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  1. Article: Regioselection in the synthesis of 4-benzyltetral-1-ones and the new 4-arylbenzosuber-1-ones

    Truong, Daniel / Howard, Brittany L. / Thompson, Philip E.

    Tetrahedron. 2021 Apr. 09, v. 85

    2021  

    Abstract: The intramolecular Friedel-Crafts acylation of 4,5-diarylpentanoic acids has the possibility to cyclise to either a 6-membered ring to give 4-benzyltetral-1-one or a 7-membered ring to give 4-arylbenzosuber-1-one. Of these, only the former compound class ...

    Abstract The intramolecular Friedel-Crafts acylation of 4,5-diarylpentanoic acids has the possibility to cyclise to either a 6-membered ring to give 4-benzyltetral-1-one or a 7-membered ring to give 4-arylbenzosuber-1-one. Of these, only the former compound class has previously been reported. The impact of the substituents positioning on the outcome of the cyclisation has been investigated. The complete formation of either the tetralone or the benzosuberone regioisomer was possible under the same reaction conditions, dependent upon the ring activation and/or deactivation of the chosen substituents. Selected bromo or methoxy substituents could be used as auxiliaries, included in precursors to afford the desired regioisomer and then subsequently removed.
    Keywords acids ; acylation ; positional isomers
    Language English
    Dates of publication 2021-0409
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 204285-x
    ISSN 1464-5416 ; 0040-4020 ; 0563-2064
    ISSN (online) 1464-5416
    ISSN 0040-4020 ; 0563-2064
    DOI 10.1016/j.tet.2021.132034
    Database NAL-Catalogue (AGRICOLA)

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    Zs.B 1076: Show issues Location:
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  2. Article ; Online: Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design.

    Howard, Brittany L / Thompson, Philip E / Manallack, David T

    Journal of computer-aided molecular design

    2011  Volume 25, Issue 8, Page(s) 753–762

    Abstract: The similarity between Plasmodium falciparum phosphodiesterase enzymes (PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE ... ...

    Abstract The similarity between Plasmodium falciparum phosphodiesterase enzymes (PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.
    MeSH term(s) Antimalarials/pharmacology ; Catalytic Domain/drug effects ; Computer Simulation ; Cyclic GMP/chemistry ; Cyclic GMP/metabolism ; Drug Design ; Humans ; Models, Molecular ; Phosphodiesterase Inhibitors/pharmacology ; Phosphoric Diester Hydrolases/chemistry ; Phosphoric Diester Hydrolases/drug effects ; Phosphoric Diester Hydrolases/metabolism ; Piperazines/pharmacology ; Plasmodium falciparum/enzymology ; Purines/pharmacology ; Purinones/pharmacology ; Sequence Alignment ; Sequence Homology, Amino Acid ; Sildenafil Citrate ; Sulfones/pharmacology
    Chemical Substances Antimalarials ; Phosphodiesterase Inhibitors ; Piperazines ; Purines ; Purinones ; Sulfones ; Sildenafil Citrate (BW9B0ZE037) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; zaprinast (GXT25D5DS0) ; Cyclic GMP (H2D2X058MU)
    Language English
    Publishing date 2011-07-16
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 808166-9
    ISSN 1573-4951 ; 0920-654X
    ISSN (online) 1573-4951
    ISSN 0920-654X
    DOI 10.1007/s10822-011-9458-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2625: Show issues Location:
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  3. Article ; Online: Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate.

    Nguyen, William / Howard, Brittany L / Jenkins, David P / Wulff, Heike / Thompson, Philip E / Manallack, David T

    Bioorganic & medicinal chemistry letters

    2012  Volume 22, Issue 23, Page(s) 7106–7109

    Abstract: Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 ... ...

    Abstract Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC(50) values.
    MeSH term(s) Diphenoxylate/chemical synthesis ; Diphenoxylate/chemistry ; Diphenoxylate/metabolism ; Humans ; Kinetics ; Kv1.3 Potassium Channel/chemistry ; Kv1.3 Potassium Channel/metabolism ; Potassium Channel Blockers/chemical synthesis ; Potassium Channel Blockers/chemistry ; Potassium Channel Blockers/metabolism ; Protein Binding ; Structure-Activity Relationship
    Chemical Substances Kv1.3 Potassium Channel ; Potassium Channel Blockers ; Diphenoxylate (73312P173G)
    Language English
    Publishing date 2012-09-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2012.09.080
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Structure–activity relationship exploration of Kv1.3 blockers based on diphenoxylate

    Nguyen, William / Howard, Brittany L / Jenkins, David P / Wulff, Heike / Thompson, Philip E / Manallack, David T

    Bioorganic & medicinal chemistry letters. 2012 Dec. 1, v. 22, no. 23

    2012  

    Abstract: Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 ... ...

    Abstract Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC50 values.
    Keywords agonists ; autoimmune diseases ; inhibitory concentration 50 ; potassium channels ; structure-activity relationships
    Language English
    Dates of publication 2012-1201
    Size p. 7106-7109.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2012.09.080
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Identification of potent phosphodiesterase inhibitors that demonstrate cyclic nucleotide-dependent functions in apicomplexan parasites.

    Howard, Brittany L / Harvey, Katherine L / Stewart, Rebecca J / Azevedo, Mauro F / Crabb, Brendan S / Jennings, Ian G / Sanders, Paul R / Manallack, David T / Thompson, Philip E / Tonkin, Christopher J / Gilson, Paul R

    ACS chemical biology

    2015  Volume 10, Issue 4, Page(s) 1145–1154

    Abstract: Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human ... ...

    Abstract Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human pathogenesis is the asexual cycle, in which parasites undergo rounds of host cell invasion, replication, and egress (exit), destroying host cell tissue in the process. Previous work has identified important roles for Protein Kinase G (PKG) and Protein Kinase A (PKA) in parasite egress and invasion, yet little is understood about the regulation of cyclic nucleotides, cGMP and cAMP, that activate these enzymes. To address this, we have focused upon the development of inhibitors of 3',5'-cyclic nucleotide phosphodiesterases (PDEs) to block the breakdown of cyclic nucleotides. This was done by repurposing human PDE inhibitors noting various similarities of the human and apicomplexan PDE binding sites. The most potent inhibitors blocked the in vitro proliferation of P. falciparum and T. gondii more potently than the benchmark compound zaprinast. 5-Benzyl-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (BIPPO) was found to be a potent inhibitor of recombinant P. falciparum PfPDEα and activated PKG-dependent egress of T. gondii and P. falciparum, likely by promoting the exocytosis of micronemes, an activity that was reversed by a specific Protein Kinase G inhibitor. BIPPO also promotes cAMP-dependent phosphorylation of a P. falciparum ligand critical for host cell invasion, suggesting that the compound inhibits single or multiple PDE isoforms that regulate both cGMP and cAMP levels. BIPPO is therefore a useful tool for the dissection of signal transduction pathways in apicomplexan parasites.
    MeSH term(s) Antiprotozoal Agents/chemical synthesis ; Antiprotozoal Agents/chemistry ; Antiprotozoal Agents/pharmacology ; Chemistry Techniques, Synthetic ; Cyclic AMP/metabolism ; Cyclic GMP/metabolism ; Drug Evaluation, Preclinical/methods ; Female ; Humans ; Phosphodiesterase Inhibitors/chemical synthesis ; Phosphodiesterase Inhibitors/chemistry ; Phosphodiesterase Inhibitors/pharmacology ; Phosphorylation/drug effects ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/physiology ; Purinones/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Pyrimidinones/chemistry ; Pyrimidinones/pharmacology ; Sequence Alignment ; Sequence Homology, Amino Acid ; Structural Homology, Protein ; Toxoplasma/drug effects ; Toxoplasma/enzymology ; Toxoplasma/physiology
    Chemical Substances 5-benzyl-3-isopropyl-1H-pyrazolo(4,3-d)pyrimidin-7(6H)-one ; Antiprotozoal Agents ; Phosphodiesterase Inhibitors ; Purinones ; Pyrazoles ; Pyrimidinones ; Cyclic AMP (E0399OZS9N) ; zaprinast (GXT25D5DS0) ; Cyclic GMP (H2D2X058MU)
    Language English
    Publishing date 2015-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/cb501004q
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Structure–activity relationship exploration of Kv1.3 blockers based on diphenoxylate

    Nguyen, William / Howard, Brittany L. / Jenkins, David P. / Wulff, Heike / Thompson, Philip E. / Manallack, David T.

    Bioorganic & medicinal chemistry letters

    Volume v. 22,, Issue no. 2

    Abstract: Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 ... ...

    Abstract Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC₅₀ values.
    Keywords structure-activity relationships ; agonists ; autoimmune diseases ; potassium channels ; inhibitory concentration 50
    Language English
    Document type Article
    ISSN 0960-894X
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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