Synthesis of 4-Aminoindole-Containing Cephalosporin Prodrugs and Their Biological Activity against Mycobacterium tuberculosis.

Indole 4-carboxamides are promising prodrugs that liberate 4-aminoindole, which poisons tryptophan biosynthesis in Mycobacterium tuberculosis (Mtb). Limiting enthusiasm for these compounds is the high rate of emergence of resistance since the amidase, which liberates the 4-aminoindole core, is nonessential. To overcome this limitation, we designed bifunctional β-lactams that, upon hydrolytic opening of the β-lactam ring, liberate 4-aminoindole. These bifunctional molecules had good potency against Mtb, which could be rescued by exogenous l-tryptophan addition. In contrast to the parental indole 4-carboxamides, resistant mutants to these bifunctional compounds developed at a much lower frequency than the parental compounds in vitro, supporting this strategy as a means to protect these agents from rapid development of resistance.