A Role for Janus Cyclohexyl Ring Motifs in Medicinal Chemistry. Incorporation Into G-Quadruplex Ligands and Anti-Trypanosoma brucei Activity.
- 1EaStChem, School of Chemistry, BSRC, University of St Andrews, St Andrews, UK.
- 2UCL School of Pharmacy, London, UK.
Abstract
The naphthalene diimide (NDI) ring system is recognized as a privileged motif for binding to G-quadruplex DNA. Accordingly, compounds with peripheral groups attached to the NDI core are being explored as antiparasitic and anticancer candidates. In this study, we have synthesized and explored a series of NDIs with peripheral all-cis ring fluorinated cyclohexyl rings to assess their relative stabilization potential for G-quadruplex and double-stranded DNA. This was explored through FRET melting experiments and measuring changes in melting temperatures (ΔTm). Compounds were also assayed against Trypanosoma brucei to assess their in vitro potency (EC₅₀) against the causative parasite of human African trypanosomiasis or African Sleeping Sickness. The study revealed significant differences in activity when changing the nature of fluorine substitutions on the cyclohexane ring and also the length and nature (ether (O) or methylene (CH₂)) of the linker to the core aromatic motif. The most active compound of the series was ether 12a which displayed nanomolar activity (EC₅₀ = 40 nM) against T. brucei although with a modest selectivity (14-fold) for the parasite over HeLa (human model) cells. The study reveals good prospects for exploring fluorinated Janus cyclohexanes in a medicinal chemistry context.
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BibTeX
@article{stewart2026role,
title = {{A Role for Janus Cyclohexyl Ring Motifs in Medicinal Chemistry. Incorporation Into G-Quadruplex Ligands and Anti-Trypanosoma brucei Activity.}},
author = {Josephine M Stewart and Mario Kehler and Vytautas Kuodis and Gary N Parkinson and Wenqian Chen and Terry K Smith and Zoë A E Waller and David O'Hagan},
journal = {Chembiochem : a European journal of chemical biology},
year = {2026},
month = oct,
doi = {10.1002/cbic.70588},
url = {https://europepmc.org/article/MED/42960692},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Role for Janus Cyclohexyl Ring Motifs in Medicinal Chemistry. Incorporation Into G-Quadruplex Ligands and Anti-Trypanosoma brucei Activity.
AU - Josephine M Stewart
AU - Mario Kehler
AU - Vytautas Kuodis
AU - Gary N Parkinson
AU - Wenqian Chen
AU - Terry K Smith
AU - Zoë A E Waller
AU - David O'Hagan
PY - 2026
DA - 2026/10/30
JO - Chembiochem : a European journal of chemical biology
DO - 10.1002/cbic.70588
UR - https://europepmc.org/article/MED/42960692
AB - The naphthalene diimide (NDI) ring system is recognized as a privileged motif for binding to G-quadruplex DNA. Accordingly, compounds with peripheral groups attached to the NDI core are being explored as antiparasitic and anticancer candidates. In this study, we have synthesized and explored a series of NDIs with peripheral all-cis ring fluorinated cyclohexyl rings to assess their relative stabilization potential for G-quadruplex and double-stranded DNA. This was explored through FRET melting experiments and measuring changes in melting temperatures (ΔTm). Compounds were also assayed against Trypanosoma brucei to assess their in vitro potency (EC₅₀) against the causative parasite of human African trypanosomiasis or African Sleeping Sickness. The study revealed significant differences in activity when changing the nature of fluorine substitutions on the cyclohexane ring and also the length and nature (ether (O) or methylene (CH₂)) of the linker to the core aromatic motif. The most active compound of the series was ether 12a which displayed nanomolar activity (EC₅₀ = 40 nM) against T. brucei although with a modest selectivity (14-fold) for the parasite over HeLa (human model) cells. The study reveals good prospects for exploring fluorinated Janus cyclohexanes in a medicinal chemistry context.
SN - 1439-4227
SN - 1439-7633
ER -