, 15:59 | Cite as

Untargeted LC–MS metabolomic studies of Asteraceae species to discover inhibitors of Leishmania major dihydroorotate dehydrogenase

  • Lucas A. Chibli
  • Annylory L. Rosa
  • Maria Cristina Nonato
  • Fernando B. Da CostaEmail author
Original Article



Interesting data about the family Asteraceae as a new source of Leishmania major dihydroorotate dehydrogenase (LmDHODH) inhibitors are presented. This key macromolecular target for parasites causing neglected diseases catalyzes the fourth reaction of the de novo pyrimidine biosynthetic pathway, which takes part in major cell functions, including DNA and RNA biosynthesis.


We aimed to (1) determine LmDHODH inhibitor candidates, revealing the type of chemistry underlying such bioactivity, and (2) predict the inhibitory potential of extracts from new untested plant species, classifying them as active or inactive based on their LC–MS based metabolic fingerprints.


Extracts from 150 species were screened for the inhibition of LmDHODH, and untargeted UHPLC-(ESI)-HRMS metabolomic studies were carried out in combination with in silico approaches.


The IC50 values determined for a subset of 59 species ranged from 148 µg mL−1 to 9.4 mg mL−1. Dereplication of the metabolic fingerprints allowed the identification of 48 metabolites. A reliable OPLS-DA model (R2 > 0.9, Q2 > 0.7, RMSECV < 0.3) indicated the inhibitor candidates; nine of these metabolites were identified using data from isolated chemical standards, one of which—4,5-di-O-E-caffeoylquinic acid (IC50 73 µM)—was capable of inhibiting LmDHODH. The predictive OPLS model was also effective, with 60% correct predictions for the test set.


Our approach was validated for (1) the discovery of LmDHODH inhibitors or interesting starting points for the optimization of new leishmanicides from Asteraceae species and (2) the prediction of extracts from untested species, classifying them as active or inactive.


Dihydroorotate dehydrogenase Leishmania major Neglected diseases Asteraceae Untargeted metabolomics UHPLC-(ESI)-HRMS 



Leishmania major dihydroorotate dehydrogenase




Sesquiterpene lactones


Ultrahigh-performance liquid chromatography


High-resolution mass spectrometry


Electrospray ionization


Orthogonal projection to latent structures


Principal component analysis


Negative ionization mode


Positive ionization mode




Root-mean-square error


Discriminant analysis


Dictionary of natural products



The authors are grateful to the São Paulo Research Foundation (FAPESP), Brazil, the National Council for Scientific and Technological Development (CNPq), Brazil, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil, for the funds and grants. We also thank Prof. José Rubens Pirani and Dr. Carolina Moriani Siniscalchi, both from the Institute of Biosciences, USP, São Paulo, Brazil, for providing us with several samples of plant material. This work is an activity within the Research Network Natural Products against Neglected Diseases (ResNet NPND;

Author contributions

LAC, FBC and MCN conceived and designed the study. LAC and ALR performed the experiments and analyzed the experimental data. LAC wrote the paper. MCN and FBC reviewed and edited the manuscript.


This study was supported by the São Paulo Research Foundation (FAPESP, Grant Nos. 2014/01443-6 and 2014/26866-7), Brazil, The National Council for Scientific and Technological Development (CNPq, Grant 304905/2015-1), Brazil, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Finance Code 001), Brazil.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Research involving human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

11306_2019_1520_MOESM1_ESM.docx (166.2 mb)
Supplementary material 1 (DOCX 170167 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.AsterBioChem Research Team, School of Pharmaceutical Sciences of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil
  2. 2.Laboratory of Protein Crystallography, School of Pharmaceutical Sciences of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil

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