Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors

Currently, there are only three FDA-approved drugs that
inhibit
human immunodeficiency virus (HIV) entry-fusion into host cells. The
situation is even worse for enterovirus EV71 infection for which no
antiviral therapies are available. We describe here the discovery
of potent entry dual inhibitors of HIV and EV71. These compounds contain
in their structure three or four tryptophan (Trp) residues linked
to a central scaffold. Critical for anti-HIV/EV71 activity is the
presence of extra phenyl rings, bearing one or two carboxylates, at
the C2 position of the indole ring of each Trp residue. The most potent
derivatives, 22 and 30, inhibit early steps
of the replicative cycles of HIV-1 and EV-A71 by interacting with
their respective viral surfaces (glycoprotein gp120 of HIV and the
fivefold axis of the EV-A71 capsid). The high potency, low toxicity,
facile chemical synthesis, and great opportunities for chemical optimization
make them useful prototypes for future medicinal chemistry studies.