RESUMO
The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids 7(a-j), 8(a-j), and 9(a-f) as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues 7i, 8j, and 9d were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues 7i, 8j, and 9d were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of 7i, 8j, and 9d and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues 7i, 8j, and 9d were assessed as potent Aß1-42 fibril modulators and protective agents against Aß1-42-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners 7i, 8j, and 9d as protective agents against Aß1-42-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. However, further pharmacokinetics, toxicology, and behavioral studies are warranted.
Assuntos
Doença de Alzheimer , Hidrazinas , Quinazolinonas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Quinazolinonas/farmacologia , Quinazolinonas/química , Quinazolinonas/síntese química , Humanos , Hidrazinas/farmacologia , Hidrazinas/química , Hidrazinas/síntese química , Acetamidas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Desenho de Fármacos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/metabolismo , Simulação de Dinâmica Molecular , Simulação por Computador , Simulação de Acoplamento MolecularRESUMO
Based on the hypothesis that the 2-mercaptoacetamide moiety chelates the copper ions of tyrosinase, 2-mercapto-N-arylacetamide (2-MAA) analogs were designed and synthesized as potential tyrosinase inhibitors. Four 2-MAA analogs showed low IC50 values ranging from 0.95 to 2.0 µM against mushroom tyrosinase, which was 12-26 times lower than that of kojic acid (IC50 value = 24.3 µM). However, according to a copper ion chelation experiment performed, the 2-MAA analogs did not participate in chelation with copper ions. To identify the mode of inhibition of the 2-MAA analogs, kinetic studies were performed, and the results were supported by docking results. In addition, docking simulation results suggested that the 2-MAA analogs strongly inhibited tyrosinase activity because of the hydrogen bonding of the amide NH group and the hydrophobic interaction of the aryl ring instead of chelation with copper ions. In experiments using B16F10 cells, 2-MAA analogs were shown to inhibit melanin production by inhibiting cellular tyrosinase activity. Western blotting showed that in addition to directly inhibiting tyrosinase activity, analog 7 also has an anti-melanogenic effect by inhibiting the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. The 2-MAA analogs showed no appreciable cytotoxicity against HaCaT and B16F10 cells, making them suitable for dermal applications. In a depigmentation experiment using zebrafish embryos, analogs 1 and 2 showed more potent depigmentation effects than kojic acid even at 1000 times lower concentration than that of kojic acid. These results suggest that the 2-MAA analogs are promising anti-melanogenic agents that can inhibit most tyrosinases in various species.
Assuntos
Acetamidas , Inibidores Enzimáticos , Melaninas , Monofenol Mono-Oxigenase , Peixe-Zebra , Animais , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Camundongos , Acetamidas/farmacologia , Acetamidas/química , Acetamidas/síntese química , Melaninas/antagonistas & inibidores , Melaninas/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Agaricales/enzimologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Relação Dose-Resposta a Droga , HumanosRESUMO
A series of novel sulfonamide and acetamide derivatives of pyrimidine were synthesized and their antimicrobial activities were assessed. Based on the Microbroth dilution method, the minimum inhibitory concentration (MIC) of the synthesized compounds demonstrated moderate to good levels of antifungal and antibacterial activity. Structure-activity relationship analysis suggested that the presence of electron-withdrawing groups, such as halogens, nitrile, and nitro groups, on the pyrimidine ring contributed to the enhanced antimicrobial potency, while electron-donating substituents led to a decrease in activity. Computational studies, including density functional theory (DFT), frontier molecular orbitals (FMO), and molecular electrostatic potential (MEP) analysis, provided insights into the electronic properties and charge distribution of the compounds. Drug-likeness evaluation using ADME/Tox analysis indicated that the synthesized compounds possess favorable physicochemical properties and could be potential drug candidates. Molecular docking against the Mycobacterium TB protein tyrosine phosphatase B (MtbPtpB) revealed that the synthesized compounds exhibited strong binding affinities (-46 kcal/mol to - 61 kcal/mol) and formed stable protein-ligand complexes through hydrogen bonding and π-π stacking interactions with key residues in the active site. The observed interactions from the docking simulations were consistent with the predicted interaction sites identified in the FMO and MEP analyses. These findings suggest that the synthesized pyrimidine derivatives could serve as promising antimicrobial agents and warrant further investigation for drug development.
Assuntos
Acetamidas , Antibacterianos , Testes de Sensibilidade Microbiana , Pirimidinas , Sulfonamidas , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Acetamidas/química , Acetamidas/farmacologia , Acetamidas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Estrutura Molecular , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Simulação de Acoplamento Molecular , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Teoria da Densidade Funcional , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
Molecular interaction fields (MIFs) are three-dimensional interaction maps that describe the intermolecular interactions expected to be formed around target molecules. In this paper, a method for the fast computation of MIFs using the approximation functions of quantum mechanics-level MIFs of small model molecules is proposed. MIF functions of N-methylacetamide with chlorobenzene, bromobenzene, and iodobenzene probes were precisely approximated and used to calculate the MIFs on protein surfaces. This method appropriately reproduced halogen-bond-formable areas around the ligand-binding sites of proteins, where halogen bond formation was suggested in a previous study.
Assuntos
Halogênios , Modelos Moleculares , Proteínas , Proteínas/química , Proteínas/metabolismo , Halogênios/química , Acetamidas/química , Teoria Quântica , Clorobenzenos/química , Conformação Proteica , Propriedades de Superfície , Iodobenzenos/química , Sítios de Ligação , Bromobenzenos/química , LigantesRESUMO
Spermatogonia cryopreservation can be a strategy for future conservation actions. The neotropical Siluriformes Pseudopimelodus mangurus was already classified as vulnerable on the Red List of Threatened Species. P. mangurus spermatogonial cells were isolated, assessed, and cryopreserved. Fragments of the testis were enzymatically dissociated, purified using Percoll density gradient, and submitted to differential plating. Fractionated cells were evaluated by microscopy, ddx4 (vasa) relative expression, and alkaline phosphatase activity. Cryopreservation was conducted using ethylene glycol, glycerol, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), and propanediol at 1 M, 1.5 M, and 2 M. Cell viability was evaluated and cell concentration was determined. Cell fractions from 20 % and 30 % Percoll gradient bands showed the highest concentrations of spermatogonia. The fraction mix showed 54 % purity and 93 % viability. After differential plating, 60 % purity and 92 % viability were obtained. Spermatogonial cells showed high alkaline phosphatase activity compared to spermatocytes and spermatids. The relative spermatogonial ddx4 expression from the Percoll density gradient was about twice as high as in samples from the testis and the differential plating. The increased ddx4 expression indicated the enrichment of spermatogonial cells by density gradient step and dead cells expressing ddx4 in differential plating, or ddx4 decreasing expression during cell culture. For this reason, cells from the Percoll gradient were chosen for cryopreservation. Propanediol at 1 M demonstrated the best condition for spermatogonial cell cryopreservation, presenting 98 % viability, while dimethylacetamide at 2 M represented the least favorable condition, with approximately 47 % viability. These findings are essential for P. mangurus spermatogonial cell cryopreservation, aiming to generate a spermatogonia cryobank for future conservation efforts.
Assuntos
Peixes-Gato , Sobrevivência Celular , Criopreservação , Espermatogônias , Animais , Masculino , Criopreservação/métodos , Criopreservação/veterinária , Espermatogônias/citologia , Crioprotetores/farmacologia , Testículo/citologia , Dimetil Sulfóxido/farmacologia , Acetamidas/farmacologia , Acetamidas/química , Etilenoglicol/farmacologia , RNA Helicases DEAD-box/metabolismo , Glicerol/farmacologia , Glicerol/metabolismo , Fosfatase Alcalina/metabolismo , Propilenoglicol/farmacologia , Separação Celular/métodosRESUMO
A novel spectrofluorimetric method with high selectivity and sensitivity was created to determine Pregabalin (PG) in pharmaceutical form, human serum, and urine. This method relies on detecting quenching in the intensity of luminescence of the europium acetylacetone complex (Eu3+-ACAC) at emission wavelength λem = 616 nm, which results from interaction with various concentrations of PG after excitation at λex = 395 nm and pH 6.5 in dimethylformamide (DMF). The calibration curve was generated using concentrations ranging from 7.6 × 10-8 to 6.3 × 10-6 mol/L. The plot showed a high correlation coefficient (r2) of 0.994 with a detection limit (LOD) of 2.81 × 10-8 mol/L and a quantification limit (LOQ) of 8.5 × 10-8 mol/L. The remarkable luminescence intensity quenching of the Eu3+-ACAC by ranged concentrations of PG was effectively employed as a photo probe to determine PG in marketable form and different body fluids. Spectroscopic characterization, such as absorption and emission spectra, confirmed the obtained sensor. The improved method is verified using a range of characteristics, such as accuracy, precision, selectivity, linearity, and robustness.
Assuntos
Európio , Limite de Detecção , Pregabalina , Espectrometria de Fluorescência , Espectrometria de Fluorescência/métodos , Európio/química , Pregabalina/sangue , Pregabalina/análise , Humanos , Pentanonas/química , Reprodutibilidade dos Testes , Acetamidas/química , Acetamidas/análiseRESUMO
The atmospheric and aqueous ozonolysis of metazachlor (MTZ) is investigated using high-level quantum chemical and kinetic calculations (M06-2X/6-311 + + G(3df,3pd)//M06-2X/6-31 + G(d,p) level of theory). The ozone (O3)-initiated degradation pathways of MTZ under three different mechanisms, namely cycloaddition, oxygen-addition, and single electron transfer (SET), are explored in the temperature range of 283-333 K and 1 atm pressure. As a result, the cycloaddition reaction at the C16C18 double bond of the benzene ring of MTZ is found to be the most dominant channel in the atmosphere with the standard Gibbs free energy of reaction (ΔrG0g) of - 129.13 kJ mol-1 and the highest branching ratio of 95.18%. In the aqueous phase, the main reaction channel turns into the SET mechanism, which owns the lowest Gibbs free energy of activation (ΔG#aq) of 73.8 kJ mol-1 and contributes 87.8% to the ktotal. Over the temperature range of 283-333 K, the total rate constant (ktotal) significantly increases from 8.42 to 5.82 × 101 M-1 s-1 in the atmosphere and from 4.10 × 102 to 2.40 × 104 M-1 s-1 in the aqueous environment. Remarkably, the ecotoxicity assessment shows that MTZ may be harmful to fish and chronically harmful to daphnia. In contrast, its main ozonolysis products exhibit no acute or chronic toxicity or mutagenic effects.
Assuntos
Herbicidas , Oxirredução , Ozônio , Ozônio/química , Herbicidas/química , Herbicidas/toxicidade , Cinética , Acetamidas/química , Acetamidas/toxicidade , Animais , Ecotoxicologia , Daphnia/efeitos dos fármacosRESUMO
Given the harmful effect of pesticide residues, it is essential to develop portable and accurate biosensors for the analysis of pesticides in agricultural products. In this paper, we demonstrated a dual-mode fluorescent/intelligent (DM-f/DM-i) lateral flow immunoassay (LFIA) for chloroacetamide herbicides, which utilized horseradish peroxidase-IgG conjugated time-resolved fluorescent nanoparticle probes as both a signal label and amplification tool. With the newly developed LFIA in the DM-f mode, the limits of detection (LODs) were 0.08 ng/mL of acetochlor, 0.29 ng/mL of metolachlor, 0.51 ng/mL of Propisochlor, and 0.13 ng/mL of their mixture. In the DM-i mode, machine learning (ML) algorithms were used for image segmentation, feature extraction, and correlation analysis to obtain multivariate fitted equations, which had high reliability in the regression model with R2 of 0.95 in the range of 2 × 102-2 × 105 pg/mL. Importantly, the practical applicability was successfully validated by determining chloroacetamide herbicides in the corn sample with good recovery rates (85.4 to 109.3%) that correlate well with the regression model. The newly developed dual-mode LFIA with reduced detection time (12 min) holds great potential for pesticide monitoring in equipment-limited environments using a portable test strip reader and laboratory conditions using ML algorithms.
Assuntos
Acetamidas , Herbicidas , Aprendizado de Máquina , Herbicidas/análise , Acetamidas/análise , Acetamidas/química , Imunoensaio/métodos , Corantes Fluorescentes/química , Limite de Detecção , Zea mays/química , AlgoritmosRESUMO
The effects of deviations from nonlinearity around the carbonyl proton acceptor of an amide group are assessed by DFT quantum chemical calculations for both CH··O and NH··O H-bonds. The proton donors are the imidazole functional group of His and the indole of Trp, which are paired respectively with N-methylacetamide and acetamide. The displacement of either CH or NH group toward the carbonyl O sp2 lone pairs stabilizes the system and strengthens the H-bond. But the two donor groups differ in their response to a shift out of the amide plane. While the NH··O H-bond is weakened by this displacement, a substantial strengthening is observed when the CH donor is moved out of this plane, in one direction versus the other. This pattern is explained on the basis of simple Coulombic considerations.
Assuntos
Ligação de Hidrogênio , Proteínas , Prótons , Proteínas/química , Teoria da Densidade Funcional , Acetamidas/químicaRESUMO
An electrophilic arginine mimetic, 2-chloroacetamidine (CAM), was deployed to enable trypsin-mediated proteolysis at cysteine residues and to enhance mass spectrometry-based proteomic detection of cysteine-containing peptides. Illustrating the value of the CAM-capping strategy, proteogenomic analysis using a two-stage false discovery rate (FDR) search revealed >50% enhanced coverage of missense variants, when compared to established workflows.
Assuntos
Cisteína , Tripsina , Cisteína/química , Tripsina/metabolismo , Tripsina/química , Acetamidas/química , Proteólise , Proteômica , Peptídeos/química , HumanosRESUMO
With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
Assuntos
Acetamidas , Antimaláricos , Plasmodium falciparum , Proteínas de Protozoários , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , Acetamidas/farmacologia , Acetamidas/química , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Antimaláricos/farmacologia , Antimaláricos/química , Animais , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Mutação , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Malária Falciparum/tratamento farmacológico , Humanos , Resistência a Medicamentos/genética , Resistência a Medicamentos/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacosRESUMO
BACKGROUND: ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients. OBJECTIVE: The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil. MATERIALS AND METHODS: Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server. RESULTS: In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the "Elite Library®" and "Synergy Library" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT. CONCLUSION: According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.
Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas p21(ras) , Solubilidade , Humanos , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Simulação por Computador , Antineoplásicos/farmacologia , Antineoplásicos/química , Acetamidas/farmacologia , Acetamidas/química , Mutação , Indóis/química , Indóis/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Alquil e Aril Transferases/antagonistas & inibidores , Alquil e Aril Transferases/metabolismo , Simulação de Acoplamento Molecular , Proteínas MetiltransferasesRESUMO
A new automated radiosynthesis of [11C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [11C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [11C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [11C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use.
Assuntos
Acetamidas , Radioisótopos de Carbono , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de AMPA , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Radioisótopos de Carbono/química , Acetamidas/síntese química , Acetamidas/química , Receptores de AMPA/metabolismo , Radioquímica/métodos , Automação , Técnicas de Química Sintética , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Nitrogenous disinfection byproducts (N-DBPs) in water are carcinogenic, teratogenic, and mutagenic. In this work, we developed a biomimetic reduction approach based on the cysteine thiol that destructed the highly toxic, select nitrogenous haloacetamides (HAMs) and haloacetonitriles (HANs) while effectively controlling the cytotoxicity of the degradation products to serve as a basis for further technological applications (e.g. immobilized contact bed for terminal users). Mechanisms on toxicity control were elucidated. Results showed the degradation and cytotoxicity control of HAMs as more efficient than that of the HANs. The cytotoxicity of the chlorinated, brominated, and iodinated HAMs and HANs was reduced to 25 %- 0.25 % of the original after biomimetic reduction using a reasonable concentration ratio. Through a combination of thiol-specific reactivity, dehalogenation, and quantitative structure-activity relationship analyses, the major toxicity control mechanisms were found to be the reductive dehalogenation of the N-DBPs. The halogenated functional groups on the N-DBPs had a more pronounced effect than the amide and nitrile groups on the cytotoxicity and detoxification effect. Patterns of toxicity interaction variations with DBPs concentrations were identified to detect possible synergistic cytotoxicity interactions under various combinations of HAMs and HANs in the presence of the cysteine thiol. Results could benefit future N-DBPs control efforts.
Assuntos
Desinfecção , Poluentes Químicos da Água , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/química , Animais , Desinfetantes/toxicidade , Desinfetantes/química , Biomimética , Sobrevivência Celular/efeitos dos fármacos , Purificação da Água/métodos , Acetamidas/toxicidade , Acetamidas/química , Cisteína/química , Compostos de Sulfidrila/química , HalogenaçãoRESUMO
Trace iron ions (Fe(III)) are commonly found in water and wastewater, where free chlorine is very likely to coexist with Fe(III) affecting the disinfectant's stability and N-DBPs' fate during UV/chlorine disinfection, and yet current understanding of these mechanisms is limited. This study investigates the effects of Fe(III) on the formation and toxicity alteration of halonitromethanes (HNMs), dichloroacetonitrile (DCAN), and dichloroacetamide (DCAcAm) from polyethyleneimine (PEI) during UV/chlorine disinfection. Results reveal that the maxima concentrations of HNMs, DCAN, and DCAcAm during UV/chlorine disinfection with additional Fe(III) were 1.39, 1.38, and 1.29 times higher than those without additional Fe(III), instead of being similar to those of Fe(III) inhibited the formation of HNMs, DCAN and DCAcAm during chlorination disinfection. Meanwhile, higher Fe(III) concentration, acidic pH, and higher chlorine dose were more favorable for forming HNMs, DCAN, and DCAcAm during UV/chlorine disinfection, which were highly dependent on the involvement of HO· and Cl·. Fe(III) in the aquatic environment partially hydrolyzed to the photoactive Fe(III)hydroxyl complexes Fe(OH)2+ and [Fe(H2O)6]3+, which undergone UV photoactivation and coupling reactions with HOCl to achieve effective Fe(III)/Fe(II) interconversion, a process that facilitated the sustainable production of HO·. Extensive product analysis and comparison verified that the HO· production enhanced by the Fe(III)/Fe(II) internal cycle played a primary role in increasing HNMs, DCAN, and DCAcAm productions during UV/chlorine disinfection. Note that the incorporation of Fe(III) increased the cytotoxicity and genotoxicity of HNMs, DCAN, and DCAcAm formed during UV/chlorine disinfection, and yet Fe(III) did not have a significant effect on the acute toxicity of water samples before, during, and after UV/chlorine disinfection. The new findings broaden the knowledge of Fe(III) affecting HNMs, DCAN, and DCAcAm formation and toxicity alteration during UV/chlorine disinfection.
Assuntos
Desinfecção , Desinfecção/métodos , Raios Ultravioleta , Cloro/química , Polietilenoimina/química , Acetonitrilas/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade , Ferro/química , Purificação da Água/métodos , Acetamidas/química , Acetamidas/toxicidade , Desinfetantes/químicaRESUMO
P2Y14 receptor (P2Y14R) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y14R antagonists and the crystallographic overlap study between the reported P2Y14R antagonist compounds 6 and 9, a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2Y14R antagonists. The most potent antagonist, compound I-17 (N-(1H-benzo[d]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC50 = 0.6 nM) without zwitterionic character, showed strong binding ability to P2Y14R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In vitro and in vivo evaluation demonstrated that compound I-17 had satisfactory inhibitory activity on the inflammatory response of monosodium urate (MSU)-induced acute gouty arthritis. I-17 decreased inflammatory factor release and cell pyroptosis through the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway. Thus, compound I-17, with potent P2Y14R antagonistic activity, in vitro and in vivo efficacy, and favorable bioavailability (F = 75%), could be a promising lead compound for acute gouty arthritis.
Assuntos
Acetamidas , Simulação de Acoplamento Molecular , Receptores Purinérgicos P2 , Acetamidas/farmacologia , Acetamidas/química , Acetamidas/síntese química , Acetamidas/farmacocinética , Humanos , Animais , Receptores Purinérgicos P2/metabolismo , Camundongos , Masculino , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Relação Estrutura-Atividade , Antagonistas do Receptor Purinérgico P2/farmacologia , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/síntese química , Descoberta de Drogas , Ratos , Cristalografia por Raios X , Ratos Sprague-Dawley , Estrutura MolecularRESUMO
Beta-1,3-glucuronosyltransferase (B3GAT3), overexpressed in hepatocellular carcinoma (HCC) and negatively correlated to prognosis, is a promising target for cancer therapy. Currently, no studies have reported small molecule inhibitors of B3GAT3. In this study, we designed and synthesized a series of small-molecule inhibitors of B3GAT3 through virtual screening and structure optimization. The lead compound TMLB-C16 exhibited potent B3GAT3 inhibitory activity (KD = 3.962 µM) by effectively suppressing proliferation and migration, and inducing cell cycle arrest and apoptosis in MHCC-97H (IC50= 6.53 ± 0.18 µM) and HCCLM3 (IC50= 6.22 ± 0.23 µM) cells. Furthermore, compound TMLB-C16 demonstrated favorable pharmacokinetic properties with a relatively high bioavailability of 68.37%. It significantly inhibited tumor growth in both MHCC-97H and HCCLM3 xenograft tumor models without causing obvious toxicity. These results indicate that compound TMLB-C16 is an effective small molecule inhibitor of B3GAT3, providing a basis for the future development of B3GAT3-targeted drugs.
Assuntos
Acetamidas , Antineoplásicos , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Acetamidas/química , Acetamidas/farmacologia , Acetamidas/síntese química , Acetamidas/uso terapêutico , Camundongos , Relação Estrutura-Atividade , Apoptose/efeitos dos fármacos , Camundongos Nus , Descoberta de Drogas , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , Simulação de Acoplamento Molecular , Masculino , Movimento Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/síntese químicaRESUMO
Sphingosine kinase 2 (SphK2) has emerged as a promising target for cancer therapy due to its critical role in tumor growth. However, the lack of potent and selective inhibitors has hindered its clinical application. Herein, we report the design and synthesis of a series of novel SphK2 inhibitors, culminating in the identification of compound 12q as a highly selective and potent inhibitor of SphK2. Molecular dynamics simulations suggest that the incorporation of larger substitution groups facilitates a more effective occupation of the binding site, thereby stabilizing the complex. Compared to the widely used inhibitor ABC294640, compound 12q exhibits superior anti-proliferative activity against various cancer cells, inducing G2 phase arrest and apoptosis in liver cancer cells HepG2. Notably, 12q inhibited migration and colony formation in HepG2 and altered intracellular sphingolipid content. Moreover, intraperitoneal administration of 12q in mice resulted in decreased levels of S1P. 12q provides a valuable tool compound for exploring the therapeutic potential of targeting SphK2 in cancer.
Assuntos
Acetamidas , Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Fosfotransferases (Aceptor do Grupo Álcool) , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Acetamidas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Estrutura Molecular , Apoptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Descoberta de Drogas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese químicaRESUMO
The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD+-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 µM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.
Assuntos
Acetamidas , Sirtuína 2 , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/química , Sirtuína 2/metabolismo , Humanos , Acetamidas/química , Acetamidas/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/químicaRESUMO
In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.