A facile domino protocol for the regioselective synthesis and discovery of novel 2-amino-5-arylthieno-[2,3-b]thiophenes as antimycobacterial agents

A series of novel 2-amino-5-arylthieno[2,3-b]thiophenes has been synthesized regioselectively from the reaction of 5-aryldihydro-3(2H)-thiophenones with ethyl cyanoacetate/malononitrile and sulfur powder in the presence of morpholine under thermal as well as microwave irradiation conditions. This transformation presumably occurs via domino Gewald reaction-dehydrogenation sequence. The 2-amino-5-arylthieno[2,3-b]thiophenes were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 12 compounds screened, ethyl 2-amino-5-(1-naphthyl)thieno[2,3-b]thiophene-3-carboxylate was found to be the most active compound with MIC of 1.1 μM against MTB and MDR-TB.