Substituted 2-Phenylimidazopyridines: A New Class of Drug Leads for Human African Trypanosomiasis

Abstract

A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl) oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of 64, a substituted 2-(3-aminophenyl) imidazopyridine. This compound showed antiparasitic activity in vitro with an EC50 of 2 nM and displayed reasonable drug-like properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound 64 cured mice infected with Trypanosoma brucei when dosed orally down to 2.5 mg/kg. Given its potent anti-parasitic properties and its ease of synthesis, compound 64 represents a new lead for the development of drugs to treat human African trypanosomiasis.

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

“…Methods for the propagation of C. parvum (IOWA-II strain) oocysts in calves (Riggs and Perryman, 1987; Riggs et al, 1989), propagation of transgenic Nanoluciferase (Nluc) expressing C. parvum (UGA1 strain) oocysts in mice (Vinayak et al, 2015; Hulverson et al, 2017), in vitro microsomal stability (Tatipaka et al, 2014), pharmacokinetic analysis of mouse plasma, faecal, and urine BKI concentrations by LC-MS/MS analysis (Ojo et al, 2012; Schaefer et al, 2016; Hulverson et al, 2017), in vitro protein binding using dialysis membranes (Tatipaka et al, 2014), Nluc expressing C. parvum in vitro growth inhibition in infected HCT-8 cells (Hulverson et al, 2017), in vitro cytotoxicity in CRL-8155 and HepG2 cells (Tatipaka et al, 2014), and in vivo mouse gastrointestinal (GI) tract tissue exposure by LC-MS/MS analysis (Arnold et al, 2017) have all been previously described. Detailed descriptions of these methods are included in Supplementary Data S1.…”

Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis

“…The propagation of C. parvum (Iowa isolate) in calves and oocyst purification [34][35][36][37], synthesis of BKIs [22,25,27,38], in vitro CpCDPK1 enzyme assay [22,25,38], in vitro determination of C. parvum BKI sensitivity [22,25,38,39], neonatal mouse [36,40] and calf models of C. parvum infection [37,[41][42][43], and pharmacologic measurement of BKI plasma and stool levels and plasma protein binding have all been previously described [27,44]. BKI-1294 and BKI-1553 were synthesized on the pyrazolo [2,3-d] pyrimidine scaffold, while BKI-1517 was synthesized on a 5-aminopyrazole-4-carboxamide scaffold [25] (Figure 1).…”

Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors

“…The assay is performed in the same procedure as described in previous publications [14,16–18] : Compounds were administered by oral gavage at a concentration of 50 mg/kg in a volume of 0.2 mL of dosing solution (7% tween80, 3% ethanol, 5% DMSO, 0.9% saline) to mice by oral gavage. Tail blood was then collected at time points of 30, 60, 120, 240, 260 and 480 minutes into a heparinized capillary tube and 30 µl was then spotted onto a Whatman FTA DMPK-C Card (GE, Fairfield, CT.) Blood samples were analyzed by extracting the dried blood spots [19] in acetonitrile for measurements of compound concentrations by liquid chromatography/tandem mass spectrometry.…”