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.
New
drugs that target Plasmodium species, the
causative agents of malaria, are needed. The enzyme N-myristoyltransferase (NMT) is an essential protein, which catalyzes
the myristoylation of protein substrates, often to mediate membrane
targeting. We screened ∼1.8 million small molecules for activity
against Plasmodium vivax (P. vivax) NMT. Hits were triaged based on potency
and physicochemical properties and further tested against P. vivax and Plasmodium falciparum (P. falciparum) NMTs. We assessed
the activity of hits against human NMT1 and NMT2 and discarded compounds
with low selectivity indices. We identified 23 chemical classes specific
for the inhibition of Plasmodium NMTs over human
NMTs, including multiple novel scaffolds. Cocrystallization of P. vivax NMT with one compound revealed peptide binding
pocket binding. Other compounds show a range of potential modes of
action. Our data provide insight into the activity of a collection
of selective inhibitors of Plasmodium NMT and serve
as a starting point for subsequent medicinal chemistry efforts.
Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.
Malaria persists as one of the most
devastating global infectious
diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase
(DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based
DHODH inhibitor 1 (DSM265) is in clinical development.
We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward
animal DHODHs. Herein we describe a series of novel triazolopyrimidines
wherein the p-SF5-aniline was replaced
with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines.
These compounds showed strong species selectivity, and several highly
potent tetrahydro-2-naphthyl derivatives were identified. Compounds
with halogen substitutions displayed sustained plasma levels after
oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl
derivatives have the potential to be efficacious for the treatment
of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
[reaction: see text] Condensation of N-substituted glycines with chiral 3-allyl-2-formyl perhydro-1,3-benzoxazines forms an azomethine ylide that cyclizes to give octahydropyrrolo[3,4-b]pyrrole derivatives. The [3 + 2] dipolar cycloadditions are stereoespecific leading to a single diastereoisomer. The chemical yields are dependent on the reaction temperature and the presence or absence of a base.
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