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Molecules (Basel, Switzerland) Jul 2023Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly...
Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that -acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-]pyridazinone. Novel compounds --- were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title -acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins-AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.
Topics: Hydrazones; Cyclooxygenase Inhibitors; Lipoxygenase Inhibitors; Pyridazines; Pyrroles; Humans; Fibroblasts; Computer Simulation; Cell Membrane Permeability; Cell Line
PubMed: 37513351
DOI: 10.3390/molecules28145479 -
Molecules (Basel, Switzerland) May 2022In this article, we present fluorescent guanidiniocarbonyl-indoles as versatile oxo-anion binders. Herein, the guanidiniocarbonyl-indole (GCI) and...
In this article, we present fluorescent guanidiniocarbonyl-indoles as versatile oxo-anion binders. Herein, the guanidiniocarbonyl-indole (GCI) and methoxy-guanidiniocarbonyl-indole (MGCI) were investigated as ethylamides and compared with the well-known guanidiniocarbonyl-pyrrole (GCP) concerning their photophysical properties as well as their binding behavior towards oxo-anions. Hence, a variety of anionic species, such as carboxylates, phosphonates and sulfonates, have been studied regarding their binding properties with GCP, GCI and MGCI using UV-Vis titrations, in combination with the determination of the complex stoichiometry using the Job method. The emission properties were studied in relation to the pH value using fluorescence spectroscopy as well as the determination of the photoluminescence quantum yields (PLQY). Density functional theory (DFT) calculations were undertaken to obtain a better understanding of the ground-lying electronic properties of the investigated oxo-anion binders. Additionally, X-ray diffraction of GCP and GCI was conducted. We found that GCI and MGCI efficiently bind carboxylates, phosphonates and sulfonates in buffered aqueous solution and in a similar range as GCP (K ≈ 1000-18,000 M, in bis-tris buffer, pH = 6); thus, they could be regarded as promising emissive oxo-anion binders. They also exhibit a visible fluorescence with a sufficient PLQY. Additionally, the excitation and emission wavelength of MGCI was successfully shifted closer to the visible region of the electromagnetic spectrum by introducing a methoxy-group into the core structure, which makes them interesting for biological applications.
Topics: Anions; Arginine; Carboxylic Acids; Fluorescent Dyes; Indoles; Organophosphonates; Pyrroles
PubMed: 35566361
DOI: 10.3390/molecules27093005 -
Trials Dec 2023Vonoprazan results in more potent acid suppression for gastroesophageal reflux disease (GERD) than proton pump inhibitors. It has only been approved for treating erosive...
Different dosages of vonoprazan for gastroesophageal reflux disease: study protocol for a pragmatic, crossover-cluster, randomized controlled trial with patient preference arms.
BACKGROUND
Vonoprazan results in more potent acid suppression for gastroesophageal reflux disease (GERD) than proton pump inhibitors. It has only been approved for treating erosive esophagitis in China, but 30-40% of GERD patients cannot achieve the goal of treatment with vonoprazan 20 mg daily. This study aims to investigate whether vonoprazan could relieve the symptoms of Chinese patients with non-erosive reflux disease (NERD) and whether increased dosage or different times of dosing could increase the response rate of GERD.
METHODS
This study is a pragmatic, open-label, crossover-cluster, randomized controlled trial with patient preference arms. Two thousand eight hundred eighty patients with GERD from 48 hospitals in China will be enrolled. These hospitals will be divided into a compulsory randomization cluster (24 hospitals) and a patient preference cluster (24 hospitals). Patients in the compulsory randomization cluster will be randomized to three regimens according to the crossover-cluster randomization. Patients in the patient preference cluster may choose to receive any regimen if they have a preference; otherwise, patients will be randomly assigned. The three treatment regimens will last 4 weeks, including (1) vonoprazan 20 mg p.o. after breakfast, (2) vonoprazan 20 mg p.o. after dinner, and (3) vonoprazan 20 mg p.o. after breakfast and after dinner. Patients will attend a baseline visit, a 4-week e-diary, a fourth-week visit, and a sixth-month visit online. The primary outcome is the symptom relief rate of all patients after 4-week therapy. Secondary outcomes include the healing rate of EE patients, the severity of symptoms, compliance with the therapy at the fourth-week follow-up visit, recurrent symptoms, and the frequency of self-conscious doctor visits at the sixth-month follow-up visit.
DISCUSSION
This trial will explore the effectiveness of different regimens of vonoprazan that will be implemented with GERD patients in China. The randomization with patient preferences considered and the crossover-cluster component may improve the robustness and extrapolation of study conclusions.
TRIAL REGISTRATION
https://www.chictr.org.cn ChiCTR2300069857. Registered on 28 March 2023.
PROTOCOL VERSION
February 18, 2023, Version 2.
Topics: Humans; Patient Preference; Gastroesophageal Reflux; Proton Pump Inhibitors; Pyrroles; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 38041136
DOI: 10.1186/s13063-023-07760-9 -
Molecules (Basel, Switzerland) May 2016The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a... (Review)
Review
The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a comparatively small number of ring-containing structures. Pyrrole, indole, pyridine, quinoline, quinazoline and related 6-membered ring-containing aza-arenes figure prominently. This review focuses on the search for fast, efficient and environmentally friendly preparative methods for these rings with specific emphasis on iminyl radical-mediated procedures. Oxime derivatives, particularly oxime esters and oxime ethers, are attractive precursors for these radicals. Their use is described in conventional thermolytic, microwave-assisted and UV-vis based preparative procedures. Photoredox-catalyzed protocols involving designer oxime ethers are also covered. Choice can be made amongst these synthetic strategies for a wide variety of 5- and 6-membered ring heterocycles including phenanthridine and related aza-arenes. Applications to selected natural products and bioactive molecules, including trispheridine, vasconine, luotonin A and rutaecarpine, are included.
Topics: Catalysis; Cyclization; Dioxoles; Free Radicals; Indole Alkaloids; Oximes; Phenanthridines; Pyridines; Pyrroles; Quinazolines; Quinones
PubMed: 27213311
DOI: 10.3390/molecules21050660 -
Molecules (Basel, Switzerland) Apr 2022Despite the tubulin-binding agents (TBAs) that are widely used in the clinic for cancer therapy, tumor resistance to TBAs (both inherited and acquired) significantly...
Despite the tubulin-binding agents (TBAs) that are widely used in the clinic for cancer therapy, tumor resistance to TBAs (both inherited and acquired) significantly impairs their effectiveness, thereby decreasing overall survival (OS) and progression-free survival (PFS) rates, especially for the patients with metastatic, recurrent, and unresectable forms of the disease. Therefore, the development of novel effective drugs interfering with the microtubules' dynamic state remains a big challenge in current oncology. We report here about the novel ethyl 2-amino-1-(furan-2-carboxamido)-5-(2-aryl/tert-butyl-2-oxoethylidene)-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates (EAPCs) exhibiting potent anti-cancer activities against the breast and lung cancer cell lines in vitro. This was due to their ability to inhibit tubulin polymerization and induce cell cycle arrest in M-phase. As an outcome, the EAPC-treated cancer cells exhibited a significant increase in apoptosis, which was evidenced by the expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin-V-positive cells. By using the in silico molecular modeling methods (e.g., induced-fit docking, binding metadynamics, and unbiased molecular dynamics), we found that EAPC-67 and -70 preferentially bind to the colchicine-binding site of tubulin. Lastly, we have shown that the EAPCs indicated above and colchicine utilizes a similar molecular mechanism to inhibit tubulin polymerization via targeting the T7 loop in the β-chain of tubulin, thereby preventing the conformational changes in the tubulin dimers required for their polymerization. Collectively, we identified the novel and potent TBAs that bind to the colchicine-binding site and disrupt the microtubule network. As a result of these events, the compounds induced a robust cell cycle arrest in M-phase and exhibited potent pro-apoptotic activities against the epithelial cancer cell lines in vitro.
Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Colchicine; Humans; Microtubules; Pyrroles; Tubulin; Tubulin Modulators
PubMed: 35566235
DOI: 10.3390/molecules27092873 -
International Journal of Molecular... Jan 2021In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides -. The compounds - were...
In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides -. The compounds - were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-]pyrrole scaffold (-) with secondary amines and an excess of formaldehyde solution in CHOH. The structural properties of the compounds were characterized by H NMR, C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound . The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.
Topics: Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Drug Design; Enzyme Assays; Humans; Imides; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Molecular Structure; Pyrroles; Structure-Activity Relationship
PubMed: 33573356
DOI: 10.3390/ijms22031410 -
Nature Communications May 2018Transition-metal-catalyzed diazo activation is a classical way to generate metal carbene, which are valuable intermediates in synthetic organic chemistry. An alternative...
Transition-metal-catalyzed diazo activation is a classical way to generate metal carbene, which are valuable intermediates in synthetic organic chemistry. An alternative iodine-catalyzed diazo activation is disclosed herein under either photo-initiated or thermal-initiated conditions, which represents an approach to enable carbene radical reactivity. This metal-free diazo activation strategy were successfully applied into olefin cyclopropanation and epoxidation, and applying this method to pyrrole synthesis under thermal-initiated conditions further demonstrates the unique reactivity using this method over typical metal-catalyzed conditions.
Topics: Alkenes; Catalysis; Chemistry, Organic; Iodine; Light; Methane; Pyrroles; Temperature
PubMed: 29773787
DOI: 10.1038/s41467-018-04331-4 -
Journal of Nippon Medical School =... 2017Reflux esophagitis is characterized by excessive esophageal acid exposure. To treat reflux esophagitis, it is necessary to reduce excessive esophageal acid exposure to... (Review)
Review
Reflux esophagitis is characterized by excessive esophageal acid exposure. To treat reflux esophagitis, it is necessary to reduce excessive esophageal acid exposure to within the normal range. The first-line drug for the treatment of reflux esophagitis is a standard-dose proton-pump inhibitor (PPI), which is also recommended by the Evidence-based Clinical Practice Guidelines 2015 for gastroesophageal disease of the Japanese Society of Gastroenterology. It has been reported that the response to a standard dose of PPI in patients with mild reflux esophagitis is 90-100%, and that in patients with severe reflux esophagitis is 80-85%. However, PPI-resistant reflux esophagitis has been increasing. When the standard dose of PPI is not effective, modification of the lifestyle with PPI therapy, switching to another PPI, or a change in the administration method (before meals), as well as double-dose PPI (in divided doses), may be effective. In addition, vonoprazan (potassium-competitive acid blocker), which has rapid and potent acid-suppressive effects, became available in February 2015 in Japan. In the clinical trial data, vonoprazan is very effective for reflux esophagitis. However, clinical data on vonoprazan are still insufficient. The establishment of a new treatment for reflux esophagitis taking advantage of the rapid and potent acid-suppressive effects is awaited.
Topics: Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance; Drug Substitution; Esophagitis, Peptic; Gastroenterology; Humans; Japan; Life Style; Practice Guidelines as Topic; Proton Pump Inhibitors; Pyrroles; Severity of Illness Index; Societies, Medical; Sulfonamides; Treatment Outcome
PubMed: 29142181
DOI: 10.1272/jnms.84.209 -
PLoS Neglected Tropical Diseases Mar 2020Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant...
Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs.
Topics: Animals; Anisomycin; Antiparasitic Agents; Cell Line; Cell Survival; Drug Repositioning; Fibroblasts; Humans; Indoles; Mice; Parasites; Parasitic Sensitivity Tests; Prodigiosin; Pyrroles; Rats
PubMed: 32196500
DOI: 10.1371/journal.pntd.0008150 -
Nature Communications Jul 2023One-pot multicomponent coupling of different units in a chemoselective manner and their late-stage diversification has wide applicability in varying chemistry fields....
One-pot multicomponent coupling of different units in a chemoselective manner and their late-stage diversification has wide applicability in varying chemistry fields. Here, we report a simple multicomponent reaction inspired by enzymes that combines thiol and amine nucleophiles in one pot via a furan-based electrophile to generate stable pyrrole heterocycles independent of the diverse functionalities on furans, thiols and amines under physiological conditions. The resulting pyrrole provides a reactive handle to introduce diverse payloads. We demonstrate the application of Furan-Thiol-Amine (FuTine) reaction for the selective and irreversible labeling of peptides, synthesis of macrocyclic and stapled peptides, selective modification of twelve different proteins with varying payloads, homogeneous engineering of proteins, homogeneous stapling of proteins, dual modification of proteins with different fluorophores using the same chemistry and labeling of lysine and cysteine in a complex human proteome.
Topics: Humans; Sulfhydryl Compounds; Amines; Furans; Pyrroles
PubMed: 37429878
DOI: 10.1038/s41467-023-39708-7