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Synthesis of 4-Aminoindole-Containing Cephalosporin Prodrugs and Their Biological Activity against Mycobacterium tuberculosis
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DOI：10.1021/acsinfecdis.6c00340.png)
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Abstract
En 中文
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.
Keywords:
Bacteria
Drug resistance
Monomers
Peptides and proteins
Pharmaceuticals
cephalosporins
4-aminoindole
prodrugs
tryptophan biosynthesis
tuberculosis
antitubercular activity
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2.4K
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