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Front. Pharmacol. | doi: 10.3389/fphar.2018.00146

QSAR-Driven Design and Discovery of Novel Compounds with Antiplasmodial and Transmission Blocking Activities

  • 1Faculty of Pharmacy, Universidade Federal de Goiás, Brazil
  • 2Department of Genetics Evolution and Bioagents, Institute of Biology, Universidade Estadual de Campinas, Brazil
  • 3PPG-SOMA, Centro Universitário de Anápolis, Brazil
  • 4Unidade de Parasitologia Médica, Instituto de Higiene e Medicina Tropical (IHMT), Universidade de Lisboa, Portugal
  • 5Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, United States
  • 6Department of Chemical Technology, Odessa National Polytechnic University, Ukraine
  • 7Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Brazil

Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium, affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum (PfdUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (Quantitative Structure-Activity Relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei. We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as PfdUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual PfdUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.

Keywords: Malaria, Virtual Screening, QSAR, Plasmodium falciparum, dUTPase, transmission blocker, inhibitors, drug design

Received: 22 Nov 2017; Accepted: 12 Feb 2018.

Edited by:

Adriano D. Andricopulo, São Carlos Institute of Physics, University of São Paulo, Brazil

Reviewed by:

Gildardo Rivera, Instituto Politécnico Nacional, Mexico
Sandra Gemma, University of Siena, Italy
Marco Tutone, Universita' di Palermo, Italy  

Copyright: © 2018 Lima, Melo-Filho, Cassiano, Neves, Alves, Braga, Cravo, Muratov, Calit, Bargieri, Costa and Andrade. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Carolina H. Andrade, Universidade Federal de Goiás, Faculty of Pharmacy, Goiânia, Brazil,