New Coumarin Hybrids from Chloramphenicol: A Step Towards Next-Generation Biocompatible Antimicrobials

Objective: Chloramphenicol is a broad-spectrum antibiotic that inhibits bacterial growth by preventing protein synthesis. However, its clinical use is highly limited due to serious side effects, including aplastic anemia. Methods: The aim of the study was to synthesize seven coumarin derivatives (CDC1–CDC7) from chloramphenicol to enhance their activity and improve compatibility with the human microbiome. The chemical synthesis began with the reduction of the nitro group of chloramphenicol to its amine counterpart. The Sandmeyer reaction was used to diazotize the resulting product, forming a compound containing a phenol group. This compound was then coupled with 3-ketoglutaric acid in a Pechmann condensation reaction, yielding the first coumarin (CDC1). By adding different phenolic compounds to this coumarin and esterifying them, (CDC2–CDC7) were synthesized with modifications to the off-side aromatic ring. The chemical structures of the synthesized coumarins were verified using various spectroscopic techniques, and their antimicrobial activities were evaluated using a broth microdilution method. The test microbes included six pathogenic bacteria, four pathogenic anaerobic bacteria, and two pathogenic fungi, while the biocompatibility of the compounds was assessed with three microbiome-derived bacteria. Results and Discussion: The synthesized coumarins exhibited a broader range of antimicrobial activity than the parent drug and showed good compatibility with the microbiome-derived bacteria tested. In addition, some structure-activity relationship (SAR) insights were obtained. The most significant finding was the influence of the off-side aromatic ring substitution on the antimicrobial activity. Specifically, chloride substitution provided the best anti-aerobic effect, methoxy substitution the best anti-anaerobic effect, and fluoride substitution the best antifungal activity. Conclusions: These results suggest that further research into the synthesized coumarins could lead to the development of a next-generation class of biocompatible broad-spectrum antimicrobial agents.