TY  - JOUR
A1  - Seethaler, Marius
A1  - Hertlein, Tobias
A1  - Hopke, Elisa
A1  - Köhling, Paul
A1  - Ohlsen, Knut
A1  - Lalk, Michael
A1  - Hilgeroth, Andreas
T1  - Novel effective fluorinated benzothiophene-indole hybrid antibacterials against S. aureus and MRSA strains
JF  - Pharmaceuticals
N2  - Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds.
KW  - antibacterial drug resistance
KW  - structure activity
KW  - synthesis
KW  - inhibition
KW  - substituent
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288253
SN  - 1424-8247
VL  - 15
IS  - 9
ER  - 
TY  - JOUR
A1  - Gehrmann, Robin
A1  - Hertlein, Tobias
A1  - Hopke, Elisa
A1  - Ohlsen, Knut
A1  - Lalk, Michael
A1  - Hilgeroth, Andreas
T1  - Novel small-molecule hybrid-antibacterial agents against S. aureus and MRSA strains
JF  - Molecules
N2  - Ongoing resistance developments against antibiotics that also affect last-resort antibiotics require novel antibacterial compounds. Strategies to discover such novel structures have been dimerization or hybridization of known antibacterial agents. We found novel antibacterial agents by dimerization of indols and hybridization with carbazoles. They were obtained in a simple one-pot reaction as bisindole tetrahydrocarbazoles. Further oxidation led to bisindole carbazoles with varied substitutions of both the indole and the carbazole scaffold. Both the tetrahydrocarbazoles and the carbazoles have been evaluated in various S. aureus strains, including MRSA strains. Those 5-cyano substituted derivatives showed best activities as determined by MIC values. The tetrahydrocarbazoles partly exceed the activity of the carbazole compounds and thus the activity of the used standard antibiotics. Thus, promising lead compounds could be identified for further studies.
KW  - antibacterial activity
KW  - synthesis
KW  - substituent
KW  - structure–activity
KW  - inhibition
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252371
SN  - 1420-3049
VL  - 27
IS  - 1
ER  - 
TY  - JOUR
A1  - Seethaler, Marius
A1  - Hertlein, Tobias
A1  - Wecklein, Björn
A1  - Ymeraj, Alba
A1  - Ohlsen, Knut
A1  - Lalk, Michael
A1  - Hilgeroth, Andreas
T1  - Novel small-molecule antibacterials against Gram-positive pathogens of Staphylococcus and Enterococcus species
JF  - Antibiotics
N2  - Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials.
KW  - antibacterial activity
KW  - synthesis
KW  - substituent
KW  - structure-activity
KW  - inhibition
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193130
SN  - 2079-6382
VL  - 8
IS  - 4
ER  -