AUTHOR=Lima Marilia N. N. , Melo-Filho Cleber C. , Cassiano Gustavo C. , Neves Bruno J. , Alves Vinicius M. , Braga Rodolpho C. , Cravo Pedro V. L. , Muratov Eugene N. , Calit Juliana , Bargieri Daniel Y. , Costa Fabio T. M. , Andrade Carolina H. 

TITLE=QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00146

DOI=10.3389/fphar.2018.00146

ISSN=1663-9812

ABSTRACT=<p>Malaria is a life-threatening infectious disease caused by parasites of the genus <italic>Plasmodium</italic>, 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 <italic>Plasmodium falciparum</italic> (<italic>Pf</italic>dUTPase) 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 <italic>in vitro</italic> experimental evaluation, we report herein the discovery of novel chemical scaffolds with <italic>in vitro</italic> potency against asexual blood stages of both <italic>P. falciparum</italic> multidrug-resistant and sensitive strains and against sporogonic development of <italic>P. berghei</italic>. We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as <italic>Pf</italic>dUTPase 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 <italic>Pf</italic>dUTPase inhibitors. Further <italic>in vitro</italic> testing on <italic>P. falciparum</italic> 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 <italic>in vitro</italic> inhibition of <italic>P. berghei</italic> ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.</p>