The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis highlights the need to discover new antitubercular agents. Here we describe the synthesis and characterization of a new series of thienopyrimidine (TP) compounds that kill both replicating and non-replicating M. tuberculosis. The strategy to determine the mechanism of action of these TP derivatives was to generate resistant mutants to the most effective compound TP053 and to isolate the genetic mutation responsible for this phenotype. The only non-synonymous mutation found was a g83c transition in the Rv2466c gene, resulting in the replacement of tryptophan 28 by a serine. The Rv2466c overexpression increased the sensitivity of M. tuberculosis wild-type and resistant mutant strains to TP053, indicating that TP053 is a prodrug activated by Rv2466c. Biochemical studies performed with purified Rv2466c demonstrated that only the reduced form of Rv2466c can activate TP053. The 1.7 Å resolution crystal structure of the reduced form of Rv2466c, a protein whose expression is transcriptionally regulated during the oxidative stress response, revealed a unique homodimer in which a β-strand is swapped between the thioredoxin domains of each subunit. A pronounced groove harboring the unusual active-site motif CPWC might account for the uncommon reactivity profile of the protein. The mutation of Trp28Ser clearly predicts structural defects in the thioredoxin fold, including the destabilization of the dimerization core and the CPWC motif, likely impairing the activity of Rv2466c against TP053. Altogether our experimental data provide insights into the molecular mechanism underlying the anti-mycobacterial activity of TP-based compounds, paving the way for future drug development programmes.

The procedures for the synthesis of substituted pyrrolo[1,2‐a]indoles and some of their biological properties are reviewed.

No abstract

At present, only a few summarizing papers devoted to the synthesis of varions heterocycles on the basis of oxindole (2indolinone) are available in the literature. The well-known monograph [ I] considered the synthesis of condensed indoles based on the 2-indolinone derivatives. Unfortunately, a recent review [2] paid little attention to the problem of heteroeyclization in these systems. We believed that it would be importaat to fill the gap, thus stimulating investigations in this direction. This review summarizes data published doting the past two decades on the annelation of various heterocycles at different "edges" of the indole cycle using substituted indoles as the initial compounds. In addition, Section IV concerns some problems related to the possible expansions of the fivemembered oxindole ring.

No abstract