Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized <i>Plasmodium falciparum</i> NODscidIL2Rγ^<i>null</i> 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^<i>null</i> 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>₁ 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