Synthesis and antimicrobial screening of novel 1,3-dioxolanes linked to N-5 of 5H-1,2,4-triazino[5,6-b]indole-3-thiol

Abstract

Synthesis of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1H-indole-
-2,3-dione (10) was achieved by coupling 1H-indole-2,3-dione (16) with (R)-
-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (15) in the presence of sodium hydride in dry N,N-dimethylformamide at room tempe­ra­ture in a closed Erlenmeyer flask. Condensation of 10 with hydrazinecarbo­thioamide in water afforded the thiosemicarbazone derivative 17; its sub­sequent cyclization with potassium carbonate in water gave the corresponding thione 18 in good yield. The 3-allylthio and 3-benzylthio derivatives 20 and 21 were also prepared by alkylating thiol 19 with alkyl halides in aqueous sodium hydroxide or coupling of 3-(allylthio/benzylthio)-5H-1,2,4-triazi­no[5,6-b]indoles (23 and 24) with compound 15 in NaH/DMF. Compound 20 was isomerized to a mixture of geometrical isomers (E/Z)-5-[(2,2-dimethyl-1,3-dioxolan-4-yl)­methyl]-3-(prop-1-en-1-ylthio)-5H-1,2,4-triazino[5,6-b]indoles (25 and 26), evi­denced by their 1H- and 13C-NMR spectra taken in deuterodimethyl sul­foxide. Structural elucidation of the synthesized compounds was realized using FT-IR, 1H-NMR, 13C-NMR, mass spectrometry and elemental analysis. The newly synthesized compounds were found to possess moderate inhibitory act­ivity against the fungus Candida albicans compared to clotrimazole as refer­ence control. Compounds 10, 17, 19, 20, 21, 23 and 24 had mean growth inhibition zones (IZ) and minimal inhibitory concentrations (MIC) in the range of 12–15 mm and 31.25–200 μg mL-1, respectively, with inhibition levels in the range 70.58–88.23 %. Compound 19 exhibited moderate activity against Gram-posi­tive bacteria Staphylococcus aureus relative to imipenem as the stan­dard drug. All compounds were inactive against Escherichia coli and Pseudo­monas aeru­ginosa.