Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.
We propose anew concept of the triple role of protic ionic liquids with nucleophilic anions:a)aregenerable solvent, b) aB rønsted acid inducing diverse transformations via general acid catalysis,a nd c) as ource of an ucleophile.T he efficiency of this strategy was demonstrated using thiocyanatebased protic ionic liquids for the ring-opening of donoracceptor cyclopropanes.Awide variety of activated cyclopropanes were found to react with 1-methylimidazolium thiocyanate under mild metal-free conditions via unusual nitrogen attacko ft he ambident thiocyanate ion on the electrophilic center of the three-membered ring affording pyrrolidine-2-thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms,r espectively,i nasingle timeefficient step.T he ability of 1-methylimidazolium thiocyanate to serve as at riplex reagent was exemplarily illustrated by (4+ +2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopropane,epoxidering-opening and other organic transformations.
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