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Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials
Author(s) -
Brengel Christian,
Thomann Andreas,
Schifrin Alexander,
Allegretta Giuseppe,
Kamal Ahmed A. M.,
Haupenthal Jörg,
Schnorr Isabell,
Cho Sang Hyun,
Franzblau Scott G.,
Empting Martin,
Eberhard Jens,
Hartmann Rolf W.
Publication year - 2017
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.201700363
Subject(s) - antimycobacterial , econazole , mycobacterium tuberculosis , computational biology , rational design , drug discovery , mode of action , mycobacterium , tuberculosis , combinatorial chemistry , chemistry , pharmacology , biology , medicine , biochemistry , microbiology and biotechnology , genetics , antifungal , miconazole , pathology
The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multidrug resistance (MDR) combined with complicated long‐term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. The best hits originating from only one structural class gave initial information about molecular motifs required for binding and activity. The initial screening procedure was followed by mode‐of‐action studies and further biological characterizations. The results demonstrate superior antimycobacterial efficacy and a decreased toxicity profile of our frontrunner compound relative to the reference compound econazole. Due to its low molecular weight, promising biological profile, and physicochemical properties, this compound is an excellent starting point for further rational optimization.