Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials.
The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Rudi
R
Oliveira
Rita C
RC
Guedes
Patrícia
P
Meireles
Inês S
IS
Albuquerque
Lídia M
LM
Gonçalves
Elisabete
E
Pires
Maria Rosário
MR
Bronze
Jiri
J
Gut
Philip J
PJ
Rosenthal
Miguel
M
Prudêncio
Rui
R
Moreira
Paul M
PM
O'Neill
Francisca
F
Lopes
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D057786:Peptidomimetics; D011743:Pyrimidines; D045568:Tetraoxanes; D003546:Cysteine Endopeptidases; C416224:falcipain 2