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Wei Huang – One of the best experts on this subject based on the ideXlab platform.

Yaquan Zhang – One of the best experts on this subject based on the ideXlab platform.

Fredrik Almqvist – One of the best experts on this subject based on the ideXlab platform.

Ujjini H. Manjunatha – One of the best experts on this subject based on the ideXlab platform.

  • Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents
    European journal of medicinal chemistry, 2015
    Co-Authors: Ujjini H. Manjunatha, Srinivasa P. S. Rao, Christian G. Noble, Luis R. Camacho, Ngai Ling, Maxime Hervé, Anne Goh, Stefan Peukert, Thierry T. Diagana

    Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB.

  • Direct inhibitors of InhA are active against Mycobacterium tuberculosis
    Science Translational Medicine, 2015
    Co-Authors: Ujjini H. Manjunatha, Srinivasa P. S. Rao, Ravinder Reddy Kondreddi, Christian G. Noble, Luis R. Camacho, Bee Huat Tan, Ng L., Suresh B. Lakshminarayana

    New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenadenineudinucleotide)–dependent manner and blocked the enoyl substrate–binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.

Kyoung S. Kim – One of the best experts on this subject based on the ideXlab platform.

  • Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.
    Journal of medicinal chemistry, 2008
    Co-Authors: Kyoung S. Kim, Liping Zhang, Robert J. Schmidt, Cai Zhen-wei, Donna D. Wei, David K. Williams, Louis J. Lombardo, George L. Trainor, Dianlin Xie, Yaquan Zhang

    Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-Pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.