Chloramphenicol Derivatization in Its Primary Hydroxyl Group with Basic Amino Acids Leads to New Pharmacophores with High Antimicrobial Activity

Abstract

In a previous study published by our group, successful modification of the antibiotic chloramphenicol (CHL) was reported, which was achieved by replacing the dichloroacetyl tail with alpha and beta amino acids, resulting in promising new antibacterial pharmacophores. In this study, CHL was further modified by linking the basic amino acids lysine, ornithine, and histidine to the primary hydroxyl group of CHL via triazole, carbamate, or amide bonding. Our results showed that while linking the basic amino acids retained antibacterial activity, it was somewhat reduced compared to CHL. However, in vitro testing demonstrated that all derivatives were comparable in activity to CHL and competed for the same ribosomal binding site with radioactive chloramphenicol. The amino acid–CHL tethering modes were evaluated either with carbamate (7, 8) derivatives, which exhibited higher activity, or with amide- (4–6) or triazole-bridged compounds (1–3), which were equally potent. Our findings suggest that these new pharmacophores have potential as antimicrobial agents, though further optimization is needed.

Navigating Antibacterial Frontiers: A Panoramic Exploration of Antibacterial Landscapes, Resistance Mechanisms, and Emerging Therapeutic Strategies

“…For example, the replacement of the chloramphenicol primary alcohol with an L-lysine amide yields a compound that binds strongly to the ribosome and inhibits puromycin effects on the ribosome, which is an inhibition characteristic of binding to the ribosome A-site. 135 Macrolides. Macrolides are macrocycles, most commonly derived from polyketide metabolism, substituted with sugars.…”

“…Further analogues of chloramphenicol have been studied to attempt to provide novel and useful antibiotics with reduced side effects. For example, the replacement of the chloramphenicol primary alcohol with an l -lysine amide yields a compound that binds strongly to the ribosome and inhibits puromycin effects on the ribosome, which is an inhibition characteristic of binding to the ribosome A-site …”

Navigating Antibacterial Frontiers: Landscape Analysis of Antibiotics, Resistance Mechanisms and Emerging Therapeutic Strategies

“…For example, the replacement of the chloramphenicol primary alcohol with an L-lysine amide yields a compound that bound strongly to the ribosome and inhibited puromycin effects on the ribosome, an inhibition characteristic of binding to the ribosome A-site. 141 Macrolides: Macrolides are macrocycles, most commonly derived from polyketide metabolism, substituted with sugars. They have broad-spectrum antibacterial activity against both Grampositive and Gram-negative bacteria, including Moraxella catarrhalis, Streptococcus pneumoniae, Legionella pneumoniae, Streptococcus pneumoniae, Mycoplasma pneumoniae, Streptococcus pyogenes, Helicobacter pylori, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Mycobacterium avium/intracellulare, Mycoplasma pneumoniae, and Chlamydia pneumoniae.…”