Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion [post]

Tobias Krämer, kevin kavanagh, Trinidad Velasco-Torrijos, Harlei Martin, Tara Somers, Fred Pfeiffer, Ryan Robson, Mathew Dwyer
2020 unpublished
<div>Candida albicans is one of the most prevalent fungal pathogens involved in</div><div>hospital acquired infections. It uses adhesins to bind to glycans at the cell surface of epithelial</div><div>cells and thus initiate infection. These interactions can be blocked by synthetic carbohydrates</div><div>(such as compound 1) that mimics the structure of cell surface glycans. Herein we report the</div><div>synthesis of a new series of divalent galactosides featuring aromatic (benzene,
more » ... benzene, squaramides)</div><div>and aliphatic (norbornenes) central scaffolds, with the latter being the first examples of their</div><div>kind as small molecule anti-adhesion glycoconjugates. The evaluation of these compounds as</div><div>inhibitors of adhesion of C. albicans o exfoliated buccal epithelial cells (BECs) revealed that</div><div>galactosides 1 and 6, built on an aromatic core, were the most efficient inhibitors of adhesion,</div><div>displacing up to 36% and 48%, respectively, of yeast cells already attached to the BECs at</div><div>0.138 μM. Conformational analysis of compound 1 identified the preference for a folded </div><div>presentation in the lowest energy conformers. Remarkably, cis-endo-norbornene 21 performed</div><div>comparably to the benzene-core derivatives, highlighting the potential of norbornenes as a new</div><div>class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.</div>
doi:10.26434/chemrxiv.12295514 fatcat:i35lps7n3rcjrh4htnyiylmpxu