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The Discovery and Structure‐Activity Evaluation of (+)‐Floyocidin B and Synthetic Analogs
Author(s) -
Kleiner Yolanda,
Pöverlein Christoph,
Klädtke Jannike,
Kurz Michael,
König Henrik F.,
Becker Jonathan,
Mihajlovic Sanja,
Zubeil Florian,
Marner Michael,
Vilcinskas Andreas,
Schäberle Till F.,
Hammann Peter,
Schuler Sören M. M.,
Bauer Armin
Publication year - 2022
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.202100644
Subject(s) - drug discovery , computational biology , chemistry , stereochemistry , combinatorial chemistry , biology , biochemistry
Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug‐resistant M. tuberculosis makes the discovery of novel anti‐tuberculosis active structures an urgent priority. Here, we show that (+)‐floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus‐derived natural products, displays promising antitubercular hit properties. (+)‐Floyocidin B was identified by activity‐guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X‐ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)‐floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure‐activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.