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Synthesis and Antimicrobial Activity of Albicidin Derivatives with Variations of the Central Cyanoalanine Building Block
Author(s) -
Grätz Stefan,
Kerwat Dennis,
Kretz Julian,
von Eckardstein Leonard,
Semsary Siamak,
Seidel Maria,
Kunert Maria,
Weston John B.,
Süssmuth R. D.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600163
Subject(s) - pharmacophore , chemistry , steric effects , dna gyrase , antibacterial activity , antimicrobial , stereochemistry , amino acid , combinatorial chemistry , threonine , lipophilicity , antibacterial agent , biochemistry , organic chemistry , antibiotics , bacteria , escherichia coli , biology , enzyme , genetics , gene , serine
To investigate the pharmacophore regions of the antibiotic albicidin, derivatives with variations on the central amino acid were synthesized. Charged as well as uncharged residues were chosen to explore the influence of charge, chirality, and steric bulk. The bioactivity of the newly synthesized derivatives was determined by a microdilution technique to obtain minimum inhibitory concentrations (MIC) values. The compounds were also tested in a cell‐free system to obtain information about their ability to inhibit their primary target, DNA gyrase. It was then shown that derivatives with uncharged side chains retain antibacterial activity, whereas incorporation of charged amino acid residues decreases the antibacterial activity dramatically, possibly due to restricted cell penetration of these derivatives. From the newly synthesized derivatives, the threonine derivative shows the most promising results in both tests. The information will help to develop the features of albicidin toward more drug‐like structures.