RESUMEN
To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM; 3 96 h IC50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements.
Asunto(s)
Antimaláricos , Oxadiazoles , Plasmodium falciparum , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/síntesis química , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , Animales , Relación Estructura-Actividad , Ratones , Pruebas de Sensibilidad Parasitaria , Estructura Molecular , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Humanos , Malaria Falciparum/tratamiento farmacológicoRESUMEN
Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). Small molecules exhibit more predictable pharmacokinetics than biologics, are less likely to induce immune responses, and can be administered orally. JAK inhibitors function by blocking the activity of JAK enzymes, which prevents the subsequent phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Nevertheless, JAK inhibitors can increase the risk of herpes zoster, cancer, major adverse cardiovascular events, and venous thromboembolism. S1PRMs bind to S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting the lymph nodes and migrating to the gut, thereby reducing inflammation and the immune response in the intestinal mucosa. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Inhibidores de las Cinasas Janus , Moduladores de los Receptores de fosfatos y esfingosina 1 , Humanos , Indanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Oxadiazoles , Piridinas , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacología , Moduladores de los Receptores de fosfatos y esfingosina 1/uso terapéutico , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inhibidores , TriazolesRESUMEN
We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28, demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.
Asunto(s)
Antineoplásicos , Anhidrasa Carbónica IX , Inhibidores de Anhidrasa Carbónica , Óxido Nítrico , Humanos , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Animales , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Óxido Nítrico/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Línea Celular Tumoral , Benzoxazoles/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/uso terapéutico , Antígenos de Neoplasias/metabolismo , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , OxadiazolesRESUMEN
PURPOSE: We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease. METHODS: A mixed model of the decision tree and a Markov model with three health states by OFF-time level (<25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects. FINDINGS: Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%. IMPLICATIONS: Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence.
Asunto(s)
Antiparkinsonianos , Inhibidores de Catecol O-Metiltransferasa , Catecoles , Análisis Costo-Beneficio , Levodopa , Cadenas de Markov , Nitrilos , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/economía , Levodopa/uso terapéutico , Levodopa/economía , Levodopa/administración & dosificación , Inhibidores de Catecol O-Metiltransferasa/uso terapéutico , Nitrilos/uso terapéutico , Nitrilos/economía , Antiparkinsonianos/economía , Antiparkinsonianos/uso terapéutico , Catecoles/economía , Catecoles/uso terapéutico , Años de Vida Ajustados por Calidad de Vida , Árboles de Decisión , Quimioterapia Combinada , Catecol O-Metiltransferasa , Análisis de Costo-Efectividad , OxadiazolesRESUMEN
Pesticides play an important role in the development of agriculture, as they can prevent and control crop diseases and pests, improve crop yield and quality. However, the abuse and improper use of pesticides can lead to negative impacts such as environmental pollution and pest resistance issues. There is an urgent need to develop green, safe, and efficient pesticides. In this work, natural product arecoline was selected as parent structure, a series of arecoline derivatives were designed, synthesized, and systematically investigated antiviral activities against tobacco mosaic virus (TMV). These compounds were found to have good to excellent anti-TMV activities for the first time. The antiviral activities of 4a, 4 h, 4 l, 4p, 6a, 6c, and 6f are higher than that of ningnanmycin. Compounds 4 h (EC50 value 146 µg/mL) and 4p (EC50 value 161 µg/mL) with simple structures and excellent activities emerged as new antiviral candidates. We chose 4 h to further investigate the antiviral mechanism, which revealed that it can cause virus fragmentation by acting on the viral coat protein (CP). We further validated this result through molecular docking. These compounds also displayed broad-spectrum fungicidal activities against 8 plant pathogenic fungi. This work lays the theoretical foundation for the application of arecoline derivatives in the agricultural field.
Asunto(s)
Antivirales , Arecolina , Diseño de Fármacos , Oxadiazoles , Virus del Mosaico del Tabaco , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Arecolina/farmacología , Arecolina/síntesis química , Arecolina/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento MolecularRESUMEN
To increase the success rate of drug discovery, one practical strategy is to begin molecular hybridisation. The presence of two or more pharmacophores in a single unit leads to a pharmacological potency greater than the sum of each individual moiety's potency. Heterocyclic compounds are very widely distributed in nature and are essential for life activities. Benzimidazole and oxadiazole are privileged structures in medicinal chemistry and are widely used in drug discovery and development due to their vast biological properties. The drug-like properties (like pharmacokinetics and pharmacodynamics) of the individual scaffolds can be improved by benzimidazole-oxadiazole chimeric molecules via a molecular hybridisation approach. Benzimidazole and oxadiazole cores can either be fused or incorporated using either functional groups/bonds. Over the last few decades, drug discovery scientists have predicted that these moieties could be interconnected to yield a novel or modified hybrid compound. Benzimidazole and oxadiazole hybrids were identified as the most potent anticancer, antimicrobial, anti-inflammatory, antioxidant, anticonvulsant, antidepressant, antihypertensive and antitubercular agents. In this context, the present review describes the biological properties of benzimidazole-oxadiazole (1,3,4 and 1,2,4) hybrids, their possible structure-activity relationship and the mechanism of action studies presented. This review article is intended to stimulate fresh ideas in the search for rational designs of more active and less toxic benzimidazole-oxadiazole hybrid prospective therapeutic candidates, as well as more effective diagnostic agents and pathologic probes.
Asunto(s)
Bencimidazoles , Oxadiazoles , Oxadiazoles/química , Oxadiazoles/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Humanos , Relación Estructura-Actividad , Química Farmacéutica , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Descubrimiento de Drogas , Antioxidantes/química , Antioxidantes/farmacologíaRESUMEN
Neurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the NF1 gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of NF1 pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.
Asunto(s)
Codón sin Sentido , Modelos Animales de Enfermedad , Neurofibromatosis 1 , Neurofibromina 1 , Animales , Codón sin Sentido/efectos de los fármacos , Ratones , Masculino , Femenino , Neurofibromatosis 1/genética , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromina 1/genética , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Humanos , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
AIM: To evaluate the efficacy and safety of azilsartan medoxomil for preoperative preparation and improving the long-term prognosis of elective percutaneous coronary intervention (PCI) in patients with ischemic heart disease (IHD), arterial hypertension (AH), and type 2 diabetes mellitus (DM). MATERIAL AND METHODS: The study sample included patients with type 2 DM referred for elective PCI who had poor blood pressure (BP) control according to 24-hour BP monitoring (24-BPM) (mean daily systolic BP ≥130 mmHg, mean daily diastolic BP ≥80 mmHg). The data were collected from 2018 through 2020. A total of 75 patients was included and distributed by simple randomization into two groups: group 1 (main, n=37) received azilsartan medoxomil as an antihypertensive drug at a dose of 40 mg/day (previously prescribed angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ARB) were discontinued); group 2 (control, n=38) continued on their previous antihypertensive therapy. The follow-up period was 6 months. During each of 5 consecutive follow-up visits, the patient was examined, 24-BPM was recorded, and urinary markers of renal dysfunction (glomerular filtration rate, GFR; neutrophil gelatinase-associated lipocalin, NGAL; urine albumin-creatinine ratio, UACR; kidney injury molecule, KIM-1; and interleukin-18, IL-18) were measured. RESULTS: During the azilsartan treatment, GFR decreased by 7.4%, while in the control group, it decreased by 18.9% (p<0.001). For 6 months of follow-up, no changes in the NGAL concentration were found in the main group, while the NGAL concentration in the control group increased by 12.9%. With azilsartan, there was a decrease in the urinary concentration of IL-18 (16.9%), while in patients of the control group, IL-18 increased (7.14%). Proteinuria progressed in both groups, which was expectable given the presence of DM; however, in patients receiving azilsartan, the UACR value increased by 37.5%, while in patients of the control group, it increased by 96.15%. These differences were statistically significant. No statistically significant differences were found in the concentrations of cystatin C and KIM-1. CONCLUSION: This study demonstrated two important facts: the possibility for diagnosing contrast-induced acute kidney injury (CI-AKI) using new, more sensitive markers of kidney damage, which is important for assessing the effectiveness of prevention, and the possibility of using ARBs, in particular azilsartan, for the prevention of CI-AKI in patients with IHD in combination with AH and DM.
Asunto(s)
Bencimidazoles , Diabetes Mellitus Tipo 2 , Hipertensión , Oxadiazoles , Intervención Coronaria Percutánea , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Oxadiazoles/efectos adversos , Oxadiazoles/administración & dosificación , Persona de Mediana Edad , Bencimidazoles/efectos adversos , Bencimidazoles/administración & dosificación , Intervención Coronaria Percutánea/métodos , Anciano , Antihipertensivos/uso terapéutico , Cuidados Preoperatorios/métodos , Isquemia MiocárdicaRESUMEN
KKL-35 is a new oxadiazole compound with potent broad-spectrum antibacterial activity against a number of gram-positive and gram-negative bacteria. However, its influences on bacterial growth are unclear. This study is to investigate phenotypic changes of Staphylococcus aureus (SA) caused by KKL-35 and evaluate antibacterial activity of combinations of KKL-35 with 7 class of antibiotics available in medical facilities. KKL-35-treated SA showed significantly lower survival under stresses of NaCl and H2O2 than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for H2O2). UV exposure significantly decreased survival of SA treated with KKL-35 than DMSO-treated ones (23.91 ± 0.71% vs. 55.45 ± 4.70% for 4.2 J/m2, 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m2, 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m2). KKL-35 significantly decreased biofilm formation (0.47 ± 0.12 vs. 1.45 ± 0.21) and bacterial survival in the serum resistance assay (42.27 ± 2.77% vs. 78.31 ± 5.64%) than DMSO. KKL-35 significantly decreased ethidium bromide uptake and efflux, as well as the cell membrane integrity. KKL-35 had low cytotoxicity and low propensity for resistance. KKL-35 inhibited SA growth in concentration-independent and time-dependent manners, and showed additivity when combined with the majority class of available antibiotics. Antibiotic combinations of KKL-35 with ciprofloxacin, rifampicin, or linezolid significantly decreased bacterial loads than the most active antibiotic in the corresponding combination. Thus, KKL-35 inhibits growth of SA by decreasing bacterial environmental adaptations, biofilm formation, membrane uptake and efflux, as well as increasing antibiotic sensitivity. Its potent antibacterial activity, low cytotoxicity, low propensity for resistance, and wide choices in antibiotic combinations make KKL-35 a promising leading compound to design new antibiotics in monotherapies and combination therapies to treat bacterial infections.
Asunto(s)
Antibacterianos , Biopelículas , Pruebas de Sensibilidad Microbiana , Oxadiazoles , Staphylococcus aureus , Humanos , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Oxadiazoles/farmacología , Fenotipo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.
Asunto(s)
Antineoplásicos , Receptores ErbB , Simulación del Acoplamiento Molecular , Naproxeno , Oxadiazoles , Receptores ErbB/antagonistas & inhibidores , Humanos , Oxadiazoles/farmacología , Oxadiazoles/química , Oxadiazoles/síntesis química , Naproxeno/farmacología , Naproxeno/análogos & derivados , Naproxeno/química , Naproxeno/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Proliferación Celular/efectos de los fármacosRESUMEN
The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.
Asunto(s)
Radioisótopos de Flúor , Inhibidores de Histona Desacetilasas , Radiofármacos , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Radioisótopos de Flúor/química , Radiofármacos/química , Radiofármacos/síntesis química , Diseño de Fármacos , Humanos , Radioquímica/métodos , Oxadiazoles/química , Oxadiazoles/síntesis químicaRESUMEN
A series of 13 new 3-substituted 5-(5-nitro-2-furyl)-1,2,4-oxadiazoles was synthesized from different aminonitriles. All compounds were screened in the disc diffusion test at a 100 µg/mL concentration to determine the bacterial growth inhibition zone presence and diameter, and then the minimum inhibitory concentrations (MICs) were determined for the most active compounds by serial dilution. The compounds showed antibacterial activity against ESKAPE bacteria, predominantly suppressing the growth of 5 species out of the panel. Some compounds had similar or lower MICs against ESKAPE pathogens compared to ciprofloxacin, nitrofurantoin, and furazidin. In particular, 3-azetidin-3-yl-5-(5-nitro-2-furyl)-1,2,4-oxadiazole (2h) inhibited S. aureus at a concentration lower than all comparators. Compound 2e (5-(5-nitro-2-furyl)-3-[4-(pyrrolidin-3-yloxy)phenyl]-1,2,4-oxadiazole) was active against Gram-positive ESKAPE pathogens as well as M. tuberculosis. Differences in the molecular periphery led to high selectivity for the compounds. The induced-fit docking (IFD) modeling technique was applied to in silico research. Molecular docking results indicated the targeting of compounds against various nitrofuran-associated biological targets.
Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Nitrofuranos , Nitrofuranos/farmacología , Nitrofuranos/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Oxadiazoles/química , Oxadiazoles/farmacología , Estructura Molecular , Staphylococcus aureus/efectos de los fármacosRESUMEN
The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process.
Asunto(s)
Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Inhibidores de las Cinasas Janus , Moduladores de los Receptores de fosfatos y esfingosina 1 , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de las Cinasas Janus/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/metabolismo , Pirazoles/farmacología , Colon/microbiología , Colon/metabolismo , Colon/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/administración & dosificación , Purinas , Azetidinas/farmacología , Azetidinas/administración & dosificación , Compuestos de Bencilo/farmacología , Compuestos de Bencilo/administración & dosificación , Piperidinas/farmacología , Piperidinas/administración & dosificación , Pirimidinas/farmacología , Pirimidinas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Oxadiazoles/farmacología , Oxadiazoles/administración & dosificación , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inhibidores , Pirroles/farmacología , Pirroles/administración & dosificación , Indanos/farmacología , Indanos/administración & dosificación , Piridinas , TriazolesRESUMEN
RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure-based virtual screening, a novel hit with 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC50 value of 1.3 µM. Further structure-activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound 2 with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development.
Asunto(s)
Simulación de Dinámica Molecular , Oxadiazoles , Inhibidores de Proteínas Quinasas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Humanos , Relación Estructura-Actividad , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Oxadiazoles/farmacología , Oxadiazoles/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Simulación del Acoplamiento Molecular , Imidazoles/farmacología , Imidazoles/química , Evaluación Preclínica de Medicamentos , Descubrimiento de Drogas/métodosRESUMEN
Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.
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Antineoplásicos , Apoptosis , Ferroptosis , Donantes de Óxido Nítrico , Neoplasias de la Mama Triple Negativas , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Ferroptosis/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/uso terapéutico , Donantes de Óxido Nítrico/síntesis química , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Oxadiazoles/química , Oxadiazoles/farmacología , Piranos/química , Piranos/farmacologíaRESUMEN
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO (NtPPO) and herbicidal activity were evaluated. Among them, compounds B11 (Ki = 9.05 nM) and B20 (Ki = 10.23 nM) showed significantly better inhibitory activity against NtPPO than that against flumiclorac-pentyl (Ki = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to NtPPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.
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Amaranthus , Diseño de Fármacos , Inhibidores Enzimáticos , Herbicidas , Simulación del Acoplamiento Molecular , Oxadiazoles , Ftalimidas , Malezas , Protoporfirinógeno-Oxidasa , Tiadiazoles , Herbicidas/química , Herbicidas/farmacología , Herbicidas/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Malezas/efectos de los fármacos , Malezas/enzimología , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/síntesis química , Relación Estructura-Actividad , Ftalimidas/química , Ftalimidas/farmacología , Ftalimidas/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Protoporfirinógeno-Oxidasa/antagonistas & inhibidores , Protoporfirinógeno-Oxidasa/química , Protoporfirinógeno-Oxidasa/metabolismo , Amaranthus/química , Amaranthus/efectos de los fármacos , Proteínas de Plantas/química , Proteínas de Plantas/antagonistas & inhibidores , Estructura Molecular , Nicotiana/químicaRESUMEN
Dinophysistoxin 1 (DTX1, 1) and okadaic acid (OA, 2), produced by the dinoflagellates Dinophysis spp. and Prorocentrum spp., are primary diarrhetic shellfish toxins (DSTs), which may cause gastric illness in people consuming such as bivalves. Both compounds convert to dinophysistoxin 3 (DTX3, 3; generic name for 1 and 2 with fatty acids conjugated at 7-OH) in bivalves. The enzyme okadaic acid O-acyl transferase (OOAT) is a membrane protein found in the microsomes of the digestive glands of bivalves. In this study, we established an in vitro enzymatic conversion reaction using 4-nitro-2,1,3-benzoxadiazole (NBD)-OA (4), an OA derivative conjugated with (R)-(-)-4-nitro-7-(3-aminopyrrolidin-1-yl)-2,1,3-benzoxadiazole (NBD-APy) on 1-CO2H, as a substrate. We detected the enzymatically produced 3, NBD-7-O-palmitoyl-OA (NBD-Pal-OA), using high-performance liquid chromatography-fluorescence detection. We believe that an OOAT assay using 4 will facilitate the fractionation and isolation of OOAT in the future.
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Aciltransferasas , Ácido Ocadaico , Cromatografía Líquida de Alta Presión/métodos , Aciltransferasas/metabolismo , Aciltransferasas/química , Animales , Oxadiazoles/química , Pruebas de Enzimas/métodosRESUMEN
This review article offers an environmentally benign synthesis of 1,3,4-oxadiazole derivatives, with a focus on sustainable methodologies that have minimal impact on the environment. These derivatives, known for their diverse applications, have conventionally been associated with synthesis methods that utilize hazardous reagents and produce significant waste, thereby raising environmental concerns. The green synthesis of 1,3,4-oxadiazole derivatives employs renewable substrates, nontoxic catalysts, and mild reaction conditions, aiming to minimize the environmental impact. Innovative techniques such as catalyst-based, catalyst-free, electrochemical synthesis, green-solvent-mediated synthesis, grinding, microwave-mediated synthesis, and photosynthesis are implemented, providing benefits in terms of scalability, cost-effectiveness, and ease of purification. This review emphasizes the significance of sustainable methodologies in the synthesis of 1,3,4-oxadiazole and boots for continued exploration in this research domain.
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Tecnología Química Verde , Oxadiazoles , Oxadiazoles/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacología , Microondas , Catálisis , Solventes/química , Estructura MolecularRESUMEN
Tioxazafen (TXF) is the first 1,2,4-oxadiazole nematicide. In the present study, the aqueous degradation of TXF was investigated in terms of hydrolysis and photolysis. Under the irradiation of simulated sunlight, TXF degraded very fast in ultrapure water and buffers with half-lives (t1/2s) <8.3 min. A sole photoproduct (PP) PP228a was isolated, and identified by spectroscopic means (UV, IR, HRMS, and 1H NMR) to be the thiophen-3-yl isomer converted from its thiophen-2-yl parent. Comparing with TXF, PP228a had quite extended t1/2s ranging from 6.9 to 7.9 d. The photolysis kinetics of TXF and PP228a showed no pH-dependence, and varied for each individual compound as affected by nitrate, fulvic acid, and humic acid. Besides, both compounds were hydrolytically stable. 6 PPs of PP228a were identified, with two of them being its isomers. The mechanisms involved in the process included the biradical photosensitization, photoinduced electron transfer, and ring contraction-ring expansion reactions. The 48 h-EC50 to Daphnia magna was 0.808 mg/L for PP228a comparing to >1.12 mg/L for TXF, while the results of Vibrio fischeri assays indicated that one or more PPs of PP228a might have higher toxicity.
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Fotólisis , Contaminantes Químicos del Agua , Cinética , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/química , Oxadiazoles/química , Oxadiazoles/toxicidad , Daphnia/efectos de los fármacos , AnimalesRESUMEN
Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention.