Falcipain inhibitors: optimization studies of the 2-pyrimidinecarbonitrile lead series.
Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
Coterón
Jose M
JM
Department of Drug Discovery Chemistry, GlaxoSmithKline, Madrid, Spain.
Catterick
David
D
Castro
Julia
J
Chaparro
María J
MJ
Díaz
Beatriz
B
Fernández
Esther
E
Ferrer
Santiago
S
Gamo
Francisco J
FJ
Gordo
Mariola
M
Gut
Jiri
J
de las Heras
Laura
L
Legac
Jennifer
J
Marco
Maria
M
Miguel
Juan
J
Muñoz
Vicente
V
Porras
Esther
E
de la Rosa
Juan C
JC
Ruiz
Jose R
JR
Sandoval
Elena
E
Ventosa
Pilar
P
Rosenthal
Philip J
PJ
Fiandor
Jose M
JM
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3