Synthesis, characterization and biological evaluation of benzo[d]isothiazole ring systems, fused to nitrogen heterocycles

Abstract

We have developed a simple and efficient synthetic route, starting from easily available starting materials, to the novel ring system benzo[4,5]isothiazolo[2,3-a]pyrazine-6,6-dioxide. A series of chalcones were synthesized which were subsequently reacted with chlorosulphonic acid to generate the chalcone sulphonyl chlorides. The chalcone sulphonyl chlorides were then treated with bromine to generate the dibromo chalcone sulphonyl chlorides. These were subsequently reacted with 1,2-diaminopropane and 2-methyl-1,2-diaminopropane in boiling ethanol resulting in compounds 22-30 and 31-39 respectively, in 12-80% yields. The products were recrystallized using appropriate solvents and were characterized by spectral analysis, melting point, infrared spectroscopy, 1H and 13C NMR and mass spectrometry. In addition to spectral analysis, X-ray crystallography data was also collected for compound 31, confirming the definitive structure of the synthesized compounds. The reaction is believed to occur by the domino effect. The less sterically hindered amino group reacts with the sulphonyl chloride group to from the sulphonamide. The sulphonamide group then reacts with the β-carbon by nucleophilic substitution to form the isothiazole ring system and then the second amino group reacts with the α-carbon with elimination of the bromide ion to form the pyrazine ring. X-Ray data confirmed the structure of compound 31 and clearly confirmed that the dimethyl groups were on the carbon atom adjacent to the NH group. The synthesized compounds have been screened for potential antimicrobial properties against Bacillus subtilis, Escherichia coli, Proteus hauseri and Staphylococcus aureus. Compound 27 displayed antibacterial activity against B. subtilis at a concentration of 416 µgml-1. Compounds 23, 24, 25, 26, 34, 35 and 36 all showed activity against B. subtilis at a concentration of 6.67 mg ml-1, generally the compounds synthesized displayed activity at the highest concentration and were more active against gram positive bacteria. A simple, efficient method for the synthesis of the novel benzo[4,5]isothiazolo[2,3-a]pyrazine-6,6-dioxide ring system which should be applicable to generate other fused pyrazine ring systems of biological interest has been developed.