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EBioMedicine Mar 2021Mitochondria play a vital role in cellular metabolism and are central mediator of intracellular signalling, cell differentiation, morphogenesis and demise. An... (Review)
Review
Mitochondria play a vital role in cellular metabolism and are central mediator of intracellular signalling, cell differentiation, morphogenesis and demise. An increasingly higher number of pathologies is linked with mitochondrial dysfunction, which can arise from either genetic defects affecting core mitochondrial components or malfunctioning pathways impairing mitochondrial homeostasis. As such, mitochondria are considered an important target in several pathologies spanning from neoplastic to neurodegenerative diseases as well as metabolic syndromes. In this review we provide an overview of the state-of-the-art in mitochondrial pharmacology, focusing on the novel compounds that have been generated in the bid to correct mitochondrial aberrations. Our work aims to serve the scientific community working on translational medical science by highlighting the most promising pharmacological approaches to target mitochondrial dysfunction in disease.
Topics: Antioxidants; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics; Neurodegenerative Diseases; Oxidative Phosphorylation; Pyrazines; Ubiquinone
PubMed: 33647769
DOI: 10.1016/j.ebiom.2021.103244 -
Organic & Biomolecular Chemistry Sep 2022Recently, direct C-H bond activation and functionalization has become a prodigious and hot topic among synthetic organic chemists due to its step-economic nature and... (Review)
Review
Recently, direct C-H bond activation and functionalization has become a prodigious and hot topic among synthetic organic chemists due to its step-economic nature and substantial synthetic versatility. On the other hand, quinoxaline, a fused bicycle of benzene and pyrazine, has omnipresent applications in medicinal-, industrial- and materials chemistry. The presence of the N-1 atom in 2-arylquinoxaline enables chelation formation with a metal catalyst leading to the formation of -substituted products. In this review, all articles related to the C-H bond functionalization of 2-arylquinoxalines published up to May 2022 are highlighted.
Topics: Benzene; Catalysis; Pyrazines; Quinoxalines; Transition Elements
PubMed: 36107011
DOI: 10.1039/d2ob01119k -
Bioorganic & Medicinal Chemistry Letters Apr 2020Mitochondrial protonophores transport protons through the mitochondrial inner membrane into the matrix to uncouple nutrient oxidation from ATP production thereby...
Mitochondrial protonophores transport protons through the mitochondrial inner membrane into the matrix to uncouple nutrient oxidation from ATP production thereby decreasing the proton motive force. Mitochondrial uncouplers have beneficial effects of decrease reactive oxygen species generation and have the potential for treating diseases such as obesity, neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), diabetes, and many others. In this study, we report the structure-activity relationship profile of the pyrazine scaffold bearing substituted aniline rings. Our work indicates that a trifluoromethyl group is best at the para position while the trifluoromethoxy group is preferred in the meta position of the aniline rings of 2,3-substituted pyrazines. As proton transport and cycling requires the formation of a negative charge that has to traverse the mitochondrial membrane, a stabilizing internal hydrogen bond is a key feature for efficient mitochondrial uncoupling activity.
Topics: Aniline Compounds; Dose-Response Relationship, Drug; Mitochondria; Molecular Structure; Pyrazines; Reactive Oxygen Species; Structure-Activity Relationship; Uncoupling Agents
PubMed: 32113842
DOI: 10.1016/j.bmcl.2020.127057 -
Food Chemistry Jul 2022The generation of pyrazines in a binary methionine/glucose (Met/Glc) mixture and corresponding methionine/glucose-derived Amadori rearrangement product (MG-ARP) was...
The generation of pyrazines in a binary methionine/glucose (Met/Glc) mixture and corresponding methionine/glucose-derived Amadori rearrangement product (MG-ARP) was studied. Quantitative analyses of pyrazines and methional revealed that MG-ARP generated more methional compared to Met/Glc, whereas lower content and fewer species of pyrazines were observed in the MG-ARP model. Comparing the availability of α-dicarbonyl compounds generated from the Met/Glc model, methylglyoxal (MGO) was a considerably effective α-dicarbonyl compound for the formation of pyrazines during MG-ARP degradation, but glyoxal (GO) produced from MG-ARP did not effectively participate in the corresponding formation of pyrazines due to the asynchrony on the formation of GO and recovered Met. Diacetyl (DA) content was not high enough to form corresponding pyrazines in the MG-ARP model. The insufficient interaction of precursors and rapid drops in pH limited the formation of pyrazines during MG-ARP degradation. Increasing reaction temperature could reduce the negative inhibitory effect by promoting the content of precursors.
Topics: Glucose; Glyoxal; Maillard Reaction; Methionine; Pyrazines
PubMed: 35245757
DOI: 10.1016/j.foodchem.2022.132500 -
Clinical Pharmacology and Therapeutics Aug 2020An outbreak of 2019-nCoV infection has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the... (Review)
Review
An outbreak of 2019-nCoV infection has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the recommended antiviral drugs, such as interferon-ɑ, lopinavir/ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA-dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug-drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.
Topics: Acetaminophen; Amides; Animals; Antiviral Agents; Clinical Trials as Topic; Coronavirus Infections; Drug Interactions; Humans; Pyrazines; COVID-19 Drug Treatment
PubMed: 32246834
DOI: 10.1002/cpt.1844 -
British Journal of Haematology Nov 2022
Topics: Humans; Benzaldehydes; Pyrazines; Pyrazoles
PubMed: 36113859
DOI: 10.1111/bjh.18455 -
Journal of Enzyme Inhibition and... Dec 2022Acipimox, a nicotinic acid derivative in clinical use for the treatment of hyperlipidaemia, incorporates a free carboxylic acid and an N-oxide moiety, functionalities...
Acipimox, a nicotinic acid derivative in clinical use for the treatment of hyperlipidaemia, incorporates a free carboxylic acid and an N-oxide moiety, functionalities known to interact with the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and inhibit its activity. Herein we report that acipimox acts as a low micromolar CA inhibitor (CAI) against most human (h) isoforms possessing catalytic activity, hCA I - XIV. By using computational techniques (docking and molecular dynamics simulations), we propose that acipimox coordinates through its carboxylate group to the zinc ion from the enzyme active site cavity, whereas the N-oxide group is hydrogen-bonded to the proton shuttle His residue in some isoforms (hCA I) or to active site Thr or Gln residues in other isoforms (hCA II, III, IV, VII, etc). As some CA isoforms are involved in lipogenesis, these data may be useful for the design of more effective CAIs with antiobesity activity.
Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; Humans; Isoenzymes; Models, Molecular; Molecular Structure; Pyrazines; Structure-Activity Relationship
PubMed: 35139721
DOI: 10.1080/14756366.2022.2037579 -
Molecules (Basel, Switzerland) Feb 2022There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and... (Review)
Review
There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and phenazine agents that have shown potential therapeutic value, including several clinically used agents. In addition, we cover some basic science related to pyrazine and phenazine heterocycles, which possess interesting reactivity profiles that have been on display in numerous cases of innovative total synthesis approaches, synthetic methodologies, drug discovery efforts, and medicinal chemistry programs. The majority of this review is focused on presenting instructive total synthesis and medicinal chemistry efforts of select pyrazine and phenazine compounds, and we believe these incredible heterocycles offer promise in medicine.
Topics: Chemistry, Pharmaceutical; Drug Discovery; Heterocyclic Compounds; Humans; Phenazines; Pyrazines
PubMed: 35164376
DOI: 10.3390/molecules27031112 -
The Annals of Pharmacotherapy Feb 2021To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). (Review)
Review
OBJECTIVE
To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD).
DATA SOURCES
A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included , , and . Other sources were derived from bibliographies of articles, product labeling, manufacturer's website, and news releases. ClinicalTrials.gov was searched for additional studies.
STUDY SELECTION AND DATA EXTRACTION
All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included.
DATA SYNTHESIS
SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs -0.1 g/dL; < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing.
CONCLUSION
Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.
Topics: Anemia, Sickle Cell; Benzaldehydes; Female; Hematologic Agents; Hemoglobins; Humans; Hydroxyurea; Male; Pyrazines; Pyrazoles; Treatment Outcome; Young Adult
PubMed: 32674605
DOI: 10.1177/1060028020943059 -
Molecules (Basel, Switzerland) Apr 2021A radical approach to late-stage functionalization using photoredox and Diversinate chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4)...
A radical approach to late-stage functionalization using photoredox and Diversinate chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.
Topics: Alcohols; Antimalarials; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Pyrazines; Structure-Activity Relationship
PubMed: 33919319
DOI: 10.3390/molecules26092421