- Modification of Biphenolic Anti-Bacterial to Achieve Broad-Spectrum Activity
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The Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria, Acinetobacter baumannii, are pathogens responsible for millions of nosocomial infections worldwide. Due to the threat of bacteria evolving resistance to antibiotics, scientists are constantly looking for new classes of compounds to treat infectious diseases. The biphenolic analogs of honokiol that were most potent against oral bacteria had similar bioactivity against MRSA. However, all the compounds proved ineffective against A. baumannii. The inability to inhibit A. baumannii is due to the difficult-to-penetrate lipopolysaccharide-coated outer membrane that makes it challenging for antibiotics to enter Gram-negative bacteria. The C 2 scaffold was optimized from the inhibition of Gram-positive bacteria to broad-spectrum antibacterial compounds that inhibit the dangerous Gram-negative pathogen A. baumannii.
- Kozlowski, Marisa C.,Ochoa, Cristian,Roenfanz, Hanna F.
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- The synthesis and glycosidase inhibitory activity of analogues of tiruchanduramine
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Five analogues (7a-e) of the metabolite tiruchanduramine 1 were prepared. Compounds 7d and 7e were specific inhibitors of yeast α-glucosidase, whilst 7e specifically inhibited Bacillus α-glucosidase. Compounds 7b and 7c were the best inhibitors of β-gluco
- Ashworth, Zackary J. R.,Bartholomew, Barbara,Evans, Daniel M.,Forde-Thomas, Josephine,Hoffmann, Karl F.,Murdoch, Reece,Murphy, Patrick J.,Nash, Robert J.,Sharp, Hazel,Whiteland, Helen
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p. 609 - 621
(2020/06/01)
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- Virtual screening guided design, synthesis and bioactivity study of benzisoselenazolones (BISAs) on inhibition of c-met and its downstream signalling pathways
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c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μMin MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.
- Zhang, Siqi,Song, Qiaoling,Wang, Xueting,Wei, Zhiqiang,Yu, Rilei,Wang, Xin,Jiang, Tao
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- Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands?
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New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S-methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.
- Pockes, Steffen,Wifling, David,Buschauer, Armin,Elz, Sigurd
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p. 285 - 297
(2019/04/04)
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- Macrocyclization of di-Boc-guanidino-alkylamines related to guazatine components: Discovery and synthesis of innovative macrocyclic amidinoureas
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The synthesis of new and innovative macrocyclic amidinoureas from linear di-Boc-guanidino-alkylamines related to guazatine was accomplished. The macrocyclization reaction proceeds under mild conditions affording 11- to 16-membered rings with a new and pre
- Castagnolo, Daniele,Raffi, Francesco,Giorgi, Gianluca,Botta, Maurizio
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supporting information; experimental part
p. 334 - 337
(2009/06/18)
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- Amine-guanidine switch: A promising approach to improve DNA binding and antiproliferative activities
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A series of polyaromatic guanidino derivatives was synthesized and evaluated for growth inhibitory properties in several human carcinoma cell lines. The properties of these guanidino compounds were compared to those of their corresponding synthetic amino precursors. The size of the polyaromatic ring system as well as the length of the tether attached to the ring had a direct impact on the observed antiproliferative profiles, compound 14 having the broadest spectrum of activity. As both series intercalate DNA, guanidine derivatives showed a remarkable affinity for DNA and the guanidinium group appeared to be essential, yet not sufficient for caspase-3/7 activation. Compound 14 also showed significant in vivo activity against breast cancer cell xenografts in NOG/SCID mice. These results suggest that the electronic nature of chain tethering an intercalator not only influences the DNA-binding process but also controls the antitumoral activity of the whole compound.
- Ohara, Keiichiro,Smietana, Michael,Restouin, Audrey,Mollard, Séverine,Borg, Jean-Paul,Collette, Yves,Vasseur, Jean-Jacques
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p. 6465 - 6475
(2008/04/12)
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- Novel hypotensive agents from Verbesina caracasana. 8. Synthesis and pharmacology of (3,4-dimethoxycinnamoyl)-N1-agmatine and synthetic analogues
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The more polar metabolites from the Venezuelan plant Verbesina caracasana, i.e., N3-prenylagmatine, (3,4-dimethoxycinnamoyl)-N1-agmatine, agmatine, and galegine (prenylguanidine), previously reported (Delle Monache, G.; et al. BioMed
- Carmignani,Volpe,Botta,Espinal,De Bonnevaux,De Luca,Botta,Corelli,Tafi,Sacco,Delle Monache
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p. 2950 - 2958
(2007/10/03)
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- Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety
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A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central 'C' region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl- guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the 'right- amide' of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.
- Lebreton, Luc,Annat, Jocelyne,Derrepas, Philippe,Dutartre, Patrick,Renaut, Patrice
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p. 277 - 290
(2007/10/03)
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- 15-deoxyspergualin analogs, their method of preparation and their use in therapeutics
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The present invention relates, by way of novel industrial products, to compounds which are structurally related to 15-deoxyspergualin and which have the formula STR1 in which: A is a single bond, a group --CH2 --, a group --CH2 O--, a group --CH2 NH--, a group --CH(OH)--, a group --CHF-- or a group --CH(OCH3)--, and n is equal to 6 or 8, and their addition salts. These novel compounds are useful especially as immunosuppressants. The invention further relates to the method of preparing said compounds.
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- 15-deoxyspergualin analogs, their method of preparation and their use in therapeutics
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The present invention relates, by way of novel industrial products, to compounds which are structurally related to 15-deoxyspergualin. These novel compounds have the formula STR1 in which: n is equal to 6 or 8 and A is a single bond, CH2, CHF, CH(OH), CH(OCH3), CH2 NH or CH2 O, and their addition salts.
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