Synthesis and antibacterial activity of angular tetrahydrocycloamino [1,2-a]quinoxalin-4-one derivatives

Abstract

Objectives: The resistance of bacteria to current antibiotics is a significant concern in treating infectious diseases, posing a strong threat to global health, food security, and development. This underscores the need for synthesizing new heterocyclic compounds as potential lead candidates in drug discovery. Quinoxalinone derivatives, known for their presence in various therapeutic agents and clinical drugs, are of particular interest. This study aimed to synthesize angular tricyclic tetrahydrocycloamino [1,2-a]quinoxalin-4-one derivatives and evaluate their antibacterial activities. Methods/analysis: The synthesis began with preparing precursors through the condensation of substituted 1-halogeno-2-nitrobenzene and cyclic amino acids in the presence of a base in ethanol, forming 2-nitrophenyl pyrrolidine/piperidine-2-carboxylic acids (acid adducts) 3a-3j. These acid adducts were then converted to amino esters 4a-4e by reacting them with thionyl chloride/ trimethylchlorosilane and methanol. Intramolecular reductive cyclization of the acid adducts or esters produced tetrahydrocycloamino [1,2-a]quinoxalin-4-ones (5a-5j) through catalytic hydrogen transfer hydrogenation. The chemical structures of the synthesized compounds were confirmed using FTIR, 1H and 13C NMR, MS, and CHN analysis. Their in vitro antibacterial activities were evaluated against ten bacterial strains using the broth microdilution method, revealing moderate to excellent activities compared to standard antibiotics streptomycin (STM) and nalidixic acid (NLD). Findings: Compound 5g demonstrated significant antibacterial activity (MIC = 15.6 μg/mL) against S. epidermidis, and compound 5c exhibited activity (MIC = 31.3 μg/mL) against S. aureus, both compared to STM and NLD. The results suggest that some of these compounds with promising antibacterial activity could serve as leads for discovering new antibacterial drugs. Novelty/improvement: The tetrahydrocycloamino [1,2-a]quinoxalin-4-ones were prepared using two methods with higher yields than previously reported, with the second method being novel for synthesizing quinoxalin-4-ones. The in vitro antibacterial studies of these compounds were reported, and substituted quinoxalin-4-ones were synthesized from N’-ethyl-N-(2-nitrophenyl)pyrrolidine-2-carboxamide 7 in good yield.

Keywords

• Antibacterial
• Condensation
• Cyclic amino acids
• Quinoxalinones
• Reductive cyclisation