spectrum antimicrobial activities and unique modes of action, are particularly relevant among several families of derivatives that have been investigated. This mini review revises the role of gold-derived molecules as antibacterial agents.

A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria.

The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 µM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents.

Polyhydroxylated Cyclopentane ß-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides.

A stereoselective synthesis of polyhydroxylated cyclopentane ß-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic ß-amino acids into peptides is also reported.

Microalgae and Cyanobacteria Strains as Producers of Lipids with Antibacterial and Antibiofilm Activity.

Lipids are one of the primary metabolites of microalgae and cyanobacteria, which enrich their utility in the pharmaceutical, feed, cosmetic, and chemistry sectors. This work describes the isolation, structural elucidation, and the antibiotic and antibiofilm activities of diverse lipids produced by different microalgae and cyanobacteria strains from two European collections (ACOI and LEGE-CC). Three microalgae strains and one cyanobacteria strain were selected for their antibacterial and/or antibiofilm activity after the screening of about 600 strains carried out under the NoMorFilm European project. The total organic extracts were firstly fractionated using solid phase extraction methods, and the minimum inhibitory concentration and minimal biofilm inhibitory concentration against an array of human pathogens were determined. The isolation was carried out by bioassay-guided HPLC-DAD purification, and the structure of the isolated molecules responsible for the observed activities was determined by HPLC-HRESIMS and NMR methods. Sulfoquinovosyldiacylglycerol, monogalactosylmonoacylglycerol, sulfoquinovosylmonoacylglycerol, α-linolenic acid, hexadeca-4,7,10,13-tetraenoic acid (HDTA), palmitoleic acid, and lysophosphatidylcholine were found among the different active sub-fractions selected. In conclusion, cyanobacteria and microalgae produce a great variety of lipids with antibiotic and antibiofilm activity against the most important pathogens causing severe infections in humans. The use of these lipids in clinical treatments alone or in combination with antibiotics may provide an alternative to the current treatments.

Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 is not available yet. Moreover, since new and deadly CoVs can emerge at any time with the potential of becoming pandemics, the development of therapeutic agents against potentially deadly CoVs is a research area of much current interest. In the search for anti-coronaviral drugs, researchers soon turned their heads towards glycosylated flavonoids. Glycosyl flavonoids, widespread in the plant kingdom, have received a lot of attention due to their widely recognized antioxidant, anti-inflammatory, neuroprotective, anticarcinogenic, antidiabetic, antimicrobial, and antiviral properties together with their capacity to modulate key cellular functions. The wide range of biological activities displayed by glycosyl flavonoids, along with their low toxicity, make them ideal candidates for drug development. In this review, we examine and discuss the up-to-date developments on glycosyl flavonoids as evidence-based natural sources of antivirals against coronaviruses and their potential role in the management of COVID-19.

Modern Synthetic Methods for the Stereoselective Construction of 1,3-Dienes.

The 1,3-butadiene motif is widely found in many natural products and drug candidates with relevant biological activities. Moreover, dienes are important targets for synthetic chemists, due to their ability to give access to a wide range of functional group transformations, including a broad range of C-C bond-forming processes. Therefore, the stereoselective preparation of dienes have attracted much attention over the past decades, and the search for new synthetic protocols continues unabated. The aim of this review is to give an overview of the diverse methodologies that have emerged in the last decade, with a focus on the synthetic processes that meet the requirements of efficiency and sustainability of modern organic chemistry.

New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-trihydroxycyclopen-tane-1-carboxylic acid: Synthesis and Structural Study.

We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural ß-amino acid incorporated into the peptidomimetic.

Chlorosphaerolactylates A-D: Natural Lactylates of Chlorinated Fatty Acids Isolated from the Cyanobacterium Sphaerospermopsis sp. LEGE 00249.

Four natural lactylates of chlorinated fatty acids, chlorosphaerolactylates A-D (1-4), were isolated from the methanolic extract of the cyanobacterium Sphaerospermopsis sp. LEGE 00249 through a combination of bioassay-guided and MS-guided approaches. Compounds 1-4 are esters of (mono-, di-, or tri)chlorinated lauric acid and lactic acid, whose structures were assigned on the basis of spectrometric and spectroscopic methods inclusive of 1D and 2D NMR experiments. High-resolution mass-spectrometry data sets also demonstrated the existence of other minor components that were identified as chlorosphaero(bis)lactylate analogues. The chlorosphaerolactylates were tested for potential antibacterial, antifungal, and antibiofilm properties using bacterial and fungal clinical isolates. Compounds 1-4 showed a weak inhibitory effect on the growth of Staphylococcus aureus S54F9 and Candida parapsilosis SMI416, as well as on the biofilm formation of coagulase-negative Staphylococcus hominis FI31.

Ionic Liquids and Ohmic Heating in Combination for Pd-catalyzed Cross-coupling Reactions: Sustainable Synthesis of Flavonoids.

In order to meet the increasing demand for environmentally benign chemical processes, we developed a Suzuki-Miyaura reaction protocol based on the combination of ohmic heating (ΩH) and supported ionic liquid phase catalysis (SILPC) in aqueous media. This methodology was applied to the synthesis of a series of flavonoid derivatives, including isoflavones, styrylisoflavones, and diarylalkenylisoflavones.

Chemotaxonomic Profiling Through NMR1.

A metabolite screening of cyanobacteria was performed by nuclear magnetic resonance (NMR) analysis of the soluble material obtained through sequential extraction of the biomass with three different extractive ability solvents (hexane, ethyl acetate, and methanol). Twenty-five strains from the Coimbra Collection of Algae (ACOI) belonging to different orders in the botanical code that represent three subsections of the Stainer-Rippka classification were used. The 1 H NMR spectra of hexane extracts showed that only two strains of Nostoc genus accumulated triacylglycerols. Monogalactosyldiacylglycerols and digalactosyldiacylglycerols were the major components of the ethyl acetate extracts in a mono- to digalactosyldiacylglycerols ratio of 4.5 estimated by integration of the signals at δ 3.99 and 3.94 ppm (sn3 glycerol methylene). Oligosaccharides of sucrose and mycosporine-like amino acids, among other polar metabolites, were detected in the methanolic extracts. Strains of Nostocales order contained heterocyst glycolipids, whereas sulphoquinovosyldiacylglycerols were absent in one of the studied strains (Microchaete tenera ACOI 1451). Phosphathidylglycerol was identified as the major phospholipid in the methanolic extracts together with minor amounts of phosphatidylcholine based on 1 H, 31 P 2D correlation experiments. Chemotaxonomic information could be easily obtained through the analysis of the δ 3.0-0.5 ppm (fatty acid distribution) and δ 1.2-1.1 ppm (terminal methyl groups of the aglycons in heterocyst glycolipids) regions of the 1 H NMR spectra of the ethyl acetate and methanol extracts, respectively.

Temperature-Controlled Stereodivergent Synthesis of 2,2'-Biflavanones Promoted by Samarium Diiodide.

In this work, the first example of a radical stereodivergent reaction directed towards the stereoselective synthesis of both (R*,R*)- and (R*,S*)-2,2'-biflavanones promoted by samarium diiodide is reported. Control experiments showed that the selectivity of this reaction was exclusively controlled by the temperature. It was possible to generate a variety of 2,2'-biflavanones bearing different substitution patterns at the aromatic ring in good-to-quantitative yields, being both stereoisomers of the desired compounds obtained with total or high control of selectivity. A mechanism that explains both the generation of the corresponding 2,2'-biflavanones and the selectivity is also discussed. The structure and stereochemistry determination of each isomer was unequivocally elucidated by single-crystal X-ray diffraction experiments.

NMR characterization and evaluation of antibacterial and antiobiofilm activity of organic extracts from stationary phase batch cultures of five marine microalgae (Dunaliella sp., D. salina, Chaetoceros calcitrans, C. gracilis and Tisochrysis lutea).

The chemical composition of five marine microalgae (Dunaliella sp., Dunaliella salina, Chaetoceros calcitrans, Chaetoceros gracilis and Tisochrysis lutea) was investigated through nuclear magnetic resonance (NMR) spectroscopic study of the soluble material obtained by sequential extraction with hexane, ethyl acetate (AcOEt) and methanol of biomass from stationary phase cultures. Hexane extracted the major lipids present in the microalgae during the stationary phase of growth, which correspond to storage lipids. Triacylglycerols (TGs) were the only storage lipids produced by Dunaliella and Chaetoceros. In contrast, T. lutea predominantly stored polyunsaturated long-chain alkenones, with sterols also detected as minor components of the hexane extract. The molecular structure of brassicasterol was determined in T. lutea and the presence of squalene in this sample was also unequivocally detected. Monogalactosyldiacylglycerols (MGDGs) and pigments were concentrated in the AcOEt extracts. C. calcitrans and D. salina constituted an exception due to the high amount of TGs and glycerol produced, respectively, by these two strains. Chlorophylls a and b and ß-carotene were the major pigments synthesized by Dunaliella and chlorophyll a and fucoxanthin were the only pigments detected in Chaetoceros and T. lutea. Information concerning the acyl chains present in TGs and MGDGs as well as the positional distribution of acyl chains on the glycerol moiety was obtained by NMR analysis of hexane and AcOEt extracts, with results consistent with those expected for the genera studied. Fatty acid composition of TGs in the two Dunaliella strains was different, with polyunsaturated acyl chains almost absent in the storage lipids produced by D. salina. Except in C. calcitrans, the polar nature of soluble compounds was inferred through the relative extraction yield using methanol as the extraction solvent. Glycerol was the major component of this fraction for the Dunaliella strains. In T. lutea 1,4/2,5-cyclohexanetetrol (CHT) and dimethylsulfoniopropionate (DMSP) preponderated. CHT was also the major polyol present in the Chaetoceros strains in which DMSP was not detected, but prominent signals of 2,3-dihydroxypropane-1-sulfonate (DHSP) were observed in the 1H NMR spectra of methanolic extracts. The presence of DHSP confirms the production of this metabolite by diatoms. In addition, several other minor compounds (digalactosyldiacyglycerols (DGDGs), sulphoquinovosyldiacylglycerols (SQDGs), amino acids, carbohydrates, scyllo-inositol, mannitol, lactic acid and homarine) were also identified in the methanolic extracts. The antibacterial and antibiofilm activities of the extracts were tested. The AcOEt extract from C. gracilis showed a moderate antibiofilm activity.

Immobilized Gold Nanoparticles Prepared from Gold(III)-Containing Ionic Liquids on Silica: Application to the Sustainable Synthesis of Propargylamines.

A cycloaurated phosphinothioic amide gold(III) complex was supported on amorphous silica with the aid of an imidazolium ionic liquid (IL) physisorbed in the SiO2 pores (SiO2⁻IL) and covalently bonded to the SiO2 (SiO2@IL). Gold(0) nanoparticles (AuNPs) were formed in situ and subsequently immobilized on the SiO2⁻IL/SiO2@IL phase. The resulting catalytic systems Au⁻SiO2⁻IL and Au⁻SiO2@IL promoted the solvent-free A³ coupling reaction of alkynes, aldehydes, and amines in high yields under solvent-free conditions with very low catalyst loading and without the use of additives. The Au⁻SiO2@IL catalyst showed good recyclability and could be reused at least five times with yields of propargylamines of ≥80%. This synthetic method provides a green and low cost way to effectively prepare propargylamines. Additionally, 31P high resolution magic angle spinning (HRMAS) NMR spectroscopy is introduced as a simple technique to establish the Au loading of the catalyst.