Design, synthesis and biological evaluation of 3-substituted 2,5-dimethyl-N-(3-(1H-tetrazol-5-yl)phenyl)pyrroles as novel potential HIV-1 gp41 inhibitors

Based on the structure of HIV-1 gp41 binding site for small-molecule inhibitors, optimization of lead 2 resulted in the discovery of a new series of 2,5-dimethyl-3-(5-(N-phenylrhodaninyl)methylene)-N-(3-(1H-tetrazol-5-yl)phenyl)pyrrole compounds with improved anti-HIV-1 activity. The most active compounds 13a and 13j exhibited significant potency against gp41 6-HB formation with IC50 values of 4.4 and 4.6μM and against HIV-1 replication in the MT-2 cells with EC50 values of 3.2 and 2.2μM, respectively, thus providing a new starting point to develop highly potent small-molecule HIV fusion inhibitors targeting gp41.