<i>N</i>‑Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds

From the phenotypic screening of the AstraZeneca corporate compound collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of <i>Plasmodium falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization of the potency against <i>Pf</i> and ADME properties resulted in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the <i>Pb</i> malaria model. Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast killing observed in the <i>in vitro</i> parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria

Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious <i>in Vivo</i>

We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis <i>in vitro</i> and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like” properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

BMS-711939 (<b>3</b>) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC₅₀ of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC₅₀ = 4.5 μM) and PPARδ (EC₅₀ > 100 μM) in PPAR-GAL4 transactivation assays. Compound <b>3</b> also demonstrated excellent <i>in vivo</i> efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure–activity relationship (SAR) studies, and <i>in vivo</i> pharmacology of <b>3</b> in preclinical animal models as well as its ADME profile are described

4‑Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure–activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC₅₀ < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb

Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (<i>Pf</i>) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure–activity relationship studies followed by pharmacokinetics optimization resulted in the identification of <b>23</b> as an attractive lead with good oral bioavailability. Compound <b>23</b> was found to be efficacious (ED₉₀ of 28.6 mg·kg^–1) in the humanized P. falciparum mouse model of malaria (<i>Pf</i>/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of <i>Pf</i> strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class