Recent synthetic strategies for N-heterocyclic β-carboline derivatives in drug discovery: chemical and biological perspectives

Abstract

β-Carboline derivatives are important nitrogen-containing heterocycles widely studied in medicinal chemistry because of their diverse biological activities and flexible chemical properties. This mini-review summarises recent progress reported from 2013 to 2025 in the synthesis and pharmacological evaluation of β-carboline-based compounds, with particular emphasis on their potential to address antimicrobial resistance. Key synthetic methods discussed include Pictet-Spengler cyclisation, oxidative aromatisation, and N-alkylation, which allow the preparation of structurally diverse derivatives such as hybrids, quaternary ammonium salts, and dimers. The review also highlights the broad therapeutic potential of these compounds, including antibacterial, antifungal, antimalarial, and antiviral activities. Structure-activity relationship studies show that modifications at positions C-1, C-3, N-2, and N-9 strongly influence important properties such as lipophilicity, membrane permeability, and biological potency. Compound 15a bearing fatty alcohol hybrid at C-3 position has a very low MIC value at 2.8 μg/mL against Bacillus subtilis MTCC 121, dimeric N2-benzylated quaternary salts displayed an exceptional low MIC value at 0.01–0.05 μmol/mL against MRSA and 1-hydrazide derivatives shows a potent antifungal efficacy by exhibiting EC50 lower than 0.23 μg/mL. In particular, N-quaternization, lipophilic chain introduction, and hybridisation with active pharmacophores can significantly enhance antimicrobial activity. Overall, β-carbolines remain promising scaffolds for future anti-infective drug development.