Design and synthesis of potential chrome-based anti-tuberculosis agents

Abstract

This dissertation describes the design and synthesis of 4-(4-oxochromen-3-yl)-3,4-dihydropyrimidin-2-one derivatives and the assessment of their biological activity against a strain of the causative agent of TB. In this investigation, two classes of chromone-based compounds were synthesised. Different reactions were exploited to synthesise target compounds. In the first route, a Vilsmeier-Haack reaction was applied to convert the 3,5-disubstituted/unsubstituted 2-hydroxyacetophenones to corresponding 6,8-disubstituted/unsubstituted chromone-3-carbaldehydes. The 6,8-disubstituted/unsubstituted chromone-3-carbaldehydes were oxidized to afford 6,8-disubstituted/unsubstituted chromone-3-carboxylic acids with poor percentage yield 15-28%. Additionally, a second series of compounds were obtained by employing the Biginelli reaction to afford ethyl 6-hydroxy-4-(6-substituted/unsubstituted chromon-3-yl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives with moderate to good percentage yield of 53 – 74%. Ethyl 6-hydroxy-4-(6-substituted/unsubstituted chromon-3-yl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates were successfully dehydrated to ethyl 4-(6-substituted/unsubstituted chromon-3-yl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives using a Dean-Stark method at 140 °C, purified by recrystallization. All target compounds were purified by recrystallization and flash chromatography, and then characterized using NMR and FTIR, LC-MS and HRMS. After fully characterizing target compounds, they were screened for activity against the Mtb H37Rv clinical strain. Three media were used for screening and MABA was used for quantitative analysis. Unfortunately, all compounds tested were inactive with an MIC value ˃62.5 μM. Ethyl 2-oxo-4-(4-oxo-6-phenyl-4H-chromen-3-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate with reported MIC of 3.39 μM also did not show any activity. The discrepancies in the results could be due to differences in media used, incubation conditions, bacteria or contamination. Derivatives with 4-substututed phenyl substituents, were insoluble with solubility <5 μM. The OH group was critical for solubility as removing it resulted in poor solubility. Ethyl 4-(6-substituted/unsubstituted chromon-3-yl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives did not show any cytotoxicity against HepG2 cell line, with all compounds showing ˃50 μM toxicity.