9 research outputs found
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Novel Antitubercular 6āDialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: StructureāActivity Relationship and Target Identification Studies
A BioFocus
DPI SoftFocus library of ā¼35āÆ000 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 cellāwall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminoĀpyrimidine 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 structureāactivity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties
The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold
Since the appearance
of resistance to the current front-line antimalarial
treatments, ACTs (artemisinin combination therapies), the discovery
of novel chemical entities to treat the disease is recognized as a
major global health priority. From the GSK antimalarial set, we identified
an aminoxadiazole with an antiparasitic profile comparable with artemisinin
(<b>1</b>), with no cross-resistance in a resistant strains
panel and a potential new mode of action. A medicinal chemistry program
allowed delivery of compounds such as <b>19</b> with high solubility
in aqueous media, an acceptable toxicological profile, and oral efficacy.
Further evaluation of the lead compounds showed that in vivo genotoxic
degradants might be generated. The compounds generated during this
medicinal chemistry program and others from the GSK collection were
used to build a pharmacophore model which could be used in the virtual
screening of compound collections and potentially identify new chemotypes
that could deliver the same antiparasitic profile
The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold
Since the appearance
of resistance to the current front-line antimalarial
treatments, ACTs (artemisinin combination therapies), the discovery
of novel chemical entities to treat the disease is recognized as a
major global health priority. From the GSK antimalarial set, we identified
an aminoxadiazole with an antiparasitic profile comparable with artemisinin
(<b>1</b>), with no cross-resistance in a resistant strains
panel and a potential new mode of action. A medicinal chemistry program
allowed delivery of compounds such as <b>19</b> with high solubility
in aqueous media, an acceptable toxicological profile, and oral efficacy.
Further evaluation of the lead compounds showed that in vivo genotoxic
degradants might be generated. The compounds generated during this
medicinal chemistry program and others from the GSK collection were
used to build a pharmacophore model which could be used in the virtual
screening of compound collections and potentially identify new chemotypes
that could deliver the same antiparasitic profile