Vanadium(V) complexes derived from triphenylphosphonium and hydrazides: cytotoxicity evaluation and interaction with biomolecules.

The development of coordination compounds with antineoplastic therapeutic properties is currently focused on non-covalent interactions with deoxyribonucleic acid (DNA). Additionally, the interaction profiles of these compounds with globular plasma proteins, particularly serum albumin, warrant thorough evaluation. In this study, we report on the interactions between biomolecules and complexes featuring hydrazone-type imine ligands coordinated with vanadium. The potential to enhance the therapeutic efficiency of these compounds through mitochondrial targeting is explored. This targeting is facilitated by the derivatization of ligands with triphenylphosphonium groups. Thus, this work presents the synthesis, characterization, interactions, and cytotoxicity of dioxidovanadium(V) complexes (C1-C5) with a triphenylphosphonium moiety. These VV-species are coordinated to hydrazone-type iminic ligands derived from (3-formyl-4-hydroxybenzyl)triphenylphosphonium chloride ([AH]Cl) and aromatic hydrazides ([H2L1]Cl-[H2L5]Cl). The structures of the five complexes were elucidated through single-crystal X-ray diffraction and vibrational spectroscopies, confirming the presence of dioxidovanadium(V) species in various geometries with degrees of distortion (τ = 0.03-0.50) and highlighting their zwitterionic characteristics. The molecular structural stability of C1-C5 in solution was ascertained using 1H, 19F, 31P, and 51V-nuclear magnetic resonance. Moreover, their interactions with biomolecules were evaluated using diverse spectroscopic methodologies and molecular docking, indicating moderate interactions (Kb ≈ 104 M-1) with calf thymus DNA in the minor groove and with human serum albumin, predominantly in the superficial IB subdomain. Lastly, the cytotoxic potentials of these complexes were assessed in keratinocytes of the HaCaT lineage, revealing that C1-C5 induce a reduction in metabolic activity and cell viability through apoptotic pathways.

Controlled Pyrazole-Hydrazone Annulation: Regiodivergent Synthesis of 1H- and 2H-Pyrazolo[3,4-d]pyridazinones.

An efficient and controlled site-selective annulation of 3,5-diethoxycarbonyl 4-hydrazonyl pyrazoles is described. The relative proportion of the products is affected by hydrazone intermediate configuration, reaction temperature, and Lewis acid employed. At a temperature of 110-120 °C, the reaction preferentially afforded 1H-pyrazolo[3,4-d]pyridazin-7(6H)-ones, whereas using Yb(OTf)3 in MeCN reflux, 2H-pyrazolo[3,4-d]pyridazin-7(6H)-ones were favored. Computational investigations were performed to clarify the mechanism and the origin of the regiodivergence.

Antibacterial, antifungal, and anti-biofilm effects of sulfamethoxazole-complexes against pulmonary infection agents.

Antibiotic resistance associated with pulmonary infection agents has become a public health problem, being considered one of the main priorities for immediate resolution. Thus, to increase the therapeutic options in the fight against resistant microorganisms, the synthesis of molecules from pre-existing drugs has shown to be a promising alternative. In this sense, the present work reports the synthesis, characterization, and biological evaluation (against fungal and bacterial agents that cause lung infections) of potential metallodrugs based on sulfamethoxazole complexed with AuI, AgI, HgII, CdII, NiII, and CuII. The minimal inhibitory concentration (MIC) value was used to evaluate the antifungal and antibacterial properties of the compounds. In addition, it was also evaluated the antibiofilm capacity in Pseudomonas aeruginosa, through the quantification of its biomass and visualization using atomic force microscopy. For each case, molecular docking calculations were carried out to suggest the possible biological target of the assayed inorganic complexes. Our results indicated that the novel inorganic complexes are better antibacterial and antifungal than the commercial antibiotic sulfamethoxazole, highlighting the AgI-complex, which was able to inhibit the growth of microorganisms that cause lung diseases with concentrations in the 2-8 µg mL-1 range, probably at targeting dihydropteroate synthetase - a key enzyme involved in the folate synthesis. Furthermore, sulfamethoxazole complexes were able to inhibit the formation of bacterial biofilms at significantly lower concentrations than free sulfamethoxazole, probably mainly targeting the active site of LysR-type transcriptional regulator (PqsR). Overall, the present study reports preliminary results that demonstrate the derivatization of sulfamethoxazole with transition metal cations to obtain potential metallodrugs with applications as antimicrobial and antifungal against pulmonary infections, being an alternative for drug-resistant strains.

A Vanadium(V) complexes derived from pyridoxal/salicylaldehyde. Interaction with CT-DNA/HSA, and molecular docking assessments.

With the increasing development of metallopharmaceuticals, coordination compounds become viable alternatives for therapeutic uses. Despite the importance of platinum derivatives in this area, first-row transition metals complexes are welcome due to their characteristics. Vanadium is a promising metal in this context, as it has a range of compounds with different biological applications, including anticancer therapeutic effects. In this effort, the study of interactions between coordination compounds with deoxyribonucleic acid and with human serum albumin is fundamental. In this way, ten iminic ligands were synthesized by condensing p-substituted aromatic benzohydrazides (OH, CH3, H, NO2, and NH2) with salicylaldehyde (L1As-L5As) or pyridoxal hydrochloride (L1P-L5P). These ligands have characteristics that allow the tridentate coordination of vanadium cations, leading to the formation of ten vanadium(V) complexes (C1As-C5As and C1P-C5P) with different structural features, all characterized by single-crystal X-ray diffraction, UV-Vis and infrared spectroscopies, and cyclic voltammetry. In addition, the complexes were tested for their interactions with calf thymus deoxyribonucleic acid and human serum albumin by spectroscopic assays and molecular docking calculations. These new results can contribute to further research and provide different ways to design new vanadium complexes with biological applications.

Stereoselective Reduction of Alkynes: Synthesis of 4-Organoselenyl Quinolines.

This study describes the reaction of 2-amino arylalkynyl ketones with organoselenolates to form (Z)-vinyl selenides, which lead to 4-organoselenyl quinolines via an intramolecular condensation. Using the optimized reaction conditions, the generality of this cyclization was studied with various arylalkynyl ketones and diorganyl diselenides. The study of the reaction mechanisms led to the isolation and identification of a vinyl selenide, which was the key intermediate for this cyclization. To expand the structural diversity and to demonstrate the applicability of the 4-organoselenyl quinolines prepared, we studied their application as substrates in the cleavage of the carbon-selenium bond using n-butyllithium followed by the capture of the lithium intermediate by electrophiles and Suzuki and Sonogashira cross-coupling reactions.

Pyridoxal water-soluble cobalt(II) helicates: Synthesis, structural analysis, and interactions with biomacromolecules.

Helical complexes composed of organic ligand strands and metallic centers, called helicates, present interactions with biomacromolecules, such as deoxyribonucleic acid, as one of their main biological applications in bioinorganic chemistry. Despite the potential antineoplastic and antibacterial results of the interactions between helicates and biomacromolecules, there is still a gap of research in the literature, primarily in terms of solubility in aqueous media. In this study, we present the synthesis, structural analysis, and interaction with biomacromolecules of two water-soluble cobalt(II) double-stranded helicates: [CoII2L22][CoII(NCS)4]∙9H2O (C1) and [CoII2L42]Cl2∙11H2O (C2). These complexes are obtained from iminic ligands (L2 and L4) derived from pyridoxal, a vitamin B6 aldehyde derivative. Through spectroscopic assays, these helical complexes were shown to have weak and moderate binding capacities with calf-thymus deoxyribonucleic acid and human serum albumin, respectively. The theoretical assays suggest that C1 and C2 interact with the minor groove of deoxyribonucleic acid and have different main binding sites with human serum albumin. Furthermore, Van der Waals and hydrogen bonds were shown to be the main intermolecular forces for these C1-C2:biomacromolecules interactions.

Synthesis of 4-(organoselenyl) oxazolones via cyclization of N-alkynyl ethylcarbamates promoted by organoselenium.

Organoselenyl iodide promoted the intramolecular nucleophilic cyclization of N-alkynyl ethylcarbamates in the synthesis of 4-(organoselenyl) oxazolones. The reaction was regioselective, giving the five-membered oxazolone products as the unique regioisomer via an initial activation of the carbon-carbon triple bond through a seleniranium intermediate, followed by an intramolecular 5-endo-dig cyclization mode. The generality of the methodology has been proven by applying the optimized reaction conditions to different organoselenyl iodides and N-alkynyl ethylcarbamates having different substituents directly bonded to the nitrogen atom and in the terminal position of the alkyne.

Palladium-Catalyzed Cascade 5-endo-dig Cyclization of Ynamides to Form 4-Alkynyloxazolones.

The selective synthesis of 4-alkynyloxazolones and their further applications as substrates to electrophile-promoted nucleophilic cyclization have been developed. The reaction of ynamides with terminal alkynes proceeded smoothly to give 4-alkynyloxazolones in the presence of a catalytic amount of palladium(II) acetate. The products were obtained with the sequential formation of new C-C and C-O bonds via a cascade procedure. The first step involved a carbon-oxygen bond formation, via a 5-endo-dig closure, which was confirmed by X-ray analyses of the crystalline sample. Subsequently, the reaction of 4-alkynyloxazolones with an electrophilic selenium source gave 3-phenylselanyl benzofuran derivatives via an electrophile-promoted nucleophilic cyclization.

Molecular docking, quorum quenching effect, antibiofilm activity and safety profile of silver-complexed sulfonamide on Pseudomonas aeruginosa.

Microbial infections caused by sessile microorganisms are known to be a more challenging issue than infections caused by the same microorganisms in the planktonic state. Pseudomonas aeruginosa is an opportunistic pathogen and biofilm-forming agent. This species presents intense cellular communication mediated by signaling molecules. This process is known as quorum sensing (QS) and induces the transcription of specific genes that favors cell density growth and three-dimensional bacterial grouping. In this context, the discovery of compounds capable of inhibiting the action of the QS signaling molecules seems to be a promising strategy against biofilms. This work aimed to evaluate the anti-biofilm action and the in vitro safety profile of a sulfamethoxazole-Ag complex. The results obtained indicate potential anti-biofilm activity through QS inhibition. In silico tests showed that the compound acts on the las and pqs systems, which are the main regulators of biofilm formation in P. aeruginosa. Additionally, the molecule proved to be safe for human peripheral blood mononuclear cells.

Helical water-soluble NiII complexes with pyridoxal ligand derivatives: Structural evaluation and interaction with biomacromolecules.

This article deals with the synthesis of Schiff-based bis-azomethine-based ligands derived from pyridoxal and aliphatic dihydrazides and the synthesis of nickel(II) complexes C1-C4. The synthesized complexes had their structures elucidated by monocrystal X-ray diffraction and were characterized by vibrational and absorption spectroscopy. The synthesized ligands have characteristics that allow the formation of self-assembly processes, thus, the flexibility or rigidity of the coordination of organic molecules added to the orbitals of the NiII cation leads to the formation of helical complexes with double helix and a dinucler nickel(II) complex. Moreover, compounds was their interactions with CT-DNA and HSA absorption and emission analysis and molecular docking calculations.

Diorganyl Diselenides and Iron(III) Chloride Drive the Regio- and Stereoselectivity in the Selenation of Ynamides.

We report here our results on the application of ynamides as substrates in the reactions with diorganyl dichalcogenides and iron(III) chloride to give selectively three different types of compounds: E-α-chloro-ß-(organoselenyl)enamides, 4-(organochalcogenyl)oxazolones, and vinyl tosylates. The results reveal that the selectivity in the formation of products was obtained by controlling the functional groups directly bonded to the nitrogen atom of the ynamides. Thus, α-chloro-ß-(organoselenyl) enamide derivatives were exclusively obtained when the TsN- and MsN-ynamides were treated with a mixture of diorganyl diselenides (1.0 equiv) and FeCl3 (3.0 equiv) in dichloroethane (DCE, 3 mL), at room temperature. The 4-(organochalcogenyl)oxazolones were selectively obtained with ynamides having an ester group, directly bonded to the nitrogen atom, upon treatment with a solution of FeCl3 (1.5 equiv) and diorganyl dichalcogenides (1.0 equiv) in dichloromethane (3 mL) at room temperature. Finally, vinyl tosylates were obtained from ynamides having an ester group, directly bonded to the nitrogen atom, by reaction with p-toluenesulfonic acid. We also studied the application of the prepared compounds as substrates for Suzuki and Sonogashira cross-coupling reactions.

1,2-Addition to trifluoromethylated ß-enamino diketones: regioselective synthesis of trifluoromethyl-containing azomethine pyrazoles and isoxazoles.

A simple and efficient methodology for highly regioselective synthesis of azomethine pyrazoles and isoxazoles containing a trifluoromethyl group is reported. The cyclocondensation of trifluoromethylated ß-enamino diketones (TBED) with phenylhydrazine and hydroxylamine hydrochloride, in the presence of BF3, provided 5-aryl-4-[(tert-butyl)iminomethyl]-3-trifluoromethylazoles by aza-Michael-type 1,2-addition. The scope of the reaction was expanded by transimination with arylamines in a one-pot method starting from TBED. Thus, 83 novel 4-[(alkyl/aryl)iminomethyl]-3-trifluoromethylazoles were obtained with high regioselectivity and in yields of 51 to 89%.

SOD activity of new copper II complexes with ligands derived from pyridoxal and toxicity in Caenorhabditis elegans.

This work presents the synthesis, characterization of copper(II) complexes (C1-C6) and the potential of these compounds to mimic the catalytic activity of the enzyme superoxide dismutase (SOD). The copper(II)complexes were obtained by reaction between the aldol condensation between substituted aromatic hydrazides and aromatic aldehydes (salicylic aldehyde and pyridoxal hydrochloride), forming two new ligands (L1 to L6), resulting in new dimeric dicopper (II) complexes (C1 and C2), new three monomeric CuII derivatives (C3, C4 and C6) and a polymeric complex (C5). The CuII complexes were fully characterized by X-ray diffraction, spectroscopic and electrochemical analysis. Subsequently, CuII derivatives were evaluated for their antioxidant activities, using the NBT (Nitro blue tetrazolium chloride) photoreduction methodology. After evaluating the antioxidant activity in vitro, it was observed that the best inhibition rates of the superoxide ion are associated to the C4 and C5 complexes. Computational analysis via molecular docking and quantum chemical calculation (Fukui map) offered a molecular level explanation on the biological activity of CuII complexes. Additionally, cytotoxicity of C1-C6 was tested in the first time in vivo in nematodes Caenorhabditis elegans, corroborating with the results identified for C4 and C5.

In vitro tyrosinase, acetylcholinesterase, and HSA evaluation of dioxidovanadium (V) complexes: An experimental and theoretical approach.

The present study reports the biological evaluation of vanadium(V) complexes (1-3) against three different proteins: tyrosinase, acetylcholinesterase (AChE), and human serum albumin (HSA), which were studied by spectroscopic techniques and molecular docking. Despite the synthesis and characterization of complexes 1 and 2 having already previously described, complex 3 is a novel dioxidovanadium(V) derivative. Complex 1 can activate both tyrosinase and AChE enzymes in about 11.5 and 47.0%, respectively. On the other hand, complexes 2 and 3 inhibited the same enzymes (1.30 and 46.0% for tyrosinase and 20.0 and 21.9% for AChE, respectively). Molecular docking calculations suggested that the presence of the hydroxyl group in complex 1 is essential to activate tyrosinase enzymes. According to theoretical analysis, hydrogen bonding, van der Waals, and hydrophobic forces are the main binding interactions for each V(V) complex and AChE. Moreover, the interaction between HSA and vanadium(V) complexes occurs via ground-state association, being only enthalpically driven for complexes 1 and 2 and entropically and enthalpically driven for complex 3. The interaction is spontaneous for all samples and the binding modes do not perturb significantly the secondary and surface structures of the albumin. As there are few reported cases in the literature that explore vanadium complexes against these three proteins, the present results may contribute to future studies by offering different scaffolds to design new vanadium(V) complexes in the hyperpigmentation process and Alzheimer's disease.

Synthesis of 3-(Organochalcogen) Chalcogenazolo Indoles via Cascade Cyclization of N-Alkynylindoles.

A transition metal-free one-pot, three-steps protocol combining N-alkynylindoles, n-butyllithium, elemental selenium, and an electrophile source was developed to allow the synthesis of 3-(organoselanyl) selenazolo indoles. Substrate scope was studied by varying the structure of N-alkynylindoles and the electrophile source. This sequential reaction proceeded selectively through an initial intramolecular 5- endo-dig mode with two new carbon-selenium bonds formation in a one-pot procedure. The reaction conditions were also compatible with elemental sulfur and tellurium, which led to construct 3-(alkylthio) thiazolo indoles and 3-(alkyltelluro) tellurazolo indoles, respectively. In addition, it was also demonstrated that a series of dichalcogenides derived from chalcogenazoloindoles ring could be easily prepared via oxidation of chalcogenolate anion in contact with air.

Sulfamethoxazole derivatives complexed with metals: a new alternative against biofilms of rapidly growing mycobacteria.

Biofilms are considered important sources of infections on biomedical surfaces, and most infections involving biofilm formation are associated with medical device implants. Therefore, there is an urgent need for new antimicrobial compounds that can combat microbial resistance associated with biofilm formation. In this context, this work aimed to evaluate the antibiofilm action of sulfamethoxazole complexed with Au, Cd, Cu, Ni and Hg on rapidly growing mycobacteria (RGM), as well as to evaluate their safety through cytotoxic assays. The results demonstrate potentiation of the novel compounds in antibiofilm activity, mainly in the complex with Au, which was able to completely inhibit biofilm formation and had the capacity to destroy the biofilm at all the concentrations tested. All cytotoxic data suggest that the majority of sulfamethoxazole metallic derivatives are antimicrobial alternatives, as well as safe molecules, which could be used as potential therapeutic agents for bacterial and biofilm elimination.

Electrophilic Cyclization Involving Carbon-Selenium/Carbon-Halide Bond Formation: Synthesis of 3-Substituted Selenophenes.

The butylselanyl propargyl alcohols reacted with iodine to afford 3-iodoselenophenes. The change of nucleophile position from propargyl to homopropargyl was crucial for the aromatization and formation of selenophene rings. The experiments revealed that bromine and N-bromosuccinimide were not able to cyclize the butylselanyl propargyl alcohols; however, when the bromine source was copper(II) bromide the corresponding 3-bromoselenophenes were obtained in good yields. In addition, the reaction of butylselanyl propargyl alcohols with diorganyl diselenides catalyzed by copper(I) iodide gave the 3-(organoselanyl)selenophenes. The reaction took place with aromatic rings substituted by either electron-donating or -withdrawing groups in the alkynes and propargyl positions. The steric effects of substituents were dominant in determining the yields, whereas electronic effects had only a minor influence. Furthermore, by monitoring the reaction by 1H NMR, we were able to identify the key intermediate, which supported the elaboration of a proposed reaction mechanism. The 3-iodoselenophenes prepared allowed the synthesis of multifunctional selenophenes via application in metal-catalyzed coupling reactions, such as Sonogashira, Ullmann and Suzuki type reactions.

New insights into the SAR and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against Mycobacterium tuberculosis.

2-(Quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (MIC) values against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains in the submicromolar range. Furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they showed intracellular activities similar to those of isoniazid and rifampin in a macrophage model of Mtb infection. Use of the checkerboard method to investigate the association profiles of lead compounds with first- and second-line antituberculosis drugs showed that 2-(quinolin-4-yloxy)acetamides have a synergistic effect with rifampin. Ultimately, the good permeability, moderate rates of metabolism and low risk of drug-drug interactions displayed by some of the synthesized compounds indicate that 2-(quinolin-4-yloxy)acetamides may yield candidates to use in the development of novel alternative therapeutics for tuberculosis treatment.

2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains.

2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 µM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 µM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 µM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.

Synthesis and biological evaluation of 2-picolylamide-based diselenides with non-bonded interactions.

In this paper, we report the synthesis and biological evaluation of picolylamide-based diselenides with the aim of developing a new series of diselenides with O···Se non-bonded interactions. The synthesis of diselenides was performed by a simple and efficient synthetic route. All the products were obtained in good yields and their structures were determined by 1H-NMR, 13C-NMR and HRMS. All these new compounds showed promising activities when tested in different antioxidant assays. These amides exhibited strong thiol peroxidase-like (TPx) activity. In fact one of the compounds showed 4.66 times higher potential than the classical standard i.e., diphenyl diselenide. The same compound significantly inhibited iron (Fe)-induced thiobarbituric acid reactive species (TBARS) production in rat's brain homogenate. In addition, the X-ray structure of the most active compound showed non-bonded interaction between the selenium and the oxygen atom that are in close proximity and may be responsible for the increased antioxidant activity. The present study provides evidence about the possible biochemical influence of nonbonding interactions on organochalcogens potency.