Diarylquinolines, synthesis pathways and quantitative structure-activity relationship studies leading to the discovery of TMC207

Janssen-Cilag France, Campus de Maigremont, BP615, 27106, Val de Reuil Cedex, France.
Future medicinal chemistry (Impact Factor: 3.74). 09/2011; 3(11):1345-60. DOI: 10.4155/fmc.11.79
Source: PubMed

ABSTRACT The emergence of multidrug-resistant strains of Mycobacterium tuberculosis and resistance to current anti-TB drugs call for the discovery and development of new effective anti-TB drugs. TMC207 is the lead candidate of a novel class of antimycobacterial agents, the diarylquinolines, which specifically inhibit mycobacterial ATP synthase and displays high activity against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis. This article covers both synthesis pathways as well as qualitative and quantitative analyses of the structure-activity relationships of the diarylquinoline series on Mycobacterium smegmatis activity.

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    ABSTRACT: TMC207 is a new antituberculous drug belonging to the diarylquinoline class which very efficiently inhibits the ATP synthase of mycobacteria such as Mycobacterium tuberculosis, one of the most important pathogens in the world. In order to map the amino acid residues involved in the binding of the drug, we have selected in vitro TMC207-resistant mutants from M. tuberculosis and diverse atypical mycobacteria. Six distinct mutations, Asp28 → Gly, Asp28 → Ala, Leu59 → Val, Glu61 → Asp, Ala63 → Pro, and Ile66 → Met, have been identified in the subunit c forming a C ring in the ATP synthase. They were studied by evaluating the levels of resistance that they confer in the selected clones and by using an isogenic complementation system in Mycobacterium smegmatis. The rates of increase of TMC207 MIC values (8- to 133-fold) were interpreted by constructing by homology modeling a structure of the mycobacterial C ring which was used for docking simulations with TMC207. Our results suggest that the residues found to be mutated in the resistant clones, together with a tyrosine specifically conserved at position 64 in mycobacteria, define a cleft located between two adjacent c subunits in the C ring. This cleft, which encompasses the proton-binding site (Glu61), is well fitted to bind TMC207 at the level of the bromoquinoline moiety, with the drug being anchored by several ionic, hydrogen, and halogen bonds with residues Glu61, Tyr64, and Asp28, respectively. These data shed light on the molecular interactions allowing TMC207 to bind specifically and efficiently at the level of the proton-binding site of the mycobacterial C ring.
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    ABSTRACT: The subunit ε of bacterial F(1)F(O) ATP synthases plays an important regulatory role in coupling and catalysis via conformational transitions of its C-terminal domain. Here we present the first low resolution solution structure of ε of Mycobacterium tuberculosis (Mtε) F(1)F(O) ATP synthase and the NMR structure of its C-terminal segment (Mtε(103-120)). The overall length of Mtε (61.6 Å) is significantly shorter compared to forms of the subunit in other bacteria, reflecting a shorter C-terminal sequence, proposed to be important in coupling processes via the catalytic β subunit. The C-terminal segment displays α-helical structure and highly positive surface charge due to the presence of arginine residues. Using NMR-, fluorescence spectroscopy and mutagenesis, we demonstrate that the new TB drug candidate TMC207, proposed to bind to the proton translocating c-ring, does also bind to Mtε. A model for the interaction of TMC207 with both, ε and the c-ring is presented, suggesting that TMC207 forms a wedge between the two rotating subunits by interacting with the residues W15 and F50 of ε and the c-ring, respectively. T19 and R37 of ε provide the necessary polar interactions with the drug molecule. This new model of the mechanism of TMC207 provides the basis for the design of new drugs, targeting the F(1)F(O) ATP synthase in M. tuberculosis.
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