Guanidine-Containing Phenyl-Pyrrole Compounds as Probes for Generating HIV Entry Inhibitors Targeted to gp120

Asp368 in the HIV-1 envelope glycoprotein gp120 plays a critical role in binding to the Arg59 of the primary cellular receptor CD4 through forming a salt-bridge to initiate HIV-1 entry and infection. The molecules capable of interfering with the entry of virus to host cells are termed HIV-1 entry/attachment inhibitors. Earlier, we designed N-(2-amino-1-(5-(hydroxymethyl)-4-methylthiazol-2-yl)ethyl)-5-(4-chloro-3-fluorophenyl)-1H-pyrrole-2-carboxamide series compounds as entry inhibitors targeted to HIV-1 gp120. Here, we report the incorporation of guanidine moiety to replace free amine in some of those HIV-1 entry inhibitors. Guanidine group is expected to simulate Arg59 and interact with Asp368 of the gp120 to form salt-bridge and thus blocking the binding of HIV-1 with the cell receptor CD4. The resulting compounds were tested against Env-pseudotyped HIV-1, and few of them showed low M inhibition. The guanidines also showed higher aqueous solubility than compounds with a free amine. One of the guanidines, N-(2-(2-guanidinoacetamido)-1-(4-(hydroxymethyl)thiazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide (10), is expected to be a lead for further optimization.