Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: towards the development of potential dual action antimalarials.
A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain-inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites.
Centro de Investigação em Química da Universidade do Porto, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, R. do Campo Alegre, 687, P-4169-007 Porto, Portugal.
Bianca C
BC
Pérez
Cátia
C
Teixeira
Marta
M
Figueiras
Jiri
J
Gut
Philip J
PJ
Rosenthal
José R B
JR
Gomes
Paula
P
Gomes
D000596:Amino Acids / Q000737:chemistry*; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002934:Cinnamates / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006418:Heme / Q000737:chemistry; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation
D000596:Amino Acids; D000634:Aminoquinolines; D000962:Antimalarials; D002934:Cinnamates; D011480:Protease Inhibitors; C029010:cinnamic acid; D006418:Heme; D003546:Cysteine Endopeptidases; C099607:falcipain; C001920:4-aminoquinoline