Synthesis of chromone-3-carbaldehyde-based derivatives as anti-tuberculosis agents

Abstract

Tuberculosis is a significant global health concern, with around 10 million people falling ill with the disease annually. The rise in multidrug-resistant and extensively drug-resistant TB cases complicates treatment efforts, reduces the efficacy of current treatment, and increases the risk of spreading. Chromones and tetrahydropyrimidines are significant scaffolds in medicinal chemistry, and they exhibit pharmacological activities, making them viable candidates as anti-tuberculosis agents. The synthetic approach was designed to explore modifications of the chromone scaffold by targeting different substituent positions on the acetophenone precursor to yield diverse chromone derivatives with potential anti-tuberculosis activity. Acetophenone analogues were subjected to a Vilsmeier-Haack reaction to afford chromone-3-carbaldehyde analogues, which were later converted to 4-oxo-4H-chromene-3-tetrahydropyrimidine-5-carboxylate analogues via the Biginelli reaction. Chromone-3-carbaldehyde analogues were successfully synthesized with yields ranging from 14 to 98%. The target compounds (4-oxo-4H-chromene-3-tetrahydropyrimidine-5-carboxylates) were successfully synthesized with moderate to excellent yields of 51 - 91% and 70 - 100% purity. Compounds with more than 95% purity were evaluated for their anti-tuberculosis potential. Synthesized compounds were characterized by NMR, FTIR and LC-MS, and their melting points were determined for physical characterisation The synthesized compounds were evaluated for their anti-tuberculosis activity against Mycobacterium tuberculosis H37RvMA. All seven compounds tested exhibited no detectable growth inhibition at the highest concentration evaluated (62.5 μM), and therefore their MIC90 values were recorded as ≥ 62.5 μM