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Molecules (Basel, Switzerland) Sep 2022Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the... (Review)
Review
Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole-pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles.
Topics: Benzimidazoles; Ligands; Pyridines; Pyrroles; Thiones
PubMed: 36234805
DOI: 10.3390/molecules27196268 -
BioMed Research International 2023Multidrug-resistant (MDR) pathogens have created a fatal problem for human health and antimicrobial treatment. Among the currently available antibiotics, many are... (Review)
Review
Multidrug-resistant (MDR) pathogens have created a fatal problem for human health and antimicrobial treatment. Among the currently available antibiotics, many are inactive against MDR pathogens. In this context, heterocyclic compounds/drugs play a vital role. Thus, it is very much essential to explore new research to combat the issue. Of the available nitrogen-bearing heterocyclic compounds/drugs, pyridine derivatives are of special interest due to their solubility. Encouragingly, some of the newly synthesized pyridine compounds/drugs are found to inhibit multidrug-resistant (MRSA). Pyridine scaffold bearing poor basicity generally improves water solubility in pharmaceutically potential molecules and has led to the discovery of numerous broad-spectrum therapeutic agents. Keeping these in mind, we have reviewed the chemistry, recent synthetic techniques, and bacterial preventative activity of pyridine derivatives since 2015. This will facilitate the development of pyridine-based novel antibiotic/drug design in the near future as a versatile scaffold with limited side effects for the next-generation therapeutics.
Topics: Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Anti-Bacterial Agents; Anti-Infective Agents; Pyridines
PubMed: 37250749
DOI: 10.1155/2023/9967591 -
MBio Jun 2019Nicotine, a toxic and addictive alkaloid from tobacco, is an environmental pollutant in areas near cigarette production facilities. Over the last decade, our group has...
Nicotine, a toxic and addictive alkaloid from tobacco, is an environmental pollutant in areas near cigarette production facilities. Over the last decade, our group has studied, in depth, the pyrrolidine pathway of nicotine degradation in S16. However, little is known regarding whole mechanism(s) regulating transcription of the nicotine degradation pathway gene cluster. In the present study, we comprehensively elucidate an overall view of the NicR2-mediated two-step mechanism regulating 3-succinoyl-pyridine (SP) biotransformation, which involves the association of free NicR2 with two promoters and the dissociation of NicR2 from the NicR2-promoter complex. NicR2 can bind to another promoter, , and regulate expression of the nicotine-degrading genes in the middle of gene cluster, which are not controlled by the previously reported promoter. We identified the function of the inverted repeat bases on the two promoters responsible for NicR2 binding and found out that the -35/-10 motif for RNA polymerase is overlapped by the NicR2 binding site. We clarify the exact role of 6-hydroxy-3-succinoyl-pyridine (HSP), which acts as an antagonist and may prevent binding of free NicR2 to the promoters but cannot release NicR2 from the promoters. Finally, a regulatory model is proposed, which consists of three parts: the interaction between NicR2 and two promoters ( and ), the interaction between NicR2 and two effectors (HSP and SP), and the interaction between NicR2 and RNA polymerase. We report the entire process underlying the NicR2 regulatory mechanism from association between free NicR2 and two promoters to dissociation of the NicR2-promoter complex. NicR2 can bind to another promoter, , which controls expression of nicotine-degrading genes that are not controlled by the promoter. We identified specific nucleotides of the promoter responsible for NicR2 binding. HSP was further demonstrated as an antagonist, which prevents the binding of NicR2 to the and promoters, by locking NicR2 in the derepression conformation. The competition between NicR2 and RNA polymerase is essential to initiate transcription of nicotine-degrading genes. This study extends our understanding of molecular mechanisms in biodegradation of environmental pollutants and toxicants.
Topics: Biodegradation, Environmental; Gene Expression Regulation, Bacterial; Metabolic Networks and Pathways; Multigene Family; Nicotine; Promoter Regions, Genetic; Pseudomonas putida; Pyridines; Succinates
PubMed: 31164460
DOI: 10.1128/mBio.00602-19 -
Molecules (Basel, Switzerland) Dec 2020The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds...
The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the "hot plate" test and in the "writhing" test. All tested imides - were more active in the "writhing" test than aspirin, and two of them, and , were similar to morphine. In addition, all of the new imides inhibited the locomotor activity in mice to a statistically significant extent, and two of them also prolonged the duration of thiopental sleep.On the basis of the results obtained for the previously synthesized imides and the results presented in this paper, an attempt was madeto determine the relationship between thechemical structure of imides and their analgesic and sedativeproperties.
Topics: Analgesics; Animals; Hypnotics and Sedatives; Locomotion; Male; Mice; Pyridines; Pyrroles; Structure-Activity Relationship
PubMed: 33322767
DOI: 10.3390/molecules25245883 -
Dalton Transactions (Cambridge, England... Jul 2022This article provides an overview (non-comprehensive) of the recent developments regarding pyridine-containing 12-membered tetraazamacrocycles with pyclen or Py2N2... (Review)
Review
This article provides an overview (non-comprehensive) of the recent developments regarding pyridine-containing 12-membered tetraazamacrocycles with pyclen or Py2N2 backbones and their metal complexes from 2017 to the present. Firstly, the syntheses of newly described ligands and complexes with relevance to medicine are described. The second part deals with the reactivity of complexes bearing these ligands and their uses in catalysis. Special emphasis on the role of the pyridine-containing ligand is highlighted throughout the text.
Topics: Catalysis; Cyclams; Ligands; Molecular Structure; Pyridines
PubMed: 35412549
DOI: 10.1039/d2dt00597b -
Oxidative Medicine and Cellular... 2022Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment...
IP-Se-06, a Selenylated Imidazo[1,2-]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1 and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells.
Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment options are still lacking. Imidazo[1,2-]pyridine derivatives and organoselenium compounds are largely used in medicinal chemistry and drug development. This study is aimed at further investigating the antitumor mechanism of IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-]pyridine), a selenylated imidazo[1,2-]pyridine derivative in glioblastoma cells. IP-Se-06 exhibited high cytotoxicity against A172 cells (IC = 1.8 M) and selectivity for this glioblastoma cell. The IP-Se-06 compound has pharmacological properties verified in its ADMET profile, especially related to blood-brain barrier (BBB) permeability. At low concentration (1 M), IP-Se-06 induced intracellular redox state modulation with depletion of TrxR and GSH levels as well as inhibition of NRF2 protein. IP-Se-06 also decreased mitochondrial membrane potential, induced cytochrome release, and chromatin condensation. Furthermore, IP-Se-06 induced apoptosis by decreasing levels of Bcl-xL while increasing levels of -H2AX and p53 proteins. Treatment with IP-Se-06 induced cell cycle arrest and showed antiproliferative effect by inhibition of Akt/mTOR/HIF-1 and ERK 1/2 signaling pathways. In addition, IP-Se-06 displayed significant inhibition of p38 MAPK and p-p38, leading to inhibition of inflammasome complex proteins (NLRP3 and caspase-1) in glioblastoma cells. These collective findings demonstrated that IP-Se-06 is a bioactive molecule that can be considered a candidate for the development of a novel drug for glioblastoma treatment.
Topics: Apoptosis; Cell Line, Tumor; Glioblastoma; Humans; Oxidation-Reduction; Proto-Oncogene Proteins c-akt; Pyridines; TOR Serine-Threonine Kinases
PubMed: 35360199
DOI: 10.1155/2022/3710449 -
The International Journal of... Jul 2016Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently,... (Review)
Review
BACKGROUND
Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic.
METHODS
Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats.
RESULTS
MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window.
CONCLUSION
Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders.
Topics: Allosteric Regulation; Animals; Cocaine; Drug-Seeking Behavior; Ethanol; Nicotine; Pyridines; Receptor, Metabotropic Glutamate 5; Self Administration; Substance-Related Disorders; Thiazoles
PubMed: 26802568
DOI: 10.1093/ijnp/pyw002 -
Journal of the American Chemical Society Nov 2019The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high...
The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine -oxides further document the utility of this approach. Demonstration of the asymmetric -oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.
Topics: Aspartic Acid; Catalysis; Heterocyclic Compounds; Hydrogen Bonding; Peptides; Pyridines; Stereoisomerism
PubMed: 31656070
DOI: 10.1021/jacs.9b10414 -
Molecules (Basel, Switzerland) Jun 2021New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from...
New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine- functionalized derivatives. The derived pyrazolpyridine--glycosides were synthesized via heterocyclization of the -thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative and the tricyclic pyrido[3',2':4,5]furo[3,2-d]pyrimidine were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone , 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1-pyrazolo[3,4-b]pyridin-3-amine (), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate () are among the most active inhibitors with IC values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC ranges of 31.3-49.0, 19.3-55.5, 22.7-44.8, and 36.8-70.7 μM, respectively compared to doxorubicin (IC 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Doxorubicin; Drug Design; Drug Screening Assays, Antitumor; Humans; Imidazoles; Inhibitory Concentration 50; Molecular Docking Simulation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Quantitative Structure-Activity Relationship
PubMed: 34206976
DOI: 10.3390/molecules26133923 -
European Journal of Medicinal Chemistry Nov 2023Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a...
Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators.
Topics: Escherichia coli; Escherichia coli Proteins; Anti-Bacterial Agents; Pyridines; Multidrug Resistance-Associated Proteins; Carrier Proteins
PubMed: 37459793
DOI: 10.1016/j.ejmech.2023.115630