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Whole cell screen based identification of spiropiperidines with potent antitubercular properties.
Tantry, Subramanyam J; Degiacomi, Giulia; Sharma, Sreevalli; Jena, Lalit Kumar; Narayan, Ashwini; Guptha, Supreeth; Shanbhag, Gajanan; Menasinakai, Sreenivasaiah; Mallya, Meenakshi; Awasthy, Disha; Balakrishnan, Gayathri; Kaur, Parvinder; Bhattacharjee, Deepa; Narayan, Chandan; Reddy, Jitendar; Naveen Kumar, C N; Shandil, Radha; Boldrin, Francesca; Ventura, Marcello; Manganelli, Riccardo; Hartkoorn, Ruben C; Cole, Stewart T; Panda, Manoranjan; Markad, Shankar D; Ramachandran, Vasanthi; Ghorpade, Sandeep R; Dinesh, Neela.
Afiliación
  • Tantry SJ; Department of Chemistry, AstraZeneca India Pvt. Ltd, India; Anthem Biosciences, Bangalore, India(§).
  • Degiacomi G; Department of Molecular Medicine, University of Padova, Italy.
  • Sharma S; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Jena LK; Department of Chemistry, AstraZeneca India Pvt. Ltd, India.
  • Narayan A; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Guptha S; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Shanbhag G; Department of Chemistry, AstraZeneca India Pvt. Ltd, India; PI Industries Limited, Udaipur, India(§).
  • Menasinakai S; Department of Chemistry, AstraZeneca India Pvt. Ltd, India.
  • Mallya M; Department of Chemistry, AstraZeneca India Pvt. Ltd, India.
  • Awasthy D; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Balakrishnan G; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Kaur P; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Bhattacharjee D; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Narayan C; Department of Biosciences, AstraZeneca India Pvt. Ltd, India; Department of Life Science, Pohang University of Science and Technology, Republic of Korea(§).
  • Reddy J; DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, India.
  • Naveen Kumar CN; DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, India.
  • Shandil R; DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, India; Foundation for Neglected Disease Research, Bangalore, India(§).
  • Boldrin F; Department of Molecular Medicine, University of Padova, Italy.
  • Ventura M; Department of Molecular Medicine, University of Padova, Italy.
  • Manganelli R; Department of Molecular Medicine, University of Padova, Italy.
  • Hartkoorn RC; Global Health Institute, École polytechnique fédérale de Lausanne, Switzerland.
  • Cole ST; Global Health Institute, École polytechnique fédérale de Lausanne, Switzerland.
  • Panda M; Department of Chemistry, AstraZeneca India Pvt. Ltd, India; BMS Biocon Research Centre, Bangalore, India(§).
  • Markad SD; Department of Chemistry, AstraZeneca India Pvt. Ltd, India; Sanofi India Limited, Ankleshwar, India(§).
  • Ramachandran V; Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
  • Ghorpade SR; Department of Chemistry, AstraZeneca India Pvt. Ltd, India. Electronic address: sandeepghorpade@hotmail.com.
  • Dinesh N; Department of Biosciences, AstraZeneca India Pvt. Ltd, India. Electronic address: neeladin@gmail.com.
Bioorg Med Chem Lett ; 25(16): 3234-45, 2015 Aug 15.
Article en En | MEDLINE | ID: mdl-26087937
Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[indene-1,4'-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[chromene-2,4'-piperidine] (abbr. spirochromenes) and 1'-benzylspiro[indole-1,4'-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ⩾ 4 log10 kill (at 2-12 µM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Compuestos de Espiro / Antituberculosos Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Compuestos de Espiro / Antituberculosos Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido