7 research outputs found
Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2
On the basis of our recent results
on a novel series of imidazopyridazine-based
antimalarials, we focused on identifying compounds with improved aqueous
solubility and hERG profile while maintaining metabolic stability
and in vitro potency. Toward this objective,
41 compounds were synthesized and evaluated for antiplasmodial activity
against NF54 (sensitive) and K1 (multidrug resistant) strains of the
malaria parasite <i>Plasmodium falciparum</i> and evaluated
for both aqueous solubility and metabolic stability. Selected compounds
were tested for in vitro hERG activity and in vivo efficacy in the <i>P. berghei</i> mouse model. Several compounds were identified
with significantly improved aqueous solubility, good metabolic stability,
and a clean hERG profile relative to a previous frontrunner lead compound.
A sulfoxide-based imidazopyridazine analog <b>45</b>, arising
from a prodrug-like strategy, was completely curative in the <i>Plasmodium berghei</i> mouse model at 4 × 50 mg/kg po
Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria
A novel 2,8-disubstituted-1,5-naphthyridine
hit compound stemming
from the open access Medicines for Malaria Venture Pathogen Box formed
a basis for a hit-to-lead medicinal chemistry program. Structure–activity
relationship investigations resulted in compounds with potent antiplasmodial
activity against both chloroquine sensitive (NF54) and multidrug resistant
(K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy
model, one of the frontrunner compounds showed in vivo efficacy at
an oral dose of 4 × 50 mg·kg<sup>–1</sup>. In vitro
mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target
Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria
A novel 2,8-disubstituted-1,5-naphthyridine
hit compound stemming
from the open access Medicines for Malaria Venture Pathogen Box formed
a basis for a hit-to-lead medicinal chemistry program. Structure–activity
relationship investigations resulted in compounds with potent antiplasmodial
activity against both chloroquine sensitive (NF54) and multidrug resistant
(K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy
model, one of the frontrunner compounds showed in vivo efficacy at
an oral dose of 4 × 50 mg·kg<sup>–1</sup>. In vitro
mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target
Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria
A novel 2,8-disubstituted-1,5-naphthyridine
hit compound stemming
from the open access Medicines for Malaria Venture Pathogen Box formed
a basis for a hit-to-lead medicinal chemistry program. Structure–activity
relationship investigations resulted in compounds with potent antiplasmodial
activity against both chloroquine sensitive (NF54) and multidrug resistant
(K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy
model, one of the frontrunner compounds showed in vivo efficacy at
an oral dose of 4 × 50 mg·kg<sup>–1</sup>. In vitro
mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target
Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized <i>Plasmodium falciparum</i> NODscidIL2Rγ<sup><i>null</i></sup> Mouse Model of Malaria
Optimization of a chemical series
originating from whole-cell phenotypic
screening against the human malaria parasite, <i>Plasmodium falciparum</i>, led to the identification of two promising 2,6-disubstituted imidazopyridine
compounds, <b>43</b> and <b>74</b>. These compounds exhibited
potent activity against asexual blood stage parasites that, together
with their in vitro absorption, distribution, metabolism, and excretion
(ADME) properties, translated to in vivo efficacy with clearance of
parasites in the <i>Pf</i>SCID mouse model for malaria within
48 h of treatment
Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized <i>Plasmodium falciparum</i> NODscidIL2Rγ<sup><i>null</i></sup> Mouse Model of Malaria
Optimization of a chemical series
originating from whole-cell phenotypic
screening against the human malaria parasite, <i>Plasmodium falciparum</i>, led to the identification of two promising 2,6-disubstituted imidazopyridine
compounds, <b>43</b> and <b>74</b>. These compounds exhibited
potent activity against asexual blood stage parasites that, together
with their in vitro absorption, distribution, metabolism, and excretion
(ADME) properties, translated to in vivo efficacy with clearance of
parasites in the <i>Pf</i>SCID mouse model for malaria within
48 h of treatment
Novel Antitubercular 6‑Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies
A BioFocus
DPI SoftFocus library of ∼35 000 compounds was screened
against <i>Mycobacterium tuberculosis</i> (Mtb) in order
to identify novel hits with antitubercular activity. The hits were
evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome <i>bc</i><sub>1</sub> complex, disruption of cell–wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure–activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties