Oligostyrylbenzene Derivatives with Antiparasitic and Antibacterial Activity as Potent G-Quadruplex Ligands

G-quadruplexes (G4s) are non-canonical secondary structures that play a crucial role in the regulation of genetic expression. This study explores the interaction between G4s and a small family of oligostyrylbenzene (OSB) derivatives, characterized by tris(styryl)benzene and tetrastyrylbenzene backbones, functionalized with either trimethylammonium or 1-methylpyridinium groups. Initially identified as DNA ligands, these OSB derivatives have now been recognized as potent G4 binders, surpassing in binding affinity commercially available ligands such as pyridostatin and displaying good selectivity for G4s over duplex DNA. Furthermore, OSB derivatives <b>1</b> and <b>2</b> demonstrated significant antiparasitic activity against bloodstream forms of <i>T. brucei</i> and extracellular <i>L. major</i>, with high selectivity indices when compared to MRC-5 healthy control cells. Derivatives <b>1</b> and <b>2</b> exhibited moderate biocidal effects against a range of Gram-positive and Gram-negative bacterial strains. Notably, a synergistic antibacterial effect was observed when these compounds were combined with traditional antibiotics, particularly against <i>Acinetobacter baumannii</i>, highlighting their potential utility in addressing drug-resistant bacterial infections. The differences in bioactivity among the OSB derivatives can be attributed to variations in cellular uptake, as proved by flow cytometry analysis. This suggests that the degree of cellular internalization plays a pivotal role in the observed antiparasitic and antibacterial efficacy.