Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating Cryptosporidium infections. The compounds target the Cryptosporidium methionyl-tRNA synthetase (MetRS), an enzyme that is essential for protein synthesis. The most potent compounds inhibited the enzyme with Ki values in the low picomolar range. Cryptosporidium cells in culture were potently inhibited with 50% effective concentrations as low as 7 nM and >1,000-fold selectivity over mammalian cells. A parasite persistence assay indicates that the compounds act by a parasiticidal mechanism. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. Pharmacological and physicochemical characteristics of compounds were investigated to determine properties that were associated with higher efficacy. The results indicate that MetRS inhibitors are excellent candidates for development for anticryptosporidiosis therapy.
Ligand-based similarity screening of proprietary pharmaceutical company libraries enables rapid hit to lead investigation of a chemotype with anti-leishmania activity.
Prolyl-tRNA synthetase
(PRS) is a clinically validated antimalarial
target. Screening of a set of PRS ATP-site binders, initially designed
for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one
derivatives representing a novel antimalarial scaffold. Evidence designates
cytoplasmic PRS as the drug target. The frontrunner
1
and its active enantiomer
1-
S
exhibited low-double-digit nanomolar activity against resistant
Plasmodium falciparum
(
Pf
) laboratory strains
and development of liver schizonts. No cross-resistance with strains
resistant to other known antimalarials was noted. In addition, a similar
level of growth inhibition was observed against clinical field isolates
of
Pf
and
P. vivax
. The slow killing
profile and the relative high propensity to develop resistance
in vitro
(minimum inoculum resistance of 8 × 10
5
parasites at a selection pressure of 3 × IC
50
) constitute unfavorable features for treatment of malaria. However,
potent blood stage and antischizontal activity are compelling for
causal prophylaxis which does not require fast onset of action. Achieving
sufficient on-target selectivity appears to be particularly challenging
and should be the primary focus during the next steps of optimization
of this chemical series. Encouraging preliminary off-target profile
and oral efficacy in a humanized murine model of
Pf
malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one
derivatives represent a promising starting point for the identification
of novel antimalarial prophylactic agents that selectively target
Plasmodium
PRS.
A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure−activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.
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