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Molecules (Basel, Switzerland) Jan 2021Heterocyclic moieties, especially five and six-membered rings containing nitrogen, oxygen or sulfur atoms, are broadly distributed in nature. Among them, synthetic and... (Review)
Review
Heterocyclic moieties, especially five and six-membered rings containing nitrogen, oxygen or sulfur atoms, are broadly distributed in nature. Among them, synthetic and natural alike are pharmacologically active compounds and have always been at the forefront of attention due to their pharmacological properties. Heterocycles can be divided into different groups based on the presence of characteristic structural motifs. The presence of β-amino acid and heterocyclic core in one compound is very interesting; additionally, it very often plays a vital role in their biological activity. Usually, such compounds are not considered to be chemicals containing a β-amino acid motif; however, considering them as this class of compounds may open new routes of their preparation and application as new drug precursors or even drugs. The possibility of their application as nonproteinogenic amino acid residues in peptide or peptide derivatives synthesis to prepare a new class of compounds is also promising. This review highlights the actual state of knowledge about β-amino acid moiety-containing heterocycles presenting antiviral, anti-inflammatory, antibacterial compounds, anaplastic lymphoma kinase (ALK) inhibitors, as well as agonist and antagonists of the receptors.
Topics: Amino Acids; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antiviral Agents; Heterocyclic Compounds; Humans
PubMed: 33467741
DOI: 10.3390/molecules26020438 -
Expert Review of Anti-infective Therapy 2016Antiretroviral therapy can effectively suppress HIV-1 infection but is ineffective against integrated proviruses. A latent viral reservoir composed of latently infected...
Antiretroviral therapy can effectively suppress HIV-1 infection but is ineffective against integrated proviruses. A latent viral reservoir composed of latently infected CD4(+)T cells persists under suppressive therapy, and infected individuals must remain indefinitely on antiretroviral therapy to prevent viral reactivation and propagation. Despite therapy, some degree of low-level ongoing replication is detected and transient viral reactivation may replenish the latent reservoir. An analog of the natural compound, Cortistatin A, blocks HIV-1 transcription by specifically targeting the viral transactivator, Tat. Treatment of latently infected cells with this Tat inhibitor promotes a state of deep-latency from which HIV reactivation capacity is greatly diminished. Here we discuss the use of Tat inhibitors to limit the latent reservoir to achieve a functional cure.
Topics: Anti-HIV Agents; HIV Infections; HIV-1; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Virus Latency; tat Gene Products, Human Immunodeficiency Virus
PubMed: 26581953
DOI: 10.1586/14787210.2016.1122525 -
RSC Advances Oct 2023Benzimidazoles are a class of heterocyclic compounds in which a benzene ring is fused to the 4 and 5 positions of an imidazole ring. Benzimidazole refers to the parent... (Review)
Review
Benzimidazoles are a class of heterocyclic compounds in which a benzene ring is fused to the 4 and 5 positions of an imidazole ring. Benzimidazole refers to the parent compound, while benzimidazoles are a class of heterocyclic compounds having similar ring structures, but different substituents. Benzimidazole derivatives possess a wide range of bioactivities including antimicrobial, anthelmintic, antiviral, anticancer, and antihypertensive activities. Many compounds possessing a benzimidazole skeleton have been employed as drugs in the market. The application of benzimidazoles in other fields has also been documented. The synthesis of benzimidazole derivatives has attracted much attention from chemists and numerous articles on the synthesis of this class of heterocyclic compound have been reported over the years. The condensation between 1,2-benzenediamine and aldehydes has received intensive interest, while many novel methods have been developed. In this article, we will give a comprehensive review of studies on the synthesis of benzimidazole, which date back to 2013. We have also tried to describe reaction mechanisms as much as we can. The work might be useful for chemists who work in the synthesis of heterocycles or drug chemistry.
PubMed: 37942457
DOI: 10.1039/d3ra05960j -
Frontiers in Bioscience (Scholar... Jan 2012Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential... (Review)
Review
Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A-940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described.
Topics: Animals; Heterocyclic Compounds, 1-Ring; Histamine Antagonists; Humans; Receptors, Histamine
PubMed: 22202103
DOI: 10.2741/s312 -
Molecules (Basel, Switzerland) Jan 20197-Oxo-1,2,4-benzotriazines (benzo[1,2,4]triazin-7-ones) are reversible thioredoxin reductase inhibitors that exhibit very strong correlations to pleurotin. In this...
7-Oxo-1,2,4-benzotriazines (benzo[1,2,4]triazin-7-ones) are reversible thioredoxin reductase inhibitors that exhibit very strong correlations to pleurotin. In this article, we provide the first synthesis of fluorinated derivatives. Fluorination using Selectfluor of benzo[1,2,4]triazin-7-ones occurs regioselectively and in high yield at the enamine-activated position. This electron N-lone pair activation overrides the activation/deactivation effects of some other substituents. The reaction time was significantly reduced with the use of microwave irradiation at 120 °C and 7 bar. The cytotoxicity and cyclic voltammetry measurements for 8-fluoro-1,3-diphenylbenzo[][1,2,4]triazin-7(1)-one () are presented and compared with its synthetic precursor, 1,3-diphenylbenzo[][1,2,4]triazin-7(1)-one ().
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diazonium Compounds; Halogenation; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Molecular Structure; Structure-Activity Relationship; Triazines
PubMed: 30646524
DOI: 10.3390/molecules24020282 -
Oncotarget Nov 2016ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers.... (Review)
Review
ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Neoplasms; Pyridines; Pyrimidines
PubMed: 27602582
DOI: 10.18632/oncotarget.11814 -
Expert Opinion on Pharmacotherapy Aug 2010Asenapine is a new atypical antipsychotic medication with high affinity for D(2) and 5HT(2A) receptors that has been approved by the FDA in adults for the acute... (Review)
Review
IMPORTANCE OF THE FIELD
Asenapine is a new atypical antipsychotic medication with high affinity for D(2) and 5HT(2A) receptors that has been approved by the FDA in adults for the acute treatment of schizophrenia in the USA. The purpose of this review is to describe the compound and examine whether it addresses some of the unmet clinical needs in treating schizophrenia.
AREAS COVERED IN THIS REVIEW
The development of asenapine is described with attention to its chemistry, pharmacodynamic and pharmacokinetic profile. Preclinical and clinical trials of safety and efficacy are reviewed. The advantages and disadvantages of asenapine relative to other antipsychotic medications are discussed.
WHAT THE READER WILL GAIN
Asenapine will be evaluated for whether it: i) causes a reduction in symptoms of schizophrenia; ii) has a side-effect profile minimizing extrapyramidal symptoms, weight gain and cardiac effects; and iii) affects negative and/or cognitive symptoms.
TAKE HOME MESSAGE
Asenapine is a recently approved agent with an acceptable cardiometabolic profile and exhibits similar efficacy as other antipsychotic medications, primarily on positive symptoms of schizophrenia. Relatively less weight gain compared with other agents may confer a notable advantage. Sublingual administration may have positive and negative effects on patient compliance. Potential 'pro-cognitive' effects of asenapine are preliminary and require more investigation.
Topics: Antipsychotic Agents; Dibenzocycloheptenes; Dopamine Antagonists; Heterocyclic Compounds, 4 or More Rings; Humans; Schizophrenia; Serotonin Antagonists; Treatment Outcome
PubMed: 20642375
DOI: 10.1517/14656566.2010.506188 -
Anti-inflammatory & Anti-allergy Agents... 2020Psoralen or furocoumarin is a linear three ring heterocyclic compound. Psoralens are planar, tricyclic compounds, consisting of a furan ring fused to a coumarin moiety.... (Review)
Review
Psoralen or furocoumarin is a linear three ring heterocyclic compound. Psoralens are planar, tricyclic compounds, consisting of a furan ring fused to a coumarin moiety. Psoralen has been known for a wide spectrum of biological activities, spanning from cytotoxic, photosensitizing, insecticidal, antibacterial to antifungal effect. Thus, several structural changes were introduced to explore the role of specific positions with respect to the biological activity. Convenient approaches utilized for the synthesis of psoralen skeleton can be categorized into two parts: (i) the preparation of the tricyclic ring system from resorcinol, (ii) the exocyclic modification of the intact ring system. Furthermore, although psoralens have been used in diverse ways, we mainly focus in this work on their clinical utility for the treatment of psioraisis, vitiligo and skin-related disorder.
Topics: Biological Availability; Dermatologic Agents; Ficusin; Furocoumarins; Humans; Photosensitizing Agents; Plants, Medicinal; Skin Diseases
PubMed: 31241020
DOI: 10.2174/1871523018666190625170802 -
Protein and Peptide Letters 2021We aim to evaluate the potential application of amine reactive fluorogenic reagents for estimating enzymatic proteolysis.
AIMS
We aim to evaluate the potential application of amine reactive fluorogenic reagents for estimating enzymatic proteolysis.
BACKGROUND
Proteolytic enzymes play important roles in regulating many physiological processes in living organisms.
OBJECTIVES
Assessment of protein degradation by using reagents for protein assay techniques.
METHODS
We have assayed samples at the start and after 30-60 minutes incubation with trypsin by Chromeo P503 (Py 1 pyrylium compound) and CBQCA (3-(4-carboxybenzoyl) quinoline-2-carboxaldehyde) as amine reactive reagents and NanoOrange as non-amine reactive dye.
RESULTS
All BSA prepared samples with trypsin have shown significantly higher fluorescence intensity (FI) versus controls (which reflects proteolysis) when assayed by Chromeo P503 (Py 1 pyrylium compound) and CBQCA (3-(4-carboxybenzoyl) quinoline-2-carboxaldehyde) as amine reactive reagents. However, same samples assayed with NanoOrange as non-amine reactive reagent did not show any significant variation between samples containing trypsin and controls.
CONCLUSION
These results are confirming reliability of highly sensitive protein assays utilizing amine reactive fluorogenic reagents for general estimation of proteolysis.
Topics: Animals; Benzoates; Cattle; Enzyme Assays; Fluorescent Dyes; Heterocyclic Compounds, 3-Ring; Humans; Kinetics; Organic Chemicals; Peptide Hydrolases; Proteolysis; Quinolines; Serum Albumin, Bovine; Solutions
PubMed: 33390107
DOI: 10.2174/0929866528999201231214954 -
Antimicrobial Agents and Chemotherapy Nov 2018African sleeping sickness is responsible for thousands of deaths annually, and new therapeutics are needed. This study evaluated aromathecins, experimental inhibitors of...
African sleeping sickness is responsible for thousands of deaths annually, and new therapeutics are needed. This study evaluated aromathecins, experimental inhibitors of mammalian topoisomerase IB, against African trypanosomes. The compounds had selectively toxic antiparasitic potency, poisoning activity against the phylogenetically unique topoisomerase in these parasites, and a representative compound intercalated into DNA with micromolar affinity. DNA intercalation and topoisomerase poisoning may contribute to the antitrypanosomal activity of aromathecins.
Topics: Antiprotozoal Agents; Heterocyclic Compounds, 4 or More Rings; Humans; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 30104277
DOI: 10.1128/AAC.00786-18