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Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis.
Wu, Jie; Mu, Ran; Sun, Mingna; Zhao, Nan; Pan, Miaomiao; Li, Hongshuang; Dong, Yi; Sun, Zhaogang; Bai, Jie; Hu, Minwan; Nathan, Carl F; Javid, Babak; Liu, Gang.
Afiliación
  • Wu J; Tsinghua-Peking Center for Life Sciences , Tsinghua University , Renhuan Building, Rm 311 , Haidian District, Beijing 100084 , P. R. China.
  • Mu R; School of Pharmaceutical Sciences , Tsinghua University , Renhuan Building, Rm 311 , Haidian District, Beijing 100084 , P. R. China.
  • Sun M; School of Pharmaceutical Sciences , Tsinghua University , Renhuan Building, Rm 311 , Haidian District, Beijing 100084 , P. R. China.
  • Zhao N; Department of Microbiology and Immunology , Weill Cornell Medical College , New York , New York 10065 , United States.
  • Pan M; Centre for Global Health and Infectious Diseases, Collaborative Innovation Centre for the Diagnosis and Treatment of Infectious Diseases , Tsinghua University School of Medicine , Beijing 100084 , China.
  • Li H; School of Pharmaceutical Sciences , Tsinghua University , Renhuan Building, Rm 311 , Haidian District, Beijing 100084 , P. R. China.
  • Dong Y; School of Pharmaceutical Sciences , Tsinghua University , Renhuan Building, Rm 311 , Haidian District, Beijing 100084 , P. R. China.
  • Sun Z; National Tuberculosis Clinical Laboratory, Beijing Chest Hospital, Capital Medical University and Beijing Key Laboratory in Drug Resistant Tuberculosis Research , Beijing Tuberculosis & Thoracic Tumor Research Institute , 9 Beiguan Street , Tongzhou District, Beijing 101149 , China.
  • Bai J; Institute of Materia Medica , Chinese Academy of Medical Sciences & Peking Union Medical College , 1 Xian Nong Tan Street , Beijing 100050 , China.
  • Hu M; Institute of Materia Medica , Chinese Academy of Medical Sciences & Peking Union Medical College , 1 Xian Nong Tan Street , Beijing 100050 , China.
  • Nathan CF; Department of Microbiology and Immunology , Weill Cornell Medical College , New York , New York 10065 , United States.
  • Javid B; Centre for Global Health and Infectious Diseases, Collaborative Innovation Centre for the Diagnosis and Treatment of Infectious Diseases , Tsinghua University School of Medicine , Beijing 100084 , China.
  • Liu G; Tsinghua-Peking Center for Life Sciences , Tsinghua University , Renhuan Building, Rm 311 , Haidian District, Beijing 100084 , P. R. China.
ACS Infect Dis ; 5(7): 1087-1104, 2019 07 12.
Article en En | MEDLINE | ID: mdl-31016962
This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pHIB) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pHIB to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pKa value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pHIB, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenoles / Mycobacterium tuberculosis Límite: Humans Idioma: En Revista: ACS Infect Dis Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenoles / Mycobacterium tuberculosis Límite: Humans Idioma: En Revista: ACS Infect Dis Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos