A Rigid Bicyclic Platform for the Generation of Conformationally Locked Neuraminidase Inhibitors

Abstract

Rapid mutation of the influenza virus through genetic mixing raises the prospect of new strains that are both highly transmissible and highly lethal, and which have the ability to evade both immunization strategies (through mutation of hemagglutinin) and current therapies (through mutation of neuraminidase). Inspired by a need for next-generation therapeutics, a synthetic strategy for a new class of rigid, bicyclic inhibitors of influenza neuraminidase is reported.

Inhibitors of the human neuraminidase enzymes

“…Additionally, the most potent compounds currently available are based on the DANA scaffold, and organic scaffolds that are more synthetically accessible or which are conformationally restricted could be an important asset to the eld. 100…”

Dipolar addition to cyclic vinyl sulfones leading to dual conformation tricycles

“…We previously described the synthesis of a family of [3.3.0] bicyclic vinyl sulfones starting from 3-sulfolene [30], and their elaboration to inhibitors of viral neuraminidase (Scheme 1) [31]. Understanding the conformational preferences of the underlying bicyclic structure was crucial to the design and assembly of such inhibitors.…”

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

“…Currently, various cyclic cores have been employed for the structural modifications, including Based on the assumption that a bicyclic derivative, which locks this ring geometry in place, would have a reduced binding entropy and enhanced target selectivity, a new series of rigid, bicyclic inhibitors of influenza neuraminidase was prepared ( Figure 12). Ultimately, the inhibition activity for racemic 82 is up to threefold lower than the activities reported for the side chain deleted derivatives of zanamivir and peramivir (79 and 81), thus, it appears likely that the rigidified bicyclic scaffold has shown its advantage (it is not proper to compare IC 50 values from different experiments) [91].…”