We describe the facile synthesis of 3-substituted indoles by Friedel–Crafts-type conjugate addition catalyzed by imidazolium salts. The reactions proceed under mild conditions with no base, solvent, or N-heterocyclic carbene. Mechanistic studies suggest the potential mechanism operates through the dual activation of indoles involving cation–π interactions of imidazolium cations with indoles and Lewis base activation by chloride anions derived from the imidazolium salts. High-level ab initio molecular orbital calculations reveal that there is a strong attraction between the imidazolium cation and the indole, and that the electrostatic and induction interactions strongly contributes to the attraction in the indole/imidazolium complex, which is a characteristic feature of the cation–π interaction.

Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14-mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized. Three types of aromatic spacers, 1,4-phenylenedimethanamine, naphthalene-2,6-diyldimethanamine, and [1,1′-biphenyl]-4,4′-diyldimethanamine, were used to build four pharmacophore groups. As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1-propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were also used. Several compounds showed significant CXCR4 binding affinity, and zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity.

The human immunodeficiency virus type 1 (HIV-1) uses CD4 and the co-receptor CCR5 or CXCR4 in the process of cell entry. The negatively charged extracellular domains of CXCR4 (CXCR4-ED) interact with positive charges on the V3 loop of gp120, facilitating binding via electrostatic interactions. The presence of highly conserved positively charged residues in the V3 loop suggests that CXCR4-ED-derived inhibitors might be broadly effective inhibitors. Synthetic peptide derivatives were evaluated for anti-HIV-1 activity. The 39-mer extracellular N-terminal region (NT) was divided into three fragments with 10-mer overlapping sites (N1–N3), and these linear peptides were synthesized. Peptide N1 contains Met 1–Asp 20 and shows significant anti-HIV-1 activity. Extracellular loops 1 and 2 (ECL1 and 2) were mimicked by cyclic peptides C1 and C2, which were synthesized by chemoselective cyclization. Cyclic peptides C1 and C2 show higher anti-HIV-1 activity than their linear peptide counterparts, L1 and L2. The cytotoxicities of C1 and C2 are lower than those of L1 and L2. These results indicate that Met 1–Asp 20 segments of the NT and cyclic peptides of ECL1 and ECL2 are potent anti-HIV-1 drug candidates.

The chemokine receptor CXCR4 is a member of the seven transmembrane GPCR family, which is implicated in multiple diseases, including HIV infection, cancers, and rheumatoid arthritis. Low-molecular-weight nonpeptidic compounds, including AMD3100 and various pyridyl macrocyclic zinc(II) complexes, have been identified as selective antagonists of CXCR4. In the present study, structure–activity relationship studies were performed by combining the common structural features of alkylamino and pyridiyl macrocyclic antagonists. Several new zinc(II) or copper(II) complexes demonstrated potent anti-HIV activity, strong CXCR4-binding activity, and significant inhibitory activity against Ca²⁺ mobilization induced by CXCL12 stimulation. These results may prove useful in the design of novel CXCR4 antagonists, and the compounds described could potentially be developed as therapeutics against CXCR4-relevant diseases or chemical probes to study the biological activity of CXCR4.