-
World Journal of Gastroenterology Apr 2020Third generation of quinolones, such as levofloxacin and moxifloxacin, -containing regimens are often used in second-line or rescue treatment of infection. However, the... (Review)
Review
Third generation of quinolones, such as levofloxacin and moxifloxacin, -containing regimens are often used in second-line or rescue treatment of infection. However, the increasing antibiotic resistance to quinolones affects the efficacies of quinolones-containing therapies in recent years. Therefore, there is a need to enhance the effectiveness of quinolones-containing therapies. Sitafloxacin, a fourth-generation quinolone, and vonoprazan, a novel potassium-competitive acid blocker, are now available as more effective treatment options. The aim of this paper is to summarize the current evidence of quinolone-containing therapies in rescue treatments, and to discuss the importance of drug sensitivity tests or analysis of mutation before treatments.
Topics: Anti-Bacterial Agents; DNA Gyrase; DNA Mutational Analysis; DNA, Bacterial; Drug Resistance, Bacterial; Drug Therapy, Combination; Evidence-Based Medicine; Fluoroquinolones; Gastroenterology; Helicobacter Infections; Helicobacter pylori; Humans; Microbial Sensitivity Tests; Mutation; Proton Pump Inhibitors; Pyrroles; Sulfonamides
PubMed: 32351290
DOI: 10.3748/wjg.v26.i15.1733 -
Microbiology Spectrum Jun 2022Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new...
Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global increase in multidrug-resistant strains necessitates alternative therapeutic options. Host-targeted therapeutics present a promising anti-infective strategy against intracellular bacterial pathogens. A cell-based assay identified a compound that inhibits proliferation in infected cells, 2-(3-hydroxypropyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione (KH-1), which is devoid of direct activity against . The compound inhibits the growth of both antibiotic-sensitive and -resistant strains inside macrophages and reduces lactate dehydrogenase (LDH) release from -infected cells. Subsequent screening of KH-1 commercial analogs identified 2-(4-fluorobenzyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-dione (KH-1-2), which is more effective in controlling growth inside macrophages. KH-1-2 treatment of infection resulted in an 8- to 10-fold reduction in bacterial load in infected macrophages. In combination with suboptimal ciprofloxacin treatment, KH-1-2 further reduces growth inside macrophages. The toxicity and efficacy of KH-1-2 in controlling infection were examined using a mouse model of typhoid fever. No significant compound-related clinical signs and histological findings of the liver, spleen, or kidney were observed from uninfected mice that were intraperitoneally treated with KH-1-2. KH-1-2 significantly protected mice from a lethal dose of infection by an antibiotic-resistant strain. Thus, our study provides support that this is a promising lead compound for the development of a novel host-targeted therapeutic agent to control typhoid fever. spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., Typhi) cause a systemic disease typically treated with antibiotics. However, growing antibiotic resistance is resulting in increased treatment failures. We screened a compound library for those that would reduce -induced macrophage toxicity, identifying compound KH-1. KH-1 has no direct effects on the bacteria but limits survival in macrophages and protects against lethal infection in a mouse model of typhoid fever. A suboptimal concentration of ciprofloxacin worked in conjunction with the compound to further decrease survival in macrophages. An analog (KH-1-2) was identified that possessed increased activity in macrophages and against both antibiotic-sensitive and -resistant strains. Thus, we report the identification of a lead compound that may be a useful scaffold as a host-directed antimicrobial against typhoid fever.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Ciprofloxacin; Humans; Pyrroles; Salmonella; Salmonella typhi; Typhoid Fever
PubMed: 35579463
DOI: 10.1128/spectrum.00619-22 -
ChemMedChem Sep 2021Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated...
Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold-hopping approach to vary the pyrrole ring of the pyrrolo[1,2-a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end-point free-energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.
Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Pyrroles; Quinoxalines; Structure-Activity Relationship
PubMed: 34137509
DOI: 10.1002/cmdc.202100338 -
Internal Medicine (Tokyo, Japan) Apr 2022
Topics: Adenomatous Polyps; Gastric Fundus; Humans; Intussusception; Polyps; Pyrroles; Stomach Neoplasms; Sulfonamides
PubMed: 34565778
DOI: 10.2169/internalmedicine.8235-21 -
Journal of the American Chemical Society Jun 2020Herein, we describe an efficient method to prepare polysubstituted pyrroles via a copper hydride (CuH)-catalyzed enyne-nitrile coupling reaction. This protocol...
Herein, we describe an efficient method to prepare polysubstituted pyrroles via a copper hydride (CuH)-catalyzed enyne-nitrile coupling reaction. This protocol accommodates both aromatic and aliphatic substituents and a broad range of functional groups, providing a variety of N-H pyrroles in good yields and with high regioselectivity. We propose that the Cu-based catalyst promotes both the initial reductive coupling and subsequent cyclization steps. Density functional theory (DFT) calculations were performed to elucidate the reaction mechanism.
Topics: Alkynes; Catalysis; Copper; Hydrogen; Molecular Structure; Nitriles; Pyrroles
PubMed: 32395998
DOI: 10.1021/jacs.0c03859 -
Antimicrobial Agents and Chemotherapy 2015Acanthamoeba is a protist pathogen that can cause serious human infections, including blinding keratitis and a granulomatous amoebic encephalitis that almost always...
Acanthamoeba is a protist pathogen that can cause serious human infections, including blinding keratitis and a granulomatous amoebic encephalitis that almost always results in death. The current treatment for these infections includes a mixture of drugs, and even then, a recurrence can occur. Photochemotherapy has shown promise in the treatment of Acanthamoeba infections; however, the selective targeting of pathogenic Acanthamoeba has remained a major concern. The mannose-binding protein is an important adhesin expressed on the surface membranes of pathogenic Acanthamoeba organisms. To specifically target Acanthamoeba, the overall aim of this study was to synthesize a photosensitizing compound (porphyrin) conjugated with mannose and test its efficacy in vitro. The synthesis of mannose-conjugated porphyrin was achieved by mixing benzaldehyde and pyrrole, yielding tetraphenylporphyrin. Tetraphenylporphyrin was then converted into mono-nitrophenylporphyrin by selectively nitrating the para position of the phenyl rings, as confirmed by nuclear magnetic resonance (NMR) spectroscopy. The mono-nitrophenylporphyrin was reduced to mono-aminophenylporphyrin in the presence of tin dichloride and confirmed by a peak at m/z 629. Finally, mono-aminoporphyrin was conjugated with mannose, resulting in the formation of an imine bond. Mannose-conjugated porphyrin was confirmed through spectroscopic analysis and showed that it absorbed light of wavelengths ranging from 425 to 475 nm. To determine the antiacanthamoebic effects of the derived product, amoebae were incubated with mannose-conjugated porphyrin for 1 h and washed 3 times to remove extracellular compound. Next, the amoebae were exposed to light of the appropriate wavelength for 1 h. The results revealed that mannose-conjugated porphyrin produced potent trophicidal effects and blocked excystation. In contrast, Acanthamoeba castellanii incubated with mannose alone and porphyrin alone did not exhibit an antiamoebic effect. Consistently, pretreatment with mannose-conjugated porphyrin reduced the A. castellanii-mediated host cell cytotoxicity from 97% to 4.9%. In contrast, treatment with porphyrin, mannose, or solvent alone had no protective effects on the host cells. These data suggest that mannose-conjugated porphyrin has application for the targeted photodynamic therapy of Acanthamoeba infections and may serve as a model in the development of therapeutic interventions against other eukaryotic infections.
Topics: Acanthamoeba castellanii; Antiprotozoal Agents; Benzaldehydes; Cell Line; Cells, Cultured; Humans; Magnetic Resonance Spectroscopy; Mannose; Porphyrins; Pyrroles
PubMed: 25753633
DOI: 10.1128/AAC.05126-14 -
Toxicological Sciences : An Official... Sep 2020Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously...
Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant. The selection of ubrogepant, following a series of mechanistic studies conducted with MK-3207 and telcagepant, was focused on key structural modifications suggesting that ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym) that incorporates quantitative assessments of mitochondrial dysfunction, disruption of bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for telcagepant and MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the approved clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207.
Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Liver; Pyridines; Pyrroles
PubMed: 32579200
DOI: 10.1093/toxsci/kfaa093 -
Nature Communications Nov 2015Palau'amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and...
Palau'amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here we report the total synthesis of palau'amine characterized by the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N-N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation) and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The synthetic palau'amine is confirmed to exhibit excellent immunosuppressive activity. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity.
Topics: Bridged Bicyclo Compounds; Guanidines; Imines; Magnetic Resonance Spectroscopy; Octanes; Pyrroles; Spiro Compounds
PubMed: 26530707
DOI: 10.1038/ncomms9731 -
Pharmaceutical Biology Dec 2020Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on...
Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats. Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 μL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS. Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant ( < 0.05). Compared with the control group, the was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h ( < 0.05), and the MRT was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h ( < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg ( < 0.05) in experimental group. Although the and of tofacitinib were increased, there were no significant differences ( > 0.05). This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Area Under Curve; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Drug Interactions; Female; Flavanones; Piperidines; Pyrimidines; Pyrroles; Rats, Sprague-Dawley; Signal-To-Noise Ratio
PubMed: 32202190
DOI: 10.1080/13880209.2020.1738504 -
Minerva Gastroenterologica E Dietologica Sep 2018Over the past 30 years, multidrug regimens consisting of a proton pump inhibitor (PPI) and two or three antibiotics have been used in treating Helicobacter pylori (H.... (Review)
Review
Over the past 30 years, multidrug regimens consisting of a proton pump inhibitor (PPI) and two or three antibiotics have been used in treating Helicobacter pylori (H. pylori) infection. In clinical practice, the optimal regimen to cure H. pylori infection should be decided regionally. Considering the first treatment, the Maastricht V/Florence Consensus Report and the American College of Gastroenterology Clinical Management Guideline highlight that in countries with low clarithromycin resistance rates (<15%), an empiric clarithromycin-based regimen can be used. In countries with high clarithromycin resistance rates or, in the American Guideline, with a previous exposure to clarithromycin, a bismuth-containing quadruple therapy (with metronidazole and tetracycline) is the first choice. In case of persistent infection, after a previous clarithromycin-containing regimen, this drug should be avoided in second line therapy. Options after initial eradication failure include tailored therapy (choosing antibiotic combinations based on antibiotic susceptibility testing), empiric bismuth-containing quadruple therapy or triple levofloxacin-based therapy. Encouraging data are reported, both for the first-line and for rescue treatments, with the use of a formulation of bismuth subcitrate potassium, metronidazole, and tetracycline contained in a single capsule, together with a PPI. Rifabutin- and furazolidone-based regimens should also be considered in rescue regimens. Vonoprazan, a new type of potassium-competitive acid blocker that produces more potent acid inhibition than PPIs, provides improved H. pylori eradication rates in combination with antibiotics. In this review, the authors provide an overview on the current knowledge on the treatment of H. pylori infection, with focus on therapeutic challenges in this field.
Topics: Anti-Bacterial Agents; Clarithromycin; Clinical Protocols; Drug Resistance, Bacterial; Helicobacter Infections; Helicobacter pylori; Humans; Pyrroles; Sulfonamides
PubMed: 29600697
DOI: 10.23736/S1121-421X.18.02492-3