- A convenient synthesis of pseudoceratidine and three analogs for biological evaluation
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The recently isolated marine natural product pseudoceratidine (1) has been synthesized from 2-trichloronactylpyrrole. Bromination in the 4- and 5-position followed by nucleophilic displacement of the trichloromethyl group with spermidine gave 1 in 79% yield. The procedure is general and can easily be adopted to the preparation of other derivatives. This was demonstrated by the synthesis of a 5,5'-didebromo derivative (2) and two analogs (3-4). The compounds 1-4 have been tested for antibacterial activity and the results compared to a previous study. Also activity against die marine brine shrimp Artemia salina is reported.
- Behrens, Carsten,Christoffersen, Martin W.,Gram, Lone,Nielsen, Per Halfdan
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- Latonduines A and B, new alkaloids isolated from the marine sponge Stylissa carteri: Structure elucidation, synthesis, and biogenetic implications
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(Matrix Presented) Latonduines A (6) and B (7), two new alkaloids with unprecedented heterocyclic skeletons, have been isolated from the Indonesian marine sponge Stylissa carteri. The structures of the latonduines were elucidated by analysis of spectroscopic data and confirmed by the total synthesis of latonduine A (6). It is proposed that ornithine is the biogenetic precursor to the aminopyrimidine fragment of the latonduines.
- Linington, Roger G.,Williams, David E.,Tahir, Akbar,Van Soest, Rob,Andersen, Raymond J.
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Read Online
- From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
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Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
- Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
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supporting information
p. 1197 - 1219
(2021/02/05)
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- Synthesis and antibacterial analysis of analogues of the marine alkaloid pseudoceratidine
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In an effort to gain more understanding on the structure activity relationship of pseudoceratidine 1, a di-bromo pyrrole spermidine alkaloid derived from the marine sponge Pseudoceratina purpurea that has been shown to exhibit potent biofouling, anti-fungal, antibacterial, and anti-malarial activities, a large series of 65 compounds that incorporated several aspects of structural variation has been synthesised through an efficient, divergent method that allowed for a number of analogues to be generated from common precursors. Subsequently, all analogues were assessed for their antibacterial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. Overall, several compounds exhibited comparable or better activity than that of pseudoceratidine 1, and it was found that this class of compounds is generally more effective against Gram-positive than Gram-negative bacteria. Furthermore, altering several structural features allowed for the establishment of a comprehensive structure activity relationship (SAR), where it was concluded that several structural features are critical for potent anti-bacterial activity, including di-halogenation (preferable bromine, but chlorine is also effective) on the pyrrole ring, two pyrrolic units in the structure and with one or more secondary amines in the chain adjoining these units, with longer chains giving rise to better activities.
- Barker, David,Lee, Stephanie,Varnava, Kyriakos G.,Sparrow, Kevin,van Rensburg, Michelle,Deed, Rebecca C.,Cadelis, Melissa M.,Li, Steven A.,Copp, Brent R.,Sarojini, Vijayalekshmi,Pilkington, Lisa I.
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supporting information
(2020/07/02)
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- Synthesis of 4,4-dimethyl-2-(2-pyrrolyl)-2-oxazolines
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– A practical synthesis of 4,4-dimethyl-2-oxazolines on pyrrole was achieved via the cyclization of the corresponding amides, which were derived from the trichloroacetylpyrroles. The established conditions were applicable to pyrroles bearing a ketone or an ester moiety. In addition to pyrroles, the method could be extended to the synthesis of the indole derivative.
- Okano, Kentaro,Morii, Kazuki,Mari, Daichi,Mori, Atsunori
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- Tryptamine derivatives disarm colistin resistance in polymyxin-resistant gram-negative bacteria
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The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.
- Barker, William T.,Chandler, Courtney E.,Melander, Roberta J.,Ernst, Robert K.,Melander, Christian
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p. 1776 - 1788
(2019/03/21)
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- Synthesis and Absolute Stereochemical Reassignment of Mukanadin F: A Study of Isomerization of Bromopyrrole Alkaloids with Implications on Marine Natural Product Isolation
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Synthesis of both enantiomers of mukanadin F was achieved by using a seven step synthesis. Comparison of the optical rotation data of synthetic samples to that reported for the isolated natural product determined that the absolute configuration of the natural product is 9S and not the reported 9R. Further studies established that the reported low magnitude of optical rotation in the isolated sample is due to compounds of this type undergoing isomerization and racemization under benign laboratory conditions. Additionally the synthetic methods developed were applied to synthesize mukanadins B and D.
- van Rensburg, Michelle,Copp, Brent R.,Barker, David
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p. 3065 - 3074
(2018/07/06)
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- Isolation, Derivative Synthesis, and Structure-Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis
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The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their antiparasitic activity against Plasmodium falciparum, Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum, and Trypanosoma cruzi, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis, and Chagas disease, respectively. The new 3-debromopseudoceratidine (4), 20-debromopseudoceratidine (5), 4-bromopseudoceratidine (6), 19-bromopseudoceratidine (7), and 4,19-dibromopseudoceratidine (8) are reported. New tedamides A-D (9-12), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1H-pyrrole-2-carboxamide moiety, are also described. Compounds 4 and 5, 6 and 7, 9 and 10, and 11 and 12 have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides 9+10 and 11+12 were obtained as optically active pairs, indicating an enzymatic formation rather than an artifactual origin. N12-Acetylpseudoceratidine (2) and N12-formylpseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The antiparasitic activity of pseudoceratidine (1) led us to synthesize 23 derivatives (16, 17, 20, 21, 23, 25, 27-29, 31, 33, 35, 38, 39, 42, 43, 46, 47, 50, and 51) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in antiparasitic assays. The measured antimalarial activity of pseudoceratidine (1) and derivatives 4, 5, 16, 23, 25, 31, and 50 provided an initial SAR evaluation of these compounds as potential leads for antiparasitics against Leishmania amastigotes and against P. falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs.
- Parra, Lizbeth L. L.,Bertonha, Ariane F.,Severo, Ivan R. M.,Aguiar, Anna C. C.,De Souza, Guilherme E.,Oliva, Glaucius,Guido, Rafael V. C.,Grazzia, Nathalia,Costa, Tábata R.,Miguel, Danilo C.,Gadelha, Fernanda R.,Ferreira, Antonio G.,Hajdu, Eduardo,Romo, Daniel,Berlinck, Roberto G. S.
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supporting information
p. 188 - 202
(2018/02/07)
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- Synthesis and biological evaluation of pyrrole-2-carboxamide derivatives: Oroidin analogues
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The reaction of pyrrole or dibromopyrrole-2-trichloroacetone with various amines results in the series of novel pyrrole-2-carboxamide bearing aromatic heterocycle or aryl or alkyl groups. Synthesized molecules were evaluated for their in vitro antibacterial activities. Most of the compounds exhibited potent activity against both Gram-positive and negative pathogens.
- Takale, Balaram S.,Desai, Neha V.,Siddiki, Afsar Ali,Chaudhari, Hemchandra K.,Telvekar, Vikas N.
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p. 1387 - 1396
(2014/03/21)
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- Reduction of 2,2,2-trichloro-1-arylethanones by RMgX: Mechanistic investigation and the synthesis of substituted α,α-dichloroketones
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2,2,2-Trichloro-1-arylethanones undergo high yielding reductions to the corresponding 2,2-dichloro-1-arylethanones in the presence of RMgX. A single electron transfer mechanism for the reaction is proposed based on trapping experiments. Reaction of the intermediate enolates with a range of electrophiles is described, providing a convenient route to substituted α,α- dichloro-β-hydroxyketones and related molecules. The Royal Society of Chemistry 2013.
- Essa, Ali H.,Lerrick, Reinner I.,Tuna, Floriana,Harrington, Ross W.,Clegg, William,Hall, Michael J.
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supporting information
p. 2756 - 2758
(2013/04/23)
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- Synthesis and evaluation of novel anti-proliferative pyrroloazepinone and indoloazepinone oximes derived from the marine natural product hymenialdisine
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The tetrahydroazepinone pharmacophore is a component of many interesting compounds, including several marine natural products, with anti-cancer properties. The synthesis and biological evaluation of a novel series of pyrroloazepinone and indoloazepinone oximes is reported. These compounds showed promising growth inhibition activity against four human cancer cell lines but did not significantly inhibit the cell cycle regulator cyclin dependent kinase 2. The most active compounds in this series displayed improved anti-proliferative activity over the related synthetic indoloazepine kenpaullone. The structure activity relationships exhibited by the azepinone pharmacophore suggests several novel lead compounds for anti-cancer drug discovery.
- White, Alex W.,Carpenter, Nicholas,Lottin, Jerome R. P.,McClelland, Richard A.,Nicholson, Robert I.
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p. 246 - 253,8
(2012/12/11)
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- An efficient approach to dispacamide A and its derivatives
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Dispacamide A and new analogs of this marine alkaloid were prepared in seven steps with an overall yield ranging from 12 to 33%. The key step of the strategy was a stereocontrolled Knoevenagel condensation under microwave dielectric heating in the last step. In this condensation, the 2-aminoimidazolin-4-one hydrochloride partners 10a-c were synthesized in three steps with good overall yields (33-79%) via the ring closure of N-guanidino acetic acids 9a-c and the aldehydes 5a,b as the two others building-blocks, in 3 steps with 60-66% overall yields. The six synthetic products have been obtained with a Z geometry about their exocyclic bond on the basis of 13C/1H long-range coupling constants using a gHSQMBC experiment.
- Guiheneuf, Solene,Paquin, Ludovic,Carreaux, Francois,Durieu, Emilie,Meijer, Laurent,Bazureau, Jean Pierre
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experimental part
p. 978 - 987
(2012/04/10)
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- Synthesis and evaluation of novel 1,3,4-oxadiazole derivatives of marine bromopyrrole alkaloids as antimicrobial agent
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In an attempt to identify new potential lead as antimicrobial agent, twenty hybrids of marine bromopyrrole alkaloids with 1,3,4-oxadiazole were designed based on molecular hybridization technique and synthesized. Synthesized molecules were evaluated for t
- Rane, Rajesh A.,Gutte, Shweta D.,Sahu, Niteshkumar U.
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supporting information
p. 6429 - 6432
(2012/10/30)
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- Total synthesis of the natural product (±)-dibromophakellin and analogues
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(±)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond.
- Hewlett, Nicole M.,Tepe, Jetze J.
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scheme or table
p. 4550 - 4553
(2011/10/13)
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- INHIBITION OF BIOFILMS IN PLANTS WITH IMIDAZOLE DERIVATIVES
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Disclosure is provided for methods of preventing, removing or inhibiting microbial biofilm formation or microbial infection in a plant or plant part thereof, including applying thereto a treatment effective amount of an active compound as described herein
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Page/Page column 46
(2009/06/27)
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- INHIBITION OF BACTERIAL BIOFILMS WITH IMIDAZOLE DERIVATIVES
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Disclosure is provided for imidazole derivative compounds that prevent, remove and/or inhibit the formation of biofilms, compositions comprising these compounds, devices comprising these compounds, and methods of using the same.
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Page/Page column 35; 39-40
(2008/12/07)
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- The utility of the classical and oxidative Heck reactions in natural product synthesis: Studies directed toward the total synthesis of dragmacidin F
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The syntheses of complex pyrrole-fused [3.3.1] and [3.3.2] bicycles using classical and oxidative Heck cyclizations are described. While both [3.3.1] and [3.2.2] bicyclic products are formed in the classical Heck reaction, the oxidative Heck cyclization r
- Garg, Neil K.,Caspi, Daniel D.,Stoltz, Brian M.
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p. 3081 - 3087
(2008/02/13)
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- Bioactive Bromopyrrole Metabolites from the Caribbean Sponge Agelas conifera
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Biologically active extracts of the Carribean sponge Agelas conifera have yielded, in exhaustive studies, the diacetate salts of seven new bromopyrroles (1, 3-8), as well as that of the known debromooroidin dimer sceptrin (2).These compounds were found to be antiviral and antibacterial and were active in barnacle settlement and biochemical prophage induction assays.The structures assigned were based on spectroscopic comparison to sceptrin and two-dimensional NMR data.Synthetic bromopyrroles were used to verify bromine substitution patterns.The oxysceptrins (4, 5) are characterized by their aminoimidazolinone group, the ageliferins (6-8) by a unique cyclohexene-based skeleton.
- Keifer, Paul A.,Schwartz, Robert E.,Koker, Moustapha E. S.,Hughes, Robert G.,Rittschof, Dan,Rinehart, Kenneth L.
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p. 2965 - 2975
(2007/10/02)
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- 4,5-Dihalopyrrole-2-carboxamides
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4,5-Dihalopyrrole-2-carboxamide derivatives, prepared by reaction of a corresponding 4,5-dihalopyrrole-2-carboxylic acid halide or a corresponding 4,5-dihalopyrrol-2-yl trihalomethyl ketone with an appropriate amine, useful as antibacterial and herbicidal
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- Herbicidal pyrrole-2-carboxamides
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4,5-Dihalopyrrole-2-carboxamide derivatives, prepared by reaction of a corresponding 4,5-dihalopyrrole-2-carboxylic acid halide or a corresponding 4,5-dihalopyrrol-2-yl trihalomethyl ketone with an appropriate amine, have antibacterial and herbicidal acti
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- Pyrrolyl oxyphenyl ketones
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4,5-Dihalopyrrol-2-yl oxyphenyl ketones, prepared either by Friedel-Crafts condensation of a 4,5-dihalopyrrole-2-carboxylic acid halide with an appropriate hydroxy or lower-alkoxy-substituted benzene or by condensation of a hydroxy or lower-alkoxy-substituted benzaldehyde with pyrrole in the presence of sodium hydride followed by halogenation, with elemental chlorine or bromine, of the resulting pyrrol-2-yl oxyphenyl ketone, useful as antibacterial and antifungal agents.
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- 4,5 Dihalopyrrol 2-yl di and tri halomethyl ketones
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4,5-Dihalopyrrol-2-yl di- and trihalomethyl ketones, prepared by reaction of pyrrole with a di- or trihaloacetyl halide or with a di- or trihaloacetic anhydride and halogenation of the resulting pyrrol-2-yl di- or trihalomethyl ketone, useful as antibacterial, herbicidal and insecticidal agents.
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