TY - JOUR
T1 - Linker and Head-Group Exploration of Anti-MRSA Triaromatic Pleuromutilins
AU - Heidtmann, Christoffer V
AU - Fisker, Christian Ding
AU - Løgstrup, Sarah
AU - Eriksen, Patrick G
AU - Storm, Louise H
AU - Stærk, Kristian
AU - Moesgaard, Laust
AU - Pedersen, Maria
AU - Madsen, Martin J
AU - Yusuf, Ahmed
AU - Urup, Krista
AU - Højgaard, Iben S
AU - Ramesh, Jayappragash
AU - Pihlsbech, Rasmus H
AU - Sørensen, Caroline B
AU - Rønn, Tore L
AU - Larsen, Alexander B
AU - Caspersen, Laurits R
AU - Møller, Mathias Æ
AU - Sixhøj, Chris R
AU - Frimodt-Møller, Niels
AU - Klitgaard, Janne K
AU - Andersen, Thomas E
AU - Nielsen, Carsten U
AU - Nielsen, Poul
PY - 2025
Y1 - 2025
N2 - Based on hit
6, a triaromatic pleuromutilin (TAP) and potent bacterial protein synthesis inhibitor, we explored the chemical space surrounding its pharmacophore by synthesizing 45 new conjugates. Herein, the adenine head was exchanged for new heterocycles, and the benzyl linker exchanged for aniline-, ether-, amide-, and hydroxybenzyl linkages, with all of them successfully engaging the pharmacophore, a result which was mirrored in a strict 3D pharmacophore model. The aniline- and amide-linked conjugates moreover demonstrated greater stability in liver microsomes, while especially conjugate
21, but also
31,
43,
45, and
55 displayed excellent potency, with MRSA activities on par with
6 or better. Docking to the ribosome suggested a shifted engagement with C2469 for
21 over
6, resulting in greater multivalency, while
43/
45 likely coordinates Mg
2+. Lastly, conjugate
21 displayed efficacy equal to commercial Fucidin LEO (
5) in a mouse
Staphylococcus aureus skin infection model, highlighting its potential as a topical antibiotic lead.
AB - Based on hit
6, a triaromatic pleuromutilin (TAP) and potent bacterial protein synthesis inhibitor, we explored the chemical space surrounding its pharmacophore by synthesizing 45 new conjugates. Herein, the adenine head was exchanged for new heterocycles, and the benzyl linker exchanged for aniline-, ether-, amide-, and hydroxybenzyl linkages, with all of them successfully engaging the pharmacophore, a result which was mirrored in a strict 3D pharmacophore model. The aniline- and amide-linked conjugates moreover demonstrated greater stability in liver microsomes, while especially conjugate
21, but also
31,
43,
45, and
55 displayed excellent potency, with MRSA activities on par with
6 or better. Docking to the ribosome suggested a shifted engagement with C2469 for
21 over
6, resulting in greater multivalency, while
43/
45 likely coordinates Mg
2+. Lastly, conjugate
21 displayed efficacy equal to commercial Fucidin LEO (
5) in a mouse
Staphylococcus aureus skin infection model, highlighting its potential as a topical antibiotic lead.
U2 - 10.1021/acs.jmedchem.5c00152
DO - 10.1021/acs.jmedchem.5c00152
M3 - Journal article
C2 - 40241444
SN - 0022-2623
VL - 68
SP - 9479
EP - 9500
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -