RESUMO
A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5 h with para cyano group manifested the most pivotal biological activity among all, displaying IC50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9 µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5 g possessing a p-CH3 at phenyl ring unfolded as most active, with calculated IC50 values 90.3 ± 1.1 µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.
Assuntos
Antioxidantes , Simulação de Acoplamento Molecular , Urease , alfa-Amilases , alfa-Glucosidases , Urease/antagonistas & inibidores , Urease/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Testes de Sensibilidade MicrobianaRESUMO
Several novel copper (II) complexes of reduced Schiff bases containing fluoride substituents were prepared and structurally characterized by single-crystal X-ray diffraction. The complexes exhibited diverse structures, with the central atom in distorted tetrahedral geometry. The biological effects of the products were evaluated, specifically their cytotoxicity, antimicrobial, and antiurease activities, as well as affinity for albumin (BSA) and DNA (ct-DNA). The complexes showed marked cytotoxic activities in the HepG2 hepatocellular carcinoma cell line, considerably higher than the standard cisplatin. The cytotoxicity depended significantly on the substitution pattern. The best activity was observed in the complex with a trifluoromethyl group in position 4 of the benzene ring-the dichloro[(±)-trans-N,N'-bis-(4-trifluoromethylbenzyl)-cyclohexane-1,2-diamine]copper (II) complex, whose activity (IC50 28.7 µM) was higher than that of the free ligand and markedly better than the activity of the standard cisplatin (IC50 336.8 µM). The same complex also showed the highest antimicrobial effect in vitro. The affinity of the complexes towards bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) was established as well, indicating only marginal differences between the complexes. In addition, all complexes were shown to be excellent inhibitors of the enzyme urease, with the IC50 values in the lower micromolar region.
Assuntos
Antineoplásicos , Complexos de Coordenação , Cobre , Bases de Schiff , Humanos , Bases de Schiff/química , Bases de Schiff/farmacologia , Cobre/química , Células Hep G2 , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Ligantes , Flúor/química , DNA/metabolismo , DNA/química , Soroalbumina Bovina/química , Urease/antagonistas & inibidores , Urease/metabolismoRESUMO
Urolithiasis, characterized by the formation of solid crystalline structures within the urinary tract, presents a significant global health burden with high recurrence rates and limited treatment efficacy. Recent research has identified various protein receptors and enzymes implicated in the pathogenesis of urolithiasis, offering potential targets for therapeutic intervention. Protein receptors such as the calcium-sensing receptor and vasopressin V2 receptor play crucial roles in regulating urinary calcium excretion and water reabsorption, respectively, influencing stone formation. Additionally, modulation of receptors like the angiotensin II receptor and aldosterone receptor can impact renal function and electrolyte balance, contributing to stone prevention. Furthermore, enzymes such as urease inhibitors and xanthine oxidase inhibitors offer targeted approaches to prevent the formation of specific stone types. This review discusses the potential of targeting these receptors and enzymes for the treatment of urolithiasis, exploring associated drugs and their mechanisms of action. Despite promising avenues for personalized and precision medicine approaches, challenges such as the need for robust clinical evidence and ensuring cost-effectiveness must be addressed for the translation of these interventions into clinical practice. By overcoming these challenges, receptor-targeted therapies and enzyme inhibitors hold promise for revolutionizing the management of urolithiasis and reducing its global burden.
Assuntos
Terapia de Alvo Molecular , Medicina de Precisão , Urolitíase , Humanos , Urolitíase/tratamento farmacológico , Urolitíase/metabolismo , Medicina de Precisão/métodos , Animais , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Urease/antagonistas & inibidores , Urease/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Receptores de Detecção de Cálcio/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo , Receptores de Vasopressinas/metabolismoRESUMO
Urease is a metalloenzyme that contains two Ni(II) ions in its active site and catalyzes the hydrolysis of urea into ammonia and carbon dioxide. The development of effective urease inhibitors is crucial not only for mitigating nitrogen losses in agriculture but also for offering an alternative treatment against infections caused by resistant pathogens that utilize urease as a virulence factor. This study focuses on synthesizing and investigating the urease inhibition potential of Biginelli Adducts bearing a boric acid group. An unsubstituted or hydroxy-substituted boronic group in the Biginelli adducts structure enhances the urease inhibitory activity. Biophysical and kinetics studies revealed that the best Biginelli adduct (4e; IC50 = 132 ± 12 µmol/L) is a mixed inhibitor with higher affinity to the urease active site over an allosteric one. Docking studies confirm the interactions of 4e with residues essential for urease activity and demonstrate its potential to coordinate with the nickel atoms through the oxygen atoms of carbonyl or boronic acid groups. Overall, the Biginelli adduct 4e shows great potential as an additive for developing enhanced efficiency fertilizers and/or for medical applications.
Assuntos
Ácidos Borônicos , Inibidores Enzimáticos , Urease , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Ácidos Borônicos/síntese química , Canavalia/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Urease/antagonistas & inibidores , Urease/metabolismo , Níquel/químicaRESUMO
Urinary tract infection caused by Klebsiella, Proteus and Streptococcus is a urease dependent process, hence treatment of these infections by antibacterial compounds lies in inhibition of their virulence factors. The crude methanolic extracts derived from sumac fruit, pomegranate peel and Indian almond leaves were separated into anthocyanin and non-anthocyanin fractions using solid phase cartridges. The inhibitory effect of these fractions was determined on the growth of urease producing species and jack bean urease activity. Known compounds in the fractions were also docked with ureases of different biological origins viz. K. pneumoniae (PDB ID: 8HCN), K. aerogenes (PDB ID: 2KAU), Helicobacter pylori (PDB ID:8HC1)and Canavalia ensiformis (jack bean) (PDB ID: 3LA4) to determine their binding affinities and interaction with the enzyme. All the fractions showed significant inhibition growth for P. mirabilis, S. epidermidis and K.pneumoniae. Among the samples, sumac showed greatest inhibition against all (MIC 6-25 mg.mL-1) while among the fractions, anthocyanin was found to be most active (MIC 6-12 mg/mL). Likewise, all fractions inhibited urease with lowest ICs50 shown by sumac fractions (21-116 µg.mL-1). Out of 39 compounds docked, 27 showed interaction with movable flaps and/or active site of ureases which explains their mode of inhibition.
Assuntos
Polifenóis , Punica granatum , Prunus dulcis , Urease , Urease/antagonistas & inibidores , Urease/metabolismo , Polifenóis/farmacologia , Polifenóis/química , Punica granatum/química , Prunus dulcis/química , Canavalia/enzimologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antibacterianos/farmacologia , Antibacterianos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Bactérias/efeitos dos fármacos , Bactérias/enzimologiaRESUMO
Thirty protoberberine derivatives, of which twenty five were new, were synthesized and evaluated for their anti-Helicobacter pylori (HP) activities, taking 2,3,10-trimethoxy-9-p-methylbenzylaminoprotopalmatine chloride 1 as the lead. Among them, berberine (BBR) derivative 7c displayed the highest potency against six tested metronidazole (MTZ)-resistant strains and two tested MTZ-susceptible strains with the MIC values of 0.4-1.6 µg/mL with favorable druglike profiles including low toxicity and high stabilities in plasma and artificial gastric fluid. Mechanistic study revealed that 7c might target HP urease with IC50 value of 0.27 µg/mL against Jack bean urease. Furthermore, 7c might change the permeability of the bacterial membrane and direct interact with HP DNA, which also contribute to its bactericidal activity. Therefore, BBR derivatives constituted a new family of anti-HP candidates, with the advantage of good safety profile and multi-target mechanisms, and are worthy for further investigation.
Assuntos
Antibacterianos , Berberina , Helicobacter pylori , Testes de Sensibilidade Microbiana , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Berberina/farmacologia , Berberina/química , Berberina/análogos & derivados , Berberina/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Descoberta de Drogas , Relação Dose-Resposta a Droga , Urease/antagonistas & inibidores , Urease/metabolismo , HumanosRESUMO
A thiophene-derived Schiff base ligand (E)-2-morpholino-N-(thiophen-2-ylmethylene)ethanamine was used for the synthesis of M(II) complexes, [TEM(M)X2] (M = Co, Cu, Zn; X = Cl; M = Cd, X = Br). Structural characterization of the synthesized complexes revealed distorted tetrahedral geometry around the M(II) center. In vitro investigation of the synthesized ligand and its M(II) complexes showed considerable anti-urease and leishmanicidal potential. The synthesized complexes also exhibited a significant inhibitory effect on urease, with IC50 values in the range of 3.50-8.05 µM. In addition, the docking results were consistent with the experimental results. A preliminary study of human colorectal cancer (HCT), hepatic cancer (HepG2), and breast cancer (MCF-7) cell lines showed marked anticancer activities of these complexes.
Assuntos
Antineoplásicos , Complexos de Coordenação , Simulação de Acoplamento Molecular , Bases de Schiff , Tiofenos , Urease , Humanos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Urease/antagonistas & inibidores , Urease/metabolismo , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/síntese química , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Leishmania/efeitos dos fármacos , Relação Estrutura-Atividade , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Bismuth(III) complexes have been reported to act as inhibitors of the enzyme urease, ubiquitously present in soils and implicated in the pathogenesis of several microorganisms. The general insolubility of Bi(III) complexes in water at neutral pH, however, is an obstacle to their utilization. In our quest to improve the solubility of Bi(III) complexes, we selected a compound reported to inhibit urease, namely [Bi(HEDTA)]·2H2O, and co-crystallized it with (i) racemic DL-histidine to obtain the conglomerate [Bi2(HEDTA)2(µ-D-His)2]·6H2O + [Bi2(HEDTA)2(µ-L-His)2]·6H2O, (ii) enantiopure L-histidine to yield [Bi2(HEDTA)2(µ-L-His)2]·6H2O, and (iii) cytosine to obtain [Bi(HEDTA)]·Cyt·2H2O. All compounds, synthesised by mechanochemical methods and by slurry, were characterized in the solid state by calorimetric (DSC and TGA) and spectroscopic (IR) methods, and their structures were determined using powder X-ray diffraction (PXRD) data. All compounds show an appreciable solubility in water, with values ranging from 6.8 mg mL-1 for the starting compound [Bi(HEDTA)]·2H2O to 36 mg mL-1 for [Bi2(HEDTA)2(µ-L-His)2]·6H2O. The three synthesized compounds as well as [Bi(HEDTA)]·2H2O were then tested for inhibition activity against urease. Surprisingly, no enzymatic inhibition was observed during in vitro assays using Canavalia ensiformis urease and in vivo assays using cultures of Helicobacter pylori, raising questions on the efficacy of Bi(III) compounds to counteract the negative effects of urease activity in the agro-environment and in human health.
Assuntos
Bismuto , Inibidores Enzimáticos , Solubilidade , Urease , Bismuto/química , Urease/antagonistas & inibidores , Urease/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Agroquímicos/farmacologia , Agroquímicos/químicaRESUMO
Thirteen novel hydrazone-Schiff bases (3-15) of fexofenadine were succesfully synthesized, structurally deduced and finally assessed their capability to inhibit urease enzyme (inâ vitro). In the series, six compounds 12 (IC50=10.19±0.16â µM), 11 (IC50=15.05±1.11â µM), 10 (IC50=17.01±1.23â µM), 9 (IC50=17.22±0.81â µM), 13 (IC50=19.31±0.18â µM), and 14 (IC50=19.62±0.21â µM) displayed strong inhibitory action better than the standard thiourea (IC50=21.14±0.24â µM), while the remaining compounds displayed significant to less inhibition. LUMO and HOMO showed the transferring of charges from molecules to biological transfer and MEP map showed the chemically reactive zone appropriate for drug action are calculated using DFT. AIM charges, non-bonding orbitals, and ELF are also computed. The urease protein binding analysis benefited from the docking studies.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Hidrazonas , Simulação de Acoplamento Molecular , Bases de Schiff , Terfenadina , Urease , Urease/antagonistas & inibidores , Urease/metabolismo , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Terfenadina/análogos & derivados , Terfenadina/química , Terfenadina/metabolismo , Terfenadina/farmacologia , Terfenadina/síntese química , Teoria da Densidade Funcional , Estrutura Molecular , Relação Estrutura-Atividade , Canavalia/enzimologiaRESUMO
Microbial Ni2+ homeostasis underpins the virulence of several clinical pathogens. Ni2+ is an essential cofactor in urease and [NiFe]-hydrogenases involved in colonization and persistence. Many microbes produce metallophores to sequester metals necessary for their metabolism and starve competing neighboring organisms. The fungal metallophore aspergillomarasmine A (AMA) shows narrow specificity for Zn2+, Ni2+, and Co2+. Here, we show that this specificity allows AMA to block the uptake of Ni2+ and attenuate bacterial Ni-dependent enzymes, offering a potential strategy for reducing virulence. Bacterial exposure to AMA perturbs H2 metabolism, ureolysis, struvite crystallization, and biofilm formation and shows efficacy in a Galleria mellonella animal infection model. The inhibition of Ni-dependent enzymes was aided by Zn2+, which complexes with AMA and competes with the native nickelophore for the uptake of Ni2+. Biochemical analyses demonstrated high-affinity binding of AMA-metal complexes to NikA, the periplasmic substrate-binding protein of the Ni2+ uptake system. Structural examination of NikA in complex with Ni-AMA revealed that the coordination geometry of Ni-AMA mimics the native ligand, Ni-(L-His)2, providing a structural basis for binding AMA-metal complexes. Structure-activity relationship studies of AMA identified regions of the molecule that improve NikA affinity and offer potential routes for further developing this compound as an anti-virulence agent.
Assuntos
Proteínas de Bactérias , Níquel , Níquel/metabolismo , Níquel/química , Animais , Virulência/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Zinco/metabolismo , Zinco/química , Mariposas/microbiologia , Urease/metabolismo , Urease/antagonistas & inibidores , Transporte BiológicoRESUMO
A series of sulfonate and sulfamate derivatives bearing benzofuran or benzothiophene scaffold exhibited potent inhibitory effect on urease enzyme. Most of the derivatives exhibited significantly higher potency than thiourea, the standard inhibitor. Compound 1s was identified as the most potent urease inhibitor with an IC50 value of 0.42 ± 0.08 µM, which is 53-fold more potent than thiourea, positive control (IC50 = 22.3 ± 0.031 µM). The docking results further revealed the binding interactions towards the urease active site. Phenotypic screening revealed that compounds 1c, 1d, 1e, 1f, 1j, 1n, and 1t exhibit high potency against H. pylori with MIC values ranging from 0.00625 to 0.05 mM and IC50 values ranging from 0.0031 to 0.0095 mM, much more potent than the positive control, acetohydroxamic acid (MIC and IC50 values were 12.5 and 7.38 mM, respectively). Additional studies were performed to investigate the toxicity of these compounds against the gastric epithelial cell line (AGS) and their selectivity profile against E. coli, and five Lactobacillus species representative of the gut microflora. Permeability characteristics of the most promising derivatives were investigated in Caco-2 cell line. The results indicate that the compounds could be targeted in the GIT only without systemic side effects.
Assuntos
Antibacterianos , Benzofuranos , Inibidores Enzimáticos , Helicobacter pylori , Simulação de Acoplamento Molecular , Ácidos Sulfônicos , Tiofenos , Urease , Urease/antagonistas & inibidores , Urease/metabolismo , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Benzofuranos/química , Benzofuranos/farmacologia , Humanos , Tiofenos/química , Tiofenos/farmacologia , Desenho de Fármacos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Descoberta de DrogasRESUMO
Urease, a pivotal enzyme in nitrogen metabolism, plays a crucial role in various microorganisms, including the pathogenic Helicobacter pylori. Inhibiting urease activity offers a promising approach to combating infections and associated ailments, such as chronic kidney diseases and gastric cancer. However, identifying potent urease inhibitors remains challenging due to resistance issues that hinder traditional approaches. Recently, machine learning (ML)-based models have demonstrated the ability to predict the bioactivity of molecules rapidly and effectively. In this study, we present ML models designed to predict urease inhibitors by leveraging essential physicochemical properties. The methodological approach involved constructing a dataset of urease inhibitors through an extensive literature search. Subsequently, these inhibitors were characterized based on physicochemical properties calculations. An exploratory data analysis was then conducted to identify and analyze critical features. Ultimately, 252 classification models were trained, utilizing a combination of seven ML algorithms, three attribute selection methods, and six different strategies for categorizing inhibitory activity. The investigation unveiled discernible trends distinguishing urease inhibitors from non-inhibitors. This differentiation enabled the identification of essential features that are crucial for precise classification. Through a comprehensive comparison of ML algorithms, tree-based methods like random forest, decision tree, and XGBoost exhibited superior performance. Additionally, incorporating the "chemical family type" attribute significantly enhanced model accuracy. Strategies involving a gray-zone categorization demonstrated marked improvements in predictive precision. This research underscores the transformative potential of ML in predicting urease inhibitors. The meticulous methodology outlined herein offers actionable insights for developing robust predictive models within biochemical systems.
Assuntos
Inibidores Enzimáticos , Aprendizado de Máquina , Urease , Urease/antagonistas & inibidores , Urease/química , Urease/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/enzimologia , Helicobacter pylori/efeitos dos fármacos , Algoritmos , HumanosRESUMO
OBJECTIVES: Dandelion has been shown to exert anti-inflammatory and anti-bacterial effects. Our study aimed to identify the effect and mechanism of dandelion flower extracts on H.â pylori-induced gastritis and screen for novel antimicrobial substances. METHODS: Anti-H.â pylori activities of water extracts(WEDF) and ethanol extracts (EEDF) of dandelion flowers were performed with disk diffusion method assay, MIC, and MBC. The H.â pylori-induced model was constructed to examine the gastroprotective of EEDF using RUT, pathological analysis, and ELISA. RESULTS: EEDF exhibited better anti- H.â pylori and urease inhibition activities than WEDF. In vivo studies, EEDF can reduce the adhesion of H.â pylori to the gastric mucosa, alleviate gastric damage, and concurrently reduce the levels of TNF-α and IL-6 in gastric tissues. The six phenolic compounds showed urease inhibition effect (IC50: 2.99±0.15 to 66.08±6.46â mmol/mL). Among them, chlorogenic acid, caffeic acid, and luteolin also had anti-H.â pylori activity (MIC: 64-256â µg/mL). CONCLUSION: EEDF exhibited anti-H.â pylori, gastroprotective and anti-inflammatory effects. Chicoric acid and luteolin may be the main active compounds of dandelion flowers to exert anti-H.â pylori, and worthy of further investigation.
Assuntos
Antibacterianos , Flores , Helicobacter pylori , Testes de Sensibilidade Microbiana , Extratos Vegetais , Taraxacum , Urease , Taraxacum/química , Helicobacter pylori/efeitos dos fármacos , Flores/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Urease/antagonistas & inibidores , Urease/metabolismo , Animais , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Masculino , Infecções por Helicobacter/tratamento farmacológico , Relação Dose-Resposta a Droga , CamundongosRESUMO
The current study details a sequence of sequential reactions for synthesizing bis-indole-based triazine bearing thiazole derivatives. Several steps were involved in the synthesis of bis-indole-based triazine bearing thiazole derivative. The synthetic reactions were monitored via thin-layer chromatography (TLC). Synthesized compounds were characterized using various spectroscopic techniques, including 1H NMR, 13C NMR, and HR-EIMS. The inhibitory activity against urease enzyme of these synthesized compounds was compared with that of thiourea, a standard drug (IC50 = 9.30 ± 0.20⯵M). A range of inhibitory potencies were observed for the synthesized compounds, ranging from moderate to excellent, as follows (IC50 = 5.10 ± 0.40⯵M to 29.80 ± 0.20⯵M). Analyzing the structure-activity relationship (SAR) provided insight into the results, showing that different substituents had different effects on aromatic rings. Several compounds displayed outstanding inhibitory properties (among those tested were 1, 2, 4, 5, and 6 with IC50 = 6.30 ± 0.80, 5.10 ± 0.40, 5.90 ± 0.50, 8.20 ± 0.10, 8.90 ± 0.60⯵M, respectively). Anti-urease evaluation of all the synthesized derivatives was conducted in which the selected compounds have shown remarkable potency compared with the standard drug thiourea (IC50 = 9.30 ± 0.20⯵M). Molecular docking analysis was carried out for investigating the better binding sites and distance of the derivatives. Moreover, the drug-like properties were explored by the ADME attributes of the synthesized analogs.
Assuntos
Inibidores Enzimáticos , Indóis , Simulação de Acoplamento Molecular , Tiazóis , Triazinas , Urease , Urease/antagonistas & inibidores , Urease/química , Tiazóis/química , Tiazóis/farmacologia , Relação Estrutura-Atividade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Triazinas/química , Triazinas/farmacologiaRESUMO
A new series of N-thioacylated ciprofloxacin 3a-n were designed and synthesized based on Willgerodt-Kindler reaction. The results of in vitro urease inhibitory assay indicated that almost all the synthesized compounds 3a-n (IC50 = 2.05 ± 0.03-32.49 ± 0.32 µM) were more potent than standard inhibitors, hydroxyurea (IC50 = 100 ± 2.5 µM) and thiourea (IC50 = 23 ± 0.84 µM). The study of antibacterial activity against Gram-positive species (S. aureus and S. epidermidis) revealed that the majority of compounds were more active than ciprofloxacin as the standard drug, and 3h derivative bearing 3-fluoro group had the same effect as ciprofloxacin against Gram-negative bacteria (P. aeruginosa and E. coli). Based on molecular dynamic simulations, compound 3n exhibited pronounced interactions with the critical residues of the urease active site and mobile flap pocket so that the quinolone ring coordinated toward the metal bi-nickel center and the essential residues at the flap site like His593, His594, and Arg609. These interactions caused blocking the active site and stabilized the movement of the mobile flap at the entrance of the active site channel, which significantly reduced the catalytic activity of urease. Noteworthy, 3n also exhibited IC50 values of 5.59 ± 2.38 and 5.72 ± 1.312 µg/ml to inhibit urease enzyme against C. neoformans and P. vulgaris in the ureolytic assay.
Assuntos
Antibacterianos , Ciprofloxacina , Inibidores Enzimáticos , Urease , Antibacterianos/química , Ciprofloxacina/farmacologia , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Urease/antagonistas & inibidoresRESUMO
1,2,4-triazoles are a major group of heterocyclic compounds. In the current work, a concise library of such triazoles synthesized through a multistep protocol. The synthesis involved hydrazinolysis of ethyl-2-(p-Cl-phenoxy) acetate followed by reflux with phenyl isothiocyanate to yield the intermediate 2-[2-(p-Cl-phenoxy)acetyl)-N-phenyl-hydrazinecarbothioamide. This intermediate was then cyclized to form 5-[p-(Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-thiol (the parent moiety) at alkaline pH. In parallel, 3-bromopropionyl bromide was reacted with a series of phenylamines to yield N-(substituted-phenyl)bromopropanamides. In the final step, N-substitution of 5-[p-(Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-thiol was carried out with N-(substituted-phenyl)bromopropanamides to give desired library of 3-[5-[(p-Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-ylthio]-N-(substituted-phenyl) propan-amides (8a-l). The prepared moieties were identified via IR, NMR, & EIMS and evaluated for urease and anti-proliferative activities. 3-[5-[(p-Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-ylthio]-N-(3-methyl-phenyl)propanamide 8k, was found to be most prominent hit as urease inhibitor (IC50= 42.57± 0.13 µM) using thiourea as standard (IC50= 21.25±0.15µM). The interaction of 8k with urease were studied using docking studies. Anti-proliferative activity results showed 8k as promising candidates and rest of the synthesized derivatives were found to be moderately anti-proliferative. Molecular docking results also displayed 8k, 8h, and 8c as potential hits for further study.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia , Urease/antagonistas & inibidores , Células HCT116 , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica , Urease/químicaRESUMO
A polyphenolic flavone Luteolin (3',4',5,7-tetrahydroxyflavone) is found in various plants and is traditionally used in Chinese medicine. It is obtained from Alstonia scholaris (L.) R.Br Flower belonging to the family Apocynaceae while investigation. Various studies have been demonstrated the antioxidant or antiulcer potential of luteolin from different plant sources. In the present investigation the antioxidant or antiulcer effect of the Luteolin has been carried out using molecular docking simulations. The objective of this study was to analyze the antioxidant and antiulcer potential of luteolin obtained during isolation. The in vitro biological evaluation has been supported by the in silico studies using Autodock vina 4 shows the ligand-protein interaction of lute olin with 1HD2, 4GY7 and 3O1Q. Luteolin showed significant DPPH scavenging and urease inhibition activity i.e., 23.4 ± 0.87, 6.21±0.45 IC50 (uM) respectively as compared to the standard BHA and thiourea 44.2±0.45, 22.4±0.29 IC50 (uM) respectively. The docking simulations showed significant binding pocket sites with the respective proteins1HD2, 4GY7 and 3O1Q with the least binding energy -6.8, -8.0 and -8.2 kcal/mol respectively. Thus, Strong evidence has been presented with their confirmation structural interaction via molecular docking with proteins that serve as binding sites for available Luteolin molecule. The findings justify the application of the compound as a novel antioxidant and antiulcer agent.
Assuntos
Alstonia/química , Luteolina/farmacologia , Compostos Fitoquímicos/farmacologia , Urease/antagonistas & inibidores , Compostos de Bifenilo , Sequestradores de Radicais Livres , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Luteolina/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Compostos Fitoquímicos/química , PicratosRESUMO
The urease enzyme has been an important target for the discovery of effective pharmacological and agricultural products. Thirteen regio-selectively alkylated benzimidazole-2-thione derivatives have been designed to carry the essential features of urease inhibitors. The urease enzyme was isolated from Helicobacter pylori as a recombinant urease utilizing the His-tag method. The isolated enzyme was purified and characterized using chromatographic and FPLC techniques showing a maximal activity of 200 mg/mL. Additionally, the commercial Jack bean urease was purchased and included in this study for comparative and mechanistic investigations. The designed compounds were synthesized and screened for their inhibitory activity against the two ureases. Compound 2 inhibited H. pylori and Jack bean ureases with IC50 values of 0.11; and 0.26 mM; respectively. While compound 5 showed IC50 values of 0.01; and 0.29 mM; respectively. Compounds 2 and 5 were docked against Helicobacter pylori urease (PDB ID: 1E9Y; resolution: 3.00 Å) and exhibited correct binding modes with free energy (ΔG) values of -9.74 and -13.82 kcal mol-1; respectively. Further; the in silico ADMET and toxicity properties of 2 and 5 indicated their general safeties and likeness to be used as drugs. Finally, the compounds' safety was authenticated by an in vitro cytotoxicity assay against fibroblast cells.
Assuntos
Benzimidazóis/química , Inibidores Enzimáticos/química , Helicobacter pylori/enzimologia , Simulação de Acoplamento Molecular , Urease , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Helicobacter pylori/genética , Urease/antagonistas & inibidores , Urease/biossíntese , Urease/genética , Urease/isolamento & purificaçãoRESUMO
The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones. Fourteen nitrothiazolacetamide bearing thioquinazolinones derivatives (8a-n) were synthesized through the reaction of isatoic anhydride with different amine, followed by reaction with carbon disulfide and KOH in ethanol. The intermediates were then converted into final products by treating them with 2-chloro-N-(5-nitrothiazol-2-yl)acetamide in DMF. All derivatives were then characterized through different spectroscopic techniques (1H, 13C-NMR, MS, and FTIR). In vitro screening of these molecules against urease demonstrated the potent urease inhibitory potential of derivatives with IC50 values ranging between 2.22 ± 0.09 and 8.43 ± 0.61 µM when compared with the standard thiourea (IC50 = 22.50 ± 0.44 µM). Compound 8h as the most potent derivative exhibited an uncompetitive inhibition pattern against urease in the kinetic study. The high anti-ureolytic activity of 8h was confirmed against two urease-positive microorganisms. According to molecular docking study, 8h exhibited several hydrophobic interactions with Lys10, Leu11, Met44, Ala47, Ala85, Phe87, and Pro88 residues plus two hydrogen bound interactions with Thr86. According to the in silico assessment, the ADME-Toxicity and drug-likeness profile of synthesized compounds were in the acceptable range.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Quinazolinonas , Urease , Aminas/química , Dissulfeto de Carbono/química , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Etanol/química , Hidróxidos/química , Simulação de Acoplamento Molecular , Oxazinas/química , Compostos de Potássio/química , Urease/antagonistas & inibidores , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/farmacologiaRESUMO
Novel pyrazoline derivatives containing benzo[d]thiazol-2(3H)-one moiety were synthesized and screened for their inhibitory properties against urease, a clinically important metabolic enzyme. Inâ vitro enzyme inhibition studies revealed that all pyrazolines (7.21-87.77â µM) were more potent than the standard inhibitor acetohydroxamic acid (251.74â µM) against the urease enzyme. Most notably, compound 2m, which is more active than the other compounds inâ vitro and molecular docking studies, showed a significant inhibition potential and efficient IC50 values (7.21±0.09â µM) and inâ silico inhibition constant (0.11â µM). Furthermore, molecular dynamics (MD) simulation analysis suggests that the binding stability of urease enzyme and compound 2m were stably maintained during the 100â ns simulation time. Compound 2m also exhibited good physicochemical and pharmacokinetic parameters. The overall results of urease inhibition have indicated that these pyrazoline derivative compounds can be further optimized and developed for the discovery of novel urease inhibitors.