Synthesis, Evaluation, and Context for Applications of SF5-Containing [1.1.1]Bicyclopentane and [2]Staffane "Hybrid Bioisosteres".
- 1Department of Chemistry, University of California, Davis, California95616, United States.
- 2Novartis BioMedical Research, Emeryville, California94608, United States.
Abstract
Bioisosteric replacements are conventionally applied as single-variable changes to a parent molecule during drug discovery campaigns. Herein, we evaluate hybrid bioisosteric replacements as strategic combinations of multiple substitutions that counterbalance the physicochemical consequences of incorporating single bioisosteres individually. In this context, we validate SF5-substituted [1.1.1]bicyclopentanes (SF5-BCPs) and SF5-[2]staffanes (SF5-BCP-BCPs) as hybrid bioisostere motifs that have not been field-tested due to lack of access to versatile building blocks. We address a key synthetic limitation by developing scalable routes to carboxylic acid-containing intermediates that facilitate incorporation of these motifs into drug-like molecules via carbonyl group manipulations. These advances enable (1) crystallographic studies that contextualize structural features of these motifs, (2) syntheses of structurally diverse pharmaceutical and agrochemical derivatives, and (3) systematic evaluation of single (SF5-Ph → SF5-BCP) and multicomponent "hybrid" bioisosteric replacements (CF3-Ph → SF5-BCP and CF3-Ph-Ph → SF5-BCP-BCP) through in vitro ADME profiling. Finally, we investigate the chemical stability profile of these novel SF5-[2]staffanes, establish an extensive suite of building blocks, and demonstrate their compatibility with reactions frequently used in medicinal chemistry. Together, the results of this extensive study position SF5-BCPs and SF5-[2]staffanes as practical hybrid bioisosteres for tuning molecular properties in drug discovery.
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BibTeX
@article{buldt2026synthesis,
title = {{Synthesis, Evaluation, and Context for Applications of SF5-Containing [1.1.1]Bicyclopentane and [2]Staffane "Hybrid Bioisosteres".}},
author = {Jón Atiba Buldt and Masiel M Belsuzarri and Ansh Hiten Patel and Yannick Kraemer and Tyson Vu and Riddhiman Banerjee and Jake Anthony Olvera and Dean J Tantillo and Lauren M Holder and Cody Ross Pitts},
journal = {Journal of the American Chemical Society},
year = {2026},
month = sep,
doi = {10.1021/jacs.6c12832},
url = {https://europepmc.org/article/MED/42937888},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synthesis, Evaluation, and Context for Applications of SF5-Containing [1.1.1]Bicyclopentane and [2]Staffane "Hybrid Bioisosteres".
AU - Jón Atiba Buldt
AU - Masiel M Belsuzarri
AU - Ansh Hiten Patel
AU - Yannick Kraemer
AU - Tyson Vu
AU - Riddhiman Banerjee
AU - Jake Anthony Olvera
AU - Dean J Tantillo
AU - Lauren M Holder
AU - Cody Ross Pitts
PY - 2026
DA - 2026/09/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c12832
UR - https://europepmc.org/article/MED/42937888
AB - Bioisosteric replacements are conventionally applied as single-variable changes to a parent molecule during drug discovery campaigns. Herein, we evaluate hybrid bioisosteric replacements as strategic combinations of multiple substitutions that counterbalance the physicochemical consequences of incorporating single bioisosteres individually. In this context, we validate SF5-substituted [1.1.1]bicyclopentanes (SF5-BCPs) and SF5-[2]staffanes (SF5-BCP-BCPs) as hybrid bioisostere motifs that have not been field-tested due to lack of access to versatile building blocks. We address a key synthetic limitation by developing scalable routes to carboxylic acid-containing intermediates that facilitate incorporation of these motifs into drug-like molecules via carbonyl group manipulations. These advances enable (1) crystallographic studies that contextualize structural features of these motifs, (2) syntheses of structurally diverse pharmaceutical and agrochemical derivatives, and (3) systematic evaluation of single (SF5-Ph → SF5-BCP) and multicomponent "hybrid" bioisosteric replacements (CF3-Ph → SF5-BCP and CF3-Ph-Ph → SF5-BCP-BCP) through in vitro ADME profiling. Finally, we investigate the chemical stability profile of these novel SF5-[2]staffanes, establish an extensive suite of building blocks, and demonstrate their compatibility with reactions frequently used in medicinal chemistry. Together, the results of this extensive study position SF5-BCPs and SF5-[2]staffanes as practical hybrid bioisosteres for tuning molecular properties in drug discovery.
SN - 0002-7863
SN - 1520-5126
ER -