Fragment‐Linked Purine Derivatives as Inhibitors of (p)ppGpp Synthetases: Design, Synthesis, and Structure‐Activity Relationships
- 1Department of Preclinical Imaging and Radiopharmacy Werner Siemens Imaging Center, Cluster of Excellence iFIT (EXC 2180) ‘Image‐Guided and Functionally Instructed Tumor Therapies', University of Tuebingen Tuebingen Germany
- 2Institute of Pharmaceutical and Medicinal Chemistry University of Münster Münster Germany
- 3Center for Synthetic Microbiology (SYNMIKRO), Faculty of Chemistry, Microbes‐for‐Climate (M4C) Cluster of Excellence Philipps University Marburg Marburg Germany
Abstract
The bacterial stringent response, mediated by the alarmone nucleotides (p)ppGpp, plays a central role in persistence of infections, stress adaptation, and antimicrobial tolerance, making (p)ppGpp synthetases attractive targets for novel antibacterial strategies/therapies. In this study, we report the design, synthesis, and biological evaluation of fragment‐linked nucleobase derivatives targeting the RelA/SpoT homolog (RSH) enzymes. Guided by structural insights into adenine and guanine binding within small alarmone synthetase (SAS2/RelP), a series of purine‐based compounds was developed to simultaneously occupy conserved nucleotide‐binding regions. Initial linker‐bridged analogues showed limited activity, primarily due to poor solubility, prompting the introduction of ribose‐containing derivatives to improve physicochemical properties. Biochemical evaluation using HPLC‐based assays revealed selective inhibition of Staphylococcus aureus SAS1, with the most potent compound displaying micromolar activity (IC50 = 1.8 µM), while little or no inhibition was observed for related SAS enzymes. Structure‐activity relationship analysis highlights the importance of linker length and nucleobase positioning for enzyme selectivity. These findings establish fragment‐linked nucleobase scaffolds as a promising starting point for the development of inhibitors targeting (p)ppGpp biosynthesis and the bacterial stringent response.
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BibTeX
@article{abdalrahman2026fragmentlinked,
title = {{Fragment‐Linked Purine Derivatives as Inhibitors of (p)ppGpp Synthetases: Design, Synthesis, and Structure‐Activity Relationships}},
author = {Rayan Aboalgasim Makawi Abdalrahman and Katharina Sophie Erlitz and Joana Massa and Christopher‐Nils Mais and Gert Bange and Anna Junker and Oliver Koch},
journal = {Archiv Der Pharmazie},
year = {2026},
month = oct,
doi = {10.1002/ardp.70368},
url = {https://doi.org/10.1002/ardp.70368},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fragment‐Linked Purine Derivatives as Inhibitors of (p)ppGpp Synthetases: Design, Synthesis, and Structure‐Activity Relationships
AU - Rayan Aboalgasim Makawi Abdalrahman
AU - Katharina Sophie Erlitz
AU - Joana Massa
AU - Christopher‐Nils Mais
AU - Gert Bange
AU - Anna Junker
AU - Oliver Koch
PY - 2026
DA - 2026/10/26
JO - Archiv Der Pharmazie
DO - 10.1002/ardp.70368
UR - https://doi.org/10.1002/ardp.70368
AB - The bacterial stringent response, mediated by the alarmone nucleotides (p)ppGpp, plays a central role in persistence of infections, stress adaptation, and antimicrobial tolerance, making (p)ppGpp synthetases attractive targets for novel antibacterial strategies/therapies. In this study, we report the design, synthesis, and biological evaluation of fragment‐linked nucleobase derivatives targeting the RelA/SpoT homolog (RSH) enzymes. Guided by structural insights into adenine and guanine binding within small alarmone synthetase (SAS2/RelP), a series of purine‐based compounds was developed to simultaneously occupy conserved nucleotide‐binding regions. Initial linker‐bridged analogues showed limited activity, primarily due to poor solubility, prompting the introduction of ribose‐containing derivatives to improve physicochemical properties. Biochemical evaluation using HPLC‐based assays revealed selective inhibition of Staphylococcus aureus SAS1, with the most potent compound displaying micromolar activity (IC50 = 1.8 µM), while little or no inhibition was observed for related SAS enzymes. Structure‐activity relationship analysis highlights the importance of linker length and nucleobase positioning for enzyme selectivity. These findings establish fragment‐linked nucleobase scaffolds as a promising starting point for the development of inhibitors targeting (p)ppGpp biosynthesis and the bacterial stringent response.
SN - 0365-6233
SN - 1521-4184
ER -