Abstract: Objective To synthesize novel aryl-substituent benzyl acid compounds targeting HIV gp41 and characterize their
anti-HIV activities. Methods Twelve analogues of aryl-substituent benzyl acid were designed and synthesized by Suzuki-
Miyaura cross-coupling and Knoevenagel condensation reactions using halo-benzyl acid or 3-carboxybenzeneboronic acid as
the raw material. The inhibitory activities of these compounds on gp41 six-helix bundle formation were tested by ELISA, and
their anti-HIV activities were determined using a luciferase assay. Results The structures of the compounds were characterized
by nuclear magnetic resonance and mass spectrography. Among the 12 compounds, 5 (7b, 7c, 7d, 7e, and 7g) could inhibit the
gp41 six-helix bundle formation, and 7d showed the most potent effect, and could also inhibit the replication of HIV-1 SF33
strain with an IC50 of 20 μmol/L. Conclusion The synthesized aryl-substituent benzyl acid compound 7d could inhibit HIV
replication by blocking the gp41 six-helix bundle formation.