title: Naphthoquinones isolated from Diospyros anisandra exhibit potent activity against pan-resistant first-line drugs Mycobacterium tuberculosis strains.
abstract: OBJECTIVE
  The recent emergence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) Mycobacterium tuberculosis (MTB) strains have further complicated the control of tuberculosis (TB). There is an urgent need of new molecules candidates to be developed as novel, active, and less toxic anti-tuberculosis (anti-TB) drugs. Medicinal plants have been an excellent source of leads for the development of drugs, particularly as anti-infective agents. In previous studies, the non-polar extract of Diospyros anisandra showed potent anti-TB activity, and three monomeric and five dimeric naphthoquinones have been obtained. In this study, we performed bioguided chemical fractionation and the isolation of eight naphthoquinones from D. anisandra and their evaluation of anti-TB and cytotoxic activities against mammalian cells.
  
  
  METHODS
  The n-hexane crude extract from the stem bark of the plant was obtained by maceration and liquid-liquid fractionation. The isolation of naphthoquinones was carried out by chromatographic methods and identified by gas chromatography and mass spectroscopy data analysis. Anti-TB activity was evaluated against two strains of MTB (H37Rv) susceptible to all five first-line anti-TB drugs and a clinical isolate that is resistant to these medications (pan-resistant, CIBIN 99) by measuring the minimal inhibitory concentration (MIC). Cytotoxicity of naphthoquinones was estimated against two mammalian cells, Vero line and primary cultures of human peripheral blood mononuclear (PBMC) cells, and their selectivity index (SI) was determined.
  
  
  RESULTS
  Plumbagin and its dimers maritinone and 3,3'-biplumbagin showed the strongest activity against both MTB strains (MIC = 1.56-3.33 μg/mL). The bioactivity of maritinone and 3,3'-biplumbagin were 32 times more potent than rifampicin against the pan-resistant strain, and both dimers showed to be non-toxic against PBMC and Vero cells. The SI of maritinone and 3,3'-biplumbagin on Vero cells was 74.34 and 194.11 against sensitive and pan-resistant MTB strains, respectively.
  
  
  CONCLUSIONS
  Maritinone and 3,3'-biplumbagin possess a very interesting potential for development as new drugs against M. tuberculosis, mainly resistant profile strains.
authors: Unidad de Biotecnología del Centro de Investigación Científica de Yucatán A.C., Calle 43, No. 130, Col. Chuburná de Hidalgo, CP 97200 Mérida, Yucatán, Mexico. Electronic address: andresuccachon@gmail.com.
authors: Andrés Humberto
authors: AH
authors: Uc-Cachón
authors: Unidad de Biotecnología del Centro de Investigación Científica de Yucatán A.C., Calle 43, No. 130, Col. Chuburná de Hidalgo, CP 97200 Mérida, Yucatán, Mexico. Electronic address: rborges@cicy.mx.
authors: Rocío
authors: R
authors: Borges-Argáez
authors: División de Biología Celular y Molecular, Centro de Investigación Biomédica del Noreste, IMSS, San Luis Potosí y 2 de Abril, Col. Independencia, CP 65720 Monterrey, Nuevo León, Mexico. Electronic address: salvador.said@gmail.com.
authors: Salvador
authors: S
authors: Said-Fernández
authors: División de Biología Celular y Molecular, Centro de Investigación Biomédica del Noreste, IMSS, San Luis Potosí y 2 de Abril, Col. Independencia, CP 65720 Monterrey, Nuevo León, Mexico. Electronic address: jvargas147@yahoo.com.mx.
authors: Javier
authors: J
authors: Vargas-Villarreal
authors: División de Biología Celular y Molecular, Centro de Investigación Biomédica del Noreste, IMSS, San Luis Potosí y 2 de Abril, Col. Independencia, CP 65720 Monterrey, Nuevo León, Mexico; Departamento de Ciencias Básicas, División de Ciencia de la Salud, Universidad de Monterrey, Ave. Ignacio Morones Prieto 4500 Pte., CP 66238 San Pedro Garza García, Nuevo León, Mexico. Electronic address: fgonz75@yahoo.com.mx.
authors: Francisco
authors: F
authors: González-Salazar
authors: Unidad de Recursos Naturales del Centro de Investigación Científica de Yucatán A.C., Calle 43, No. 130, Col. Chuburná de Hidalgo, CP 97200 Mérida, Yucatán, Mexico. Electronic address: mar@cicy.mx.
authors: Martha
authors: M
authors: Méndez-González
authors: Unidad de Biotecnología del Centro de Investigación Científica de Yucatán A.C., Calle 43, No. 130, Col. Chuburná de Hidalgo, CP 97200 Mérida, Yucatán, Mexico. Electronic address: bella@cicy.mx.
authors: Mirbella
authors: M
authors: Cáceres-Farfán
authors: División de Biología Celular y Molecular, Centro de Investigación Biomédica del Noreste, IMSS, San Luis Potosí y 2 de Abril, Col. Independencia, CP 65720 Monterrey, Nuevo León, Mexico. Electronic address: gmolina70@gmail.com.
authors: Gloria María
authors: GM
authors: Molina-Salinas
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D029788:Diospyros / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D009285:Naphthoquinones / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D024301:Plant Bark; D010936:Plant Extracts / Q000494:pharmacology; D018547:Plant Stems; D012293:Rifampin / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D009285:Naphthoquinones; D010936:Plant Extracts; D012293:Rifampin
keywords: 3,3′-Biplumbagin; Diospyros anisandra; Maritinone; Multidrug-resistant; Mycobacterium tuberculosis; Naphthoquinone