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Journal of Medicinal Chemistry Aug 2005We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS),...
We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC(50) < or = 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Folic Acid Antagonists; Furans; Glutamic Acid; Humans; Peptide Synthases; Pyrimidines; Pyrimidinones; Pyrroles; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase
PubMed: 16078850
DOI: 10.1021/jm058213s -
International Journal of Biological... Jul 2023As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel...
As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and M main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with M, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for M and RdRp.
Topics: Humans; SARS-CoV-2; Molecular Docking Simulation; COVID-19; COVID-19 Drug Treatment; Antiviral Agents; RNA-Dependent RNA Polymerase; Molecular Dynamics Simulation; Pyrimidines
PubMed: 37148943
DOI: 10.1016/j.ijbiomac.2023.124443 -
Bioorganic & Medicinal Chemistry Letters Jun 2018Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu negative allosteric modulators...
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
Topics: Allosteric Regulation; Animals; Dose-Response Relationship, Drug; Drug Discovery; Humans; Male; Molecular Structure; Pyrimidines; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Structure-Activity Relationship
PubMed: 29705142
DOI: 10.1016/j.bmcl.2018.04.053 -
Molecules (Basel, Switzerland) Jan 2022The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of... (Meta-Analysis)
Meta-Analysis
The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.
Topics: Adenosine Monophosphate; Alanine; Amides; COVID-19; Catalytic Domain; Computational Biology; Coronavirus RNA-Dependent RNA Polymerase; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pyrazines; Pyrimidines; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Triazoles; Virus Replication; COVID-19 Drug Treatment
PubMed: 35164069
DOI: 10.3390/molecules27030801 -
Molecules (Basel, Switzerland) Jun 2021Discovery of compound as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit...
Discovery of compound as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9-purine or 1-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7-pyrrolo[2,3-d]pyrimidines and their analogs including compounds , and as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.
Topics: Antiviral Agents; Cell Line, Tumor; Humans; Pyrimidines; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 34206327
DOI: 10.3390/molecules26133779 -
Journal of Medicinal Chemistry Jan 2021Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the...
Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized, and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity, and pharmacokinetics.
Topics: Animals; Brain; Cell Line; Cells, Cultured; Computer Simulation; Humans; Mice; Mice, Transgenic; Microtubules; Models, Molecular; Molecular Docking Simulation; Neurodegenerative Diseases; Neurons; Pyrimidines; Rats; Structure-Activity Relationship; Tauopathies; Triazoles
PubMed: 33411523
DOI: 10.1021/acs.jmedchem.0c01605 -
ChemMedChem Jan 2016SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of...
SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of virtual screening and experimental exploration of the surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA-21, and studied a series of analogues by systematic dissections of the core scaffold. Evaluation of these analogues allowed us to establish an initial structure-activity relationship in SecA inhibition. The best compounds in this group are potent inhibitors of SecA-dependent protein-conducting channel activity and protein translocation activity at low- to sub-micromolar concentrations. They also have minimal inhibitory concentration (MIC) values against various strains of bacteria that correlate well with the SecA and protein translocation inhibition data. These compounds are effective against methicillin-resistant Staphylococcus aureus strains with various levels of efflux pump activity, indicating the capacity of SecA inhibitors to null the effect of multidrug resistance. Results from studies of drug-affinity-responsive target stability and protein pull-down assays are consistent with SecA as a target for these compounds.
Topics: Adenosine Triphosphatases; Bacterial Proteins; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Membrane Transport Proteins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Pyrimidines; SEC Translocation Channels; SecA Proteins; Structure-Activity Relationship; Triazoles
PubMed: 26607404
DOI: 10.1002/cmdc.201500447 -
Medicinal Chemistry (Shariqah (United... 2019Platelet aggregation plays a pathogenic role in the development of arterial thrombi, which are responsible for common diseases caused by thrombotic arterial occlusion,...
BACKGROUND
Platelet aggregation plays a pathogenic role in the development of arterial thrombi, which are responsible for common diseases caused by thrombotic arterial occlusion, such as myocardial infarction and stroke. Much efforts are directed toward developing platelet aggregation inhibitors that act through several mechanisms: The main antiplatelet family of COXinhibitors, phosphodiesterase inhibitors, and thrombin inhibitors. Recently, the important role in the platelet aggregation of adenosine diphosphate (ADP)-activated P2Y12 and P2Y1 receptors, Gprotein coupled receptors of the P2 purinergic family, has emerged, and their inhibitors are explored as potential therapeutic antithrombotics. P2Y12 inhibitors, i.e. clopidogrel, prasugrel, ticagrelor, and cangrelor, are already used clinically to reduce coronary artery thrombosis risk and prevent acute coronary syndromes. The search for new P2Y12 inhibitors, with better risk-to-benefit profiles is still ongoing.
METHODS
Several years ago, our group prepared a series of 6-amino-2-thio-3H-pyrimidin-4-one derivatives that displayed an interesting platelet aggregation inhibiting activity. In order to probe the structure-activity relationships and improve their inhibitory effects of these compounds, we synthesized variously substituted 6-amino-2-thio-3H-pyrimidin-4-one derivatives and substituted 4-amino-2-thiopyrimidine-5-carboxylic acid analogues. All the synthesized compounds were tested by light trasmission aggregometry (LTA) as inducers or inhibitors of platelet aggregation in citrated platelet-rich plasma (PRP).
RESULTS
Among the 6-amino-2-thio-3H-pyrimidin-4-one derivatives, compounds 2c and 2h displayed marked inhibitory activity, with a capability to inhibit the ADP(10-6M)-induced platelet aggregation by 91% and 87% at 10-4M concentration, respectively. Selected 4-amino-2- thiopyrimidine-5-carboxylic acid derivatives were tested as P2Y12 and P2Y1 antagonists and found to display negligible activity.
CONCLUSION
These negative findings demonstrated that this heterocyclic nucleus is not a useful common pharmacophore for developing P2Y-dependent inhibitors of platelet aggregation. Nevertheless, compounds 2c and 2h could represent a new chemotype to further develop inhibitors of platelet aggregation.
Topics: Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrimidines; Structure-Activity Relationship
PubMed: 30734681
DOI: 10.2174/1573406415666190208124534 -
The Journal of Biological Chemistry Aug 1953
Topics: Acetylglucosamine; Glucosamine; Pyrimidines; Uridine; Uridine Diphosphate N-Acetylglucosamine
PubMed: 13084676
DOI: No ID Found -
Proceedings of the National Academy of... Oct 2017According to a current "RNA first" model for the origin of life, RNA emerged in some form on early Earth to become the first biopolymer to support Darwinism here....
According to a current "RNA first" model for the origin of life, RNA emerged in some form on early Earth to become the first biopolymer to support Darwinism here. Threose nucleic acid (TNA) and other polyelectrolytes are also considered as the possible first Darwinian biopolymer(s). This model is being developed by research pursuing a "Discontinuous Synthesis Model" (DSM) for the formation of RNA and/or TNA from precursor molecules that might have been available on early Earth from prebiotic reactions, with the goal of making the model less discontinuous. In general, this is done by examining the reactivity of isolated products from proposed steps that generate those products, with increasing complexity of the reaction mixtures in the proposed mineralogical environments. Here, we report that adenine, diaminopurine, and hypoxanthine nucleoside phosphates and a noncanonical pyrimidine nucleoside (zebularine) phosphate can be formed from the direct coupling reaction of cyclic carbohydrate phosphates with the free nucleobases. The reaction is stereoselective, giving only the β-anomer of the nucleotides within detectable limits. For purines, the coupling is also regioselective, giving the -9 nucleotide for adenine as a major product. In the DSM, phosphorylated carbohydrates are presumed to have been available via reactions explored previously [Krishnamurthy R, Guntha S, Eschenmoser A (2000) 39:2281-2285], while nucleobases are presumed to have been available from hydrogen cyanide and other nitrogenous species formed in Earth's primitive atmosphere.
Topics: Adenine; Carbohydrates; Chromatography, High Pressure Liquid; Cytidine; Evolution, Chemical; Hypoxanthine; Magnetic Resonance Spectroscopy; Organophosphates; Origin of Life; Phosphorylation; Purine Nucleotides; Pyrimidine Nucleotides
PubMed: 29073050
DOI: 10.1073/pnas.1710778114