The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone ...derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure–activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme–inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood–brain barrier permeability, thus being a valid candidate for subsequent animal studies.
Antibacterial resistance poses a critical public health threat, challenging the prevention and treatment of bacterial infections. The search for innovative antibacterial agents has spurred ...significant interest in quaternary heteronium salts (QHSs), such as quaternary ammonium and phosphonium compounds as potential candidates. In this study, a library of 49 structurally related QHSs was synthesized, varying the cation type and alkyl chain length. Their antibacterial activities against
, including antibiotic-resistant strains, were evaluated by determining minimum inhibitory/bactericidal concentrations (MIC/MBC) ≤ 64 µg/mL. Structure-activity relationship analyses highlighted alkyl-triphenylphosphonium and alkyl-methylimidazolium salts as the most effective against
CECT 976. The length of the alkyl side chain significantly influenced the antibacterial activity, with optimal chain lengths observed between C
and C
. Dose-response relationships were assessed for selected QHSs, showing dose-dependent antibacterial activity following a non-linear pattern. Survival curves indicated effective eradication of
CECT 976 by QHSs at low concentrations, particularly compounds
,
, and
. Moreover, in vitro human cellular data indicated that compounds
,
, and
showed favourable safety profiles at concentrations ≤ 2 µg/mL. These findings highlight the potential of these QHSs as effective agents against susceptible and resistant bacterial strains, providing valuable insights for the rational design of bioactive QHSs.
6-Bromochromone-2-carboxylic acid (
) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base/number of reagent ...equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds
-
) were obtained with good yields (54-93%). Only in the case of the nitro substituent (compound
), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.
The synthetic power of the recently developed cascade annulations of β‐(hetero)aryl‐α‐nitro‐α,β‐enals with the pyrrolidine‐derived enamine of 2,2‐dimethyl‐1,3‐dioxan‐5‐one is demonstrated by the ...first convergent route to (±)‐tetrodotoxin.
A batch preparation (11 g) of the protected nitrocyclitol 7 and its capability to sustain a convergent formal synthesis of (±)‐tetrodotoxin in only 26 steps illustrate the practicability of the formal 3+3 annulation ofβ‐heteroaryl‐α‐nitro‐α,β‐enals as well as its versatility for the synthesis of natural products containing highly oxygenated cyclohexanes.
Recent studies have shown that besides the well-known T3 (triiodothyronine) and T4 (thyroxine) there might be other important thyroid hormones, in particular T0AM (thyronamine) and T1AM ...(3-iodothyronamine). The absence of a large number of studies showing their precise importance might be explained by the limited number of analytical methodologies available. This work aims to show an electroanalytical alternative making use of electropolymerized molecularly imprinted polymer (MIPs). The MIPs' polymerization is performed on the surface of screen-printed carbon electrodes (SPCEs), using 4–aminobenzoic acid (4-ABA) as the building and functional monomer and the analyte T0AM as the template. The step-by-step construction of the SPCE-MIP sensor was studied by cyclic voltammetry (CV) and by electrochemical impedance spectroscopy (EIS). After optimization, by means of square-wave voltammetry, the SPCE-MIP showed suitable selectivity (in comparison with other thyroid hormones and catechol amines), repeatability (intra-day of 3.9%), a linear range up to 10 μmol L−1 (0.23 × 103 μg dL−1) with an r2 of 0.998 and a limit of detection (LOD) and quantification (LOQ) of 0.081 and 0.27 μmol L−1 (1.9 and 6.2 μg dL−1), respectively.
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•First time a sensor was developed for T0AM (thyronamine);•Electroanalytical methodology for T0AM;•Molecularly imprinted polymers (MIPs) were developed for T0AM;•MIPs' polymerization (4–aminobenzoic acid to a poly(4-aminobenzoic acid) film) occurred in the surface of screen-printed carbon electrodes (SPCEs);•The SPCE-MIP selectively analyzed T0AM by square-wave voltammetry (SWV).
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The infections by multidrug-resistant bacteria are a growing threat to human health, and the efficacy of the available antibiotics is gradually decreasing. As such, new antibiotic ...classes are urgently needed.
This study aims to evaluate the antimicrobial activity, safety and mechanism of action of phytochemical-based triphenylphosphonium (TPP+) conjugates.
A library of phytochemical-based TPP+ conjugates was repositioned and extended, and its antimicrobial activity was evaluated against a panel of Gram-positive (methicillin-resistant Staphylococcus aureus – MRSA) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) and fungi (Candida albicans, Cryptococcus neoformans var. grubii). The compounds’ cytotoxicity and haemolytic profile were also evaluated. To unravel the mechanism of action of the best compounds, the alterations in the surface charge, bacterial membrane integrity, and cytoplasmic leakage were assessed.
Structure-activity-toxicity data revealed the contributions of the different structural components (phenolic ring, carbon-based spacers, carboxamide group, alkyl linker) to the compounds’ bioactivity and safety. Dihydrocinnamic derivatives 5 m and 5n stood out as safe, potent and selective antibacterial agents against S. aureus (MIC < 0.25 µg/mL; CC50 > 32 µg/mL; HC10 > 32 µg/mL). Mechanistic studies suggest that the antibacterial activity of compounds 5 m and 5n may result from interactions with the bacterial cell wall and membrane.
Collectively, these studies demonstrate the potential of phytochemical-based TPP+ conjugates as a new class of antibiotics.
Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22–27) based on a dietary antioxidant ...(caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure–activity–toxicity–property relationships, and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants. In general, AntiOxCINs derivatives prevented lipid peroxidation and acted as inhibitors of the mitochondrial permeability transition pore. AntiOxCINs toxicity profile was found to be dependent on the structural modifications performed on the dietary antioxidant. On the basis of mitochondrial and cytotoxicity/antioxidant cellular data, compound 25 emerged as a potential candidate for the development of a drug candidate with therapeutic application in mitochondrial oxidative stress-related diseases. Compound 25 increased GSH intracellular levels and showed no toxicity on mitochondrial morphology and function.
2-(1,3-Benzothiazol-2-yl)-4
H
-chromen-4-one and spiro1,4-benzothiazine-2,2'-chromene-3,4'(3'
H
,4
H
)-dione have been synthesized from 4-oxo-4
H
-chromene-2-carboxylic acid. The course of the ...reaction that usually occurs between the activated carboxylic acid and aromatic amines was changed upon the use of different reaction conditions (acidic or basic) and 2-aminobenzenethiol. As a result, new heterocyclic derivatives were obtained. Structures of the compounds have been established on the basis of spectral (1D and 2D NMR spectra) and X-ray data.
Disinfection is crucial to control and prevent microbial pathogens on surfaces. Nonetheless, disinfectants misuse in routine disinfection has increased the concern on their impact on bacterial ...resistance and cross-resistance. This work aims to develop a formulation for surface disinfection based on the combination of a natural product, cinnamaldehyde, and a widely used biocide, cetyltrimethylammonium bromide. The wiping method was based on the Wiperator test (ASTM E2967-15) and the efficacy evaluation of surface disinfection wipes test (EN 16615:2015). After formulation optimization, the wiping of a contaminated surface with 6.24 log
colony-forming units (CFU) of
or 7.10 log
CFU of
led to a reduction of 4.35 log
CFU and 4.27 log
CFU when the wipe was impregnated with the formulation in comparison with 2.45 log
CFU and 1.50 log
CFU as a result of mechanical action only for
and
, respectively. Furthermore, the formulation prevented the transfer of bacteria to clean surfaces. The work presented highlights the potential of a combinatorial approach of a classic biocide with a phytochemical for the development of disinfectant formulations, with the advantage of reducing the concentration of synthetic biocides, which reduces the potentially negative environmental and public health impacts from their routine use.
Substituted phenethylamines including 2C (2,5-dimethoxyphenethylamines) and NBOMe (N-(2-methoxybenzyl)phenethylamines) drugs are potent psychoactive substances with little to no knowledge available ...on their toxicity. In the present in vitro study, we explored the mechanisms underlying the neurotoxicity of six substituted phenethylamines: 2C-T-2, 2C-T-4, 2C-T-7 and their corresponding NBOMes. These drugs were synthesized and chemically characterized, and their cytotoxicity (0–1000 μM) was evaluated in differentiated SH-SY5Y cells and primary rat cortical cultures, by the NR uptake and MTT reduction assays. In differentiated SH-SY5Y cells, mitochondrial membrane potential, intracellular ATP and calcium levels, reactive oxygen species production, and intracellular total glutathione levels were also evaluated. All the tested drugs exhibited concentration-dependent cytotoxic effects towards differentiated SH-SY5Y cells and primary rat cortical cultures. The NBOMe drugs presented higher cytotoxicity than their counterparts, which correlates with the drug’s lipophilicity. These cytotoxic effects were associated with mitochondrial dysfunction, evident through mitochondrial membrane depolarization and lowered intracellular ATP levels. Intracellular calcium imbalance was observed for 2C-T-7 and 25T7-NBOMe, implying a disrupted calcium regulation. Although reactive species levels remained unchanged, a reduction in intracellular total GSH content was observed. Overall, these findings contribute to a deeper understanding of these drugs, shedding light on the mechanisms underpinning their neurotoxicity.
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