Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired
immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million
deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics,
in particular combination antiretroviral therapy, have significantly improved the treatment of HIV
infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic
disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid
emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an
urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life
cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the
cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target
for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists
are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone,
oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates.
Herein, we discuss the current state of research with respect to the design, synthesis and biological
evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing
small molecule as inhibitors of gp120 and HIV entry.
Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors