Linker and Head-Group Exploration of Anti-MRSA Triaromatic Pleuromutilins

被引：0

作者：

Heidtmann, Christoffer V. ^{[1
]}

Fisker, Christian Ding ^{[1
]}

Logstrup, Sarah ^{[1
]}

Eriksen, Patrick G. ^{[1
]}

Storm, Louise H. ^{[1
]}

Staerk, Kristian ^{[2
,3
,4
]}

Moesgaard, Laust ^{[1
]}

Pedersen, Maria ^{[1
]}

Madsen, Martin J. ^{[1
]}

Yusuf, Ahmed ^{[1
]}

Urup, Krista ^{[1
]}

Hojgaard, Iben S. ^{[1
]}

Ramesh, Jayappragash ^{[1
]}

Pihlsbech, Rasmus H. ^{[1
]}

Sorensen, Caroline B. ^{[1
]}

Ronn, Tore L. ^{[1
]}

Larsen, Alexander B. ^{[1
]}

Caspersen, Laurits R. ^{[1
]}

Moller, Mathias A. E. ^{[1
]}

Sixhoj, Chris R. ^{[1
]}

Frimodt-Moller, Niels ^{[5
]}

Klitgaard, Janne K. ^{[2
,6
]}

Andersen, Thomas E. ^{[2
,7
]}

Nielsen, Carsten U. ^{[1
]}

Nielsen, Poul ^{[1
]}

机构：

[1] Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark

[2] Univ Southern Denmark, Dept Clin Res, Res Unit Clin Microbiol, DK-5000 Odense M, Denmark

[3] Univ Southern Denmark, Dept Dermatol, DK-5230 Odense M, Denmark

[4] Univ Southern Denmark, Allergy Ctr, DK-5230 Odense M, Denmark

[5] Copenhagen Univ Hosp Rigshosp, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark

[6] Univ Southern Denmark, Dept Biochem & Mol Biol, Res Unit Mol Microbiol, DK-5230 Odense M, Denmark

[7] Odense Univ Hosp, Dept Clin Microbiol, DK-5000 Odense, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 09期

关键词：

CLICK CHEMISTRY APPROACH; STAPHYLOCOCCUS-AUREUS; NUCLEOSIDES; DERIVATIVES; INHIBITION; TIAMULIN; BINDING;

D O I：

10.1021/acs.jmedchem.5c00152

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Mg2+. 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.

引用

页码：9479 / 9500

页数：22

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