Design, synthesis and biological evaluation of novel triarylmethane analogues as HIV-1 entry inhibitors

Small molecule-based entry inhibitors (EIs) may be promising to reduce human immunodeficiency virus (HIV) infection. Taking our recently described HIV entry inhibitor, ADS-J21, as prototype, a new series of triarylmethane analogues have been designed and synthesized. Among them, compound L14 emerged as the most promising showing significant antiviral activity against HIV-1_IIIB infection (IC₅₀: 0.39 μM) and low cytotoxicity (CC₅₀: 210.03 μM, SI: 537.1). L14 also exhibit cell-cell fusion inhibition activity and antiviral activity against both HIV-1 T20-resistant and primary strains, with potency in the submicromolar range. Mechanistically, L14 interacts by hydrogen bonding and π-π stacking with Lys35, Gln38 and Trp32 residues present in the gp41 NHR pocket. Additionally, L14 did not show significant toxicity in acute and subacute toxicity studies performed on healthy Kunming mice. The oral bioavailability of L14 in Sprague Dawley (SD) rats is about 7.0 %. Therefore, compound L14 holds promise as a novel HIV-1 small-molecule entry inhibitor although a further ten-fold improvement in activity is needed for further development.