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Medicinal Research Reviews May 2018Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the... (Review)
Review
Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.
Topics: Alkaloids; Animals; Humans; Immunologic Factors; Protective Agents; Quinazolines; Quinolines
PubMed: 28902434
DOI: 10.1002/med.21466 -
Drugs in R&D 2011RVX 208 (RVX-208; RVX000222) is a first-in-class novel small molecule in development by Resverlogix Corporation for acute coronary syndromes, atherosclerosis and... (Review)
Review
RVX 208 (RVX-208; RVX000222) is a first-in-class novel small molecule in development by Resverlogix Corporation for acute coronary syndromes, atherosclerosis and Alzheimer disease. It increases the levels of apolipoprotein A1 and high-density lipoprotein cholesterol, thereby potentially reducing the risk for cardiovascular disease. This review discusses the key development milestones and therapeutic trials of this drug. This summary has been extracted from Wolters Kluwer's R&D Insight drug pipeline database. R&D Insight tracks and evaluates drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch. This is an open access article published under the terms of the Creative Commons License "Attribution-NonCommercial-NoDerivative 3.0" (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits non-commercial use, distribution, and reproduction, provided the original work is properly cited and not altered.
Topics: Acute Coronary Syndrome; Alzheimer Disease; Animals; Atherosclerosis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Quinazolines; Quinazolinones
PubMed: 21679009
DOI: 10.2165/11595140-000000000-00000 -
Molecules (Basel, Switzerland) Nov 2022The synthesis of quinazoline 3-oxides and their derivatives has attracted considerable attention due to their reactivity as intermediates in the synthesis of quinazoline... (Review)
Review
The synthesis of quinazoline 3-oxides and their derivatives has attracted considerable attention due to their reactivity as intermediates in the synthesis of quinazoline analogues and their ring-expanded derivatives. Despite this, there is no comprehensive review dedicated to the synthesis and chemical transformation of these biologically relevant azaaromatic oxides. This review aims to provide an up-to-date record of the synthesis of quinazoline 3-oxides and their chemical transformation. It is hoped that this information will help medicinal chemistry researchers to design and synthesize new derivatives or analogues to treat various diseases.
Topics: Humans; Oxides; Quinazolines; Chemistry, Pharmaceutical; Research Personnel
PubMed: 36432084
DOI: 10.3390/molecules27227985 -
Medicinal Research Reviews Sep 2018To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the... (Review)
Review
To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.
Topics: Alkaloids; Anti-Inflammatory Agents; Antioxidants; Humans; Protective Agents; Quinazolines; Quinolines
PubMed: 29485730
DOI: 10.1002/med.21492 -
Molecules (Basel, Switzerland) Mar 2022Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which... (Review)
Review
Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.
Topics: Antineoplastic Agents; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms; Quinazolines
PubMed: 35408693
DOI: 10.3390/molecules27072294 -
Marine Drugs Dec 2020Three new phenylhydrazones, penoxahydrazones A-C (compounds -), and two new quinazolines, penoxazolones A (compound ) and B (compound ), with unique linkages were...
Three new phenylhydrazones, penoxahydrazones A-C (compounds -), and two new quinazolines, penoxazolones A (compound ) and B (compound ), with unique linkages were isolated from the fungus obtained from the deep sea cold seep. Their structures and relative configurations were assigned by analysis of 1D/2D NMR and mass spectroscopic data, and the absolute configurations of , , and were established on the basis of X-ray crystallography or ECD calculations. Compound represents the first natural phenylhydrazone-bearing steroid, while compounds and are rarely occurring phenylhydrazone tautomers. Compounds and are enantiomers that feature quinazoline and cinnamic acid units. Some isolates exhibited inhibition of several marine phytoplankton species and marine-derived bacteria.
Topics: Anti-Bacterial Agents; Bacteria; Geologic Sediments; Hydrazones; Molecular Structure; Penicillium; Phytoplankton; Quinazolines; Structure-Activity Relationship
PubMed: 33379196
DOI: 10.3390/md19010009 -
Molecules (Basel, Switzerland) Dec 2017Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to...
Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (-) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and TK kinases. Compounds and which exhibited the most potent inhibitory activities against EGFR (IC = 0.02 µM and 0.01 µM, respectively), VEGFR-2 (IC = 0.05 µM and 0.08 µM, respectively), and good antiproliferative activities, also displayed competitive anti-tumor activities than sorafenib in vivo by B16 melanoma xenograft model test.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Design; ErbB Receptors; Humans; Melanoma, Experimental; Mice, Inbred C57BL; Molecular Docking Simulation; Protein Binding; Quinazolines; Sorafenib; Thiourea; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays
PubMed: 29295519
DOI: 10.3390/molecules23010024 -
Nature Communications Oct 2021Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A...
Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.
Topics: Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Cryoelectron Microscopy; Cyclic Nucleotide Phosphodiesterases, Type 3; Drug Design; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Intracellular Signaling Peptides and Proteins; Mice; Multiprotein Complexes; Naphthyridines; Pyridazines; Quinazolines; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 34707099
DOI: 10.1038/s41467-021-26546-8 -
Molecules (Basel, Switzerland) Apr 2021Multidrug resistance of bacteria is a worrying concern in the therapeutic field and an alternative method to combat it is designing new efflux pump inhibitors (EPIs)....
Multidrug resistance of bacteria is a worrying concern in the therapeutic field and an alternative method to combat it is designing new efflux pump inhibitors (EPIs). This article presents a molecular study of two quinazoline derivatives, labelled BG1189 and BG1190, proposed as EPIs. approach investigates the pharmacodynamic and pharmacokinetic profile of BG1189 and BG1190 quinazolines. Molecular docking and predicted ADMET features suggest that BG1189 and BG1190 may represent attractive candidates as antimicrobial drugs. UV-Vis absorption spectroscopy was employed to study the time stability of quinazoline solutions in water or in dimethyl sulfoxide (DMSO), in constant environmental conditions, and to determine the influence of usual storage temperature, normal room lighting and laser radiation (photostability) on samples stability. The effects of irradiation on BG1189 and BG1190 molecules were also assessed through Fourier-transform infrared (FTIR) spectroscopy. FTIR spectra showed that laser radiation breaks some chemical bonds affecting the substituents and the quinazoline radical of the compounds.
Topics: Anti-Bacterial Agents; Models, Molecular; Molecular Docking Simulation; Quinazolines; Spectroscopy, Fourier Transform Infrared
PubMed: 33921798
DOI: 10.3390/molecules26082374 -
Molecules (Basel, Switzerland) Sep 2022A series of 5'-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, -phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the...
A series of 5'-phosphorylated (dialkyl phosphates, diaryl phosphates, phosphoramidates, -phosphonates, phosphates) 1,2,3-triazolyl nucleoside analogues in which the 1,2,3-triazole-4-yl-β-D-ribofuranose fragment is attached via a methylene group or a butylene chain to the -1 atom of the heterocycle moiety (uracil or quinazoline-2,4-dione) was synthesized. All compounds were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1). Antiviral assays revealed three compounds, , and , which showed moderate activity against influenza virus A (H1N1) with IC values of 17.9 μM, 51 μM, and 25 μM, respectively. In the first two compounds, the quinazoline-2,4-dione moiety is attached via a methylene or a butylene linker, respectively, to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5'-diphenyl phosphate substituent. In compound , the uracil moiety is attached via the methylene unit to the 1,2,3-triazole-4-yl-β-D-ribofuranosyl fragment possessing a 5'-(phenyl methoxy-L-alaninyl)phosphate substituent. The remaining compounds appeared to be inactive against influenza virus A/PR/8/34/(H1N1). The results of molecular docking simulations indirectly confirmed the literature data that the inhibition of viral replication is carried out not by nucleoside analogues themselves, but by their 5'-triphosphate derivatives.
Topics: Alkenes; Antiviral Agents; Influenza A Virus, H1N1 Subtype; Molecular Docking Simulation; Nucleosides; Organophosphonates; Phosphates; Quinazolines; Structure-Activity Relationship; Triazoles; Uracil
PubMed: 36234748
DOI: 10.3390/molecules27196214