Synthesis and evaluation of influenza A viral neuraminidase candidate inhibitors based on a bicyclo[3.1.0]hexane scaffold.
This manuscript describes a novel class of derivatives based on a bicyclo[3.1.0]hexane scaffold, proposed as mimics of sialic acid in a distorted boat conformation that is on the catalytic pathway of neuraminidases (sialidases). A general synthetic route for these constrained-ring molecules was developed using a photochemical reaction followed by a Johnson-Corey-Chaykovsky cyclopropanation. Functionalization with the goal of occupying the 150-cavity was also exploited. Inhibition assays demonstrated low micromolar inhibition against both group-1 (H5N1) and group-2 (H9N2) influenza neuraminidase subtypes, indicating good affinity for the alpha and beta sialic acid mimics and 150-cavity-targeted derivatives. These results provide a validation of a bicyclo[3.1.0]hexane scaffold as a mimic of a distorted sialic acid bound in the neuraminidase active site during catalysis.
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada V5A 1S6. bennet@sfu.ca and Università degli Studi di Milano, Dipartimento di Chimica, Via Golgi 19, I-20133 Milano, Italy.
Cinzia
C
Colombo
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada V5A 1S6. bennet@sfu.ca.
B Mario
BM
Pinto
Università degli Studi di Milano, Dipartimento di Chimica, Via Golgi 19, I-20133 Milano, Italy.
Anna
A
Bernardi
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada V5A 1S6. bennet@sfu.ca.
Andrew J
AJ
Bennet
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology*; D053127:Influenza A Virus, H9N2 Subtype / Q000201:enzymology*; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation
D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; C046059:bicyclo(3.1.0)hexane; D009439:Neuraminidase