226087-02-1Relevant articles and documents
COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS AND POTENTIATION OF ANTIBIOTICS
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Page/Page column 97; 118, (2021/06/26)
Compounds and methods for use to treat a bacterial infection caused by, for example, gram positive bacteria, gram negative bacteria, and/or mycobacteria are provided herein. Also provided herein are compounds and methods for use in potentiating the effect of an antibiotic in the treatment of a bacterial infection. Pharmaceutical compositions including the compounds as described herein are also provided.
AMIDINES AND AMIDINE ANALOGS FOR THE TREATMENT OF BACTERIAL INFECTIONS AND POTENTIATION ANTIBIOTICS
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Page/Page column 405, (2020/01/08)
Compounds and methods for the treatment of a bacterial infection or the potentiation of an antibiotic in treating a bacterial infection are described herein.
Synthesis and structure-activity relationships of small-molecular di-basic esters, amides and carbamates as flaviviral protease inhibitors
Sundermann, Tom R.,Benzin, Clarissa V.,Dra?i?, Tonko,Klein, Christian D.
, p. 187 - 194 (2019/05/21)
Inhibitors of the flaviviral serine proteases, which are crucial for the replication of dengue and West-Nile virus, have attracted much attention over the last years. A dibasic 4-guanidinobenzoate was previously reported as inhibitor of the dengue protease with potency in the low-micromolar range. In the present study, this lead structure was modified with the intent to explore structure-activity relationships and obtain compounds with increased drug-likeness. Substitutions of the guanidine moieties, the aromatic rings, and the ester with other functionalities were evaluated. All changes were accompanied by a loss of inhibition, indicating that the 4-guanidinobenzoate scaffold is an essential element of this compound class. Further experiments indicate that the target recognition of the compounds involves the reversible formation of a covalent adduct.
ANTIMICROBIAL GUANIDINIUM AND THIOURONIUM FUNCTIONALIZED POLYMERS
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Paragraph 00170-00171; 00184-00185, (2016/12/07)
Antimicrobial cationic polycarbonates and polyurethanes have been prepared comprising one or more pendent guanidinium and/or isothiouronium groups. Additionally, antimicrobial particles were prepared having a silica core linked to surface groups comprising a guanidinium and/or isothiouronium group. The cationic polymers and cationic particles can be potent antimicrobial agents against Gram-negative microbes, Gram-positive microbes, and/or fungi.
Papain-catalyzed peptide bond formation: Enzyme-specific activation with guanidinophenyl esters
de Beer, Roseri J.A.C.,Zarzycka, Barbara,Amatdjais-Groenen, Helene I.V.,Jans, Sander C.B.,Nuijens, Timo,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
experimental part, p. 2201 - 2207 (2012/05/05)
The substrate mimetics approach is a versatile method for small-scale enzymatic peptide-bond synthesis in aqueous systems. The protease-recognized amino acid side chain is incorporated in an ester leaving group, the substrate mimetic. This shift of the specific moiety enables the acceptance of amino acids and peptide sequences that are normally not recognized by the enzyme. The guanidinophenyl group (OGp), a known substrate mimetic for the serine proteases trypsin and chymotrypsin, has now been applied for the first time in combination with papain, a cheap and commercially available cysteine protease. To provide insight in the binding mode of various Z-XAA-OGp esters, computational docking studies were performed. The results strongly point at enzyme-specific activation of the OGp esters in papain through a novel mode of action, rather than their functioning as mimetics. Furthermore, the scope of a model dipeptide synthesis was investigated with respect to both the amino acid donor and the nucleophile. Molecular dynamics simulations were carried out to prioritize 22 natural and unnatural amino acid donors for synthesis. Experimental results correlate well with the predicted ranking and show that nearly all amino acids are accepted by papain.
Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket
Frederick, Raphael,Charlier, Caroline,Robert, Severine,Wouters, Johan,Masereel, Bernard,Pochet, Lionel
, p. 2017 - 2021 (2007/10/03)
The synthesis of novel coumarins bearing on the lateral side chain in the 3-position an amine or a guanidine group is described. In vitro evaluation highlighted 14d which possesses a meta aniline side chain as a very potent THR inhibitor. Surprisingly, the introduction of a guanidine moiety always led to a decrease in THR inhibiting properties. We, thus, used docking experiments to rationalize the SAR in the series. This study showed the crucial role of a conserved water molecule in the specificity pocket of THR during docking simulation in order to explain the inactivity of guanidine derivatives.
Protease-mediated ligation of abiotic oligomers
Yoo, Barney,Kirshenbaum, Kent
, p. 17132 - 17133 (2007/10/03)
We demonstrate that proteases can catalyze the ligation of peptidomimetic oligomers. The enzyme clostripain was used to facilitate the native ligation of N-substituted glycine oligomers, or peptoids. In addition to mediating the efficient condensation of
Protease-catalyzed peptide synthesis for the site-specific incorporation of α-fluoroalkyl amino acids into peptides
Thust, Sven,Koksch, Beate
, p. 2290 - 2296 (2007/10/03)
Substitution of native amino acids by fluoroalkyl analogues represents a new approach for the design of biologically active peptides with increased metabolic stability as well as defined secondary structure and provides a powerful label for spectroscopic investigations. Here, we introduce a methodology for the incorporation of sterically demanding Cα-fluoroalkyl amino acids into the P1 position of peptides catalyzed by the commercially available proteases trypsin and α-chymotrypsin. The combination of 4-guanidinophenyl ester of Cα-fluoroalkyl amino acids as substrate mimetics with frozen-state reaction conditions provided the most efficient strategy for protease-catalyzed site-specific introduction of this kind of nonnatural amino acids into peptide sequences. Consequently, a library of di-, tri-, and tetrapeptides containing α-methyl, α-difluoromethyl, and α-trifluoromethyl alanine, leucine, and phenylalanine in the P1 position was synthesized catalyzed by trypsin as well as α-chymotrypsin. Trypsin was shown to be the more versatile protease.
A convenient and versatile method for the synthesis of protected guanidines
Guo, Zhao-Xia,Cammidge, Andrew N.,Horwell, David C.
, p. 2933 - 2943 (2007/10/03)
Aromatic, aliphatic and sterically hindered amines react smoothly with commercially available N, N'-bis-BOC-S-methylisothiourea 2 in the presence of mercury chloride to give the protected guanidine in good yield. It is particularly noteworthy that 2 can a
2-aroylbenzoyl serine proteases: Photoreversible inhibition or photoaffinity labeling?
Jones, Paul B.,Porter, Ned A.
, p. 2753 - 2761 (2007/10/03)
Phenyl esters of 2-benzoylbenzoates were determined to be inhibitors of the serine protease enzymes chymotrypsin and thrombin. Thus, p- guanidinophenyl 2-benzoylbenzoate (lb) inhibited thrombin while the corresponding p-nitrophenyl ester (1a) inhibited ch
