Structure–Activity-Relationship Studies around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in Vivo Activity

Abstract

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei -infected mice, compound 4 was completely curative at an oral dose of 4 × 10 mg/kg.

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

“…Using previously acquired data, we assessed the solubility and in vitro metabolic stability of the most promising compounds from this study (Table ) . This data indicated that all compounds displayed good solubility in acidic media, with reduced solubility at pH 6.5, which presumably is a consequence of their inherent basicity.…”

“…However, bioisosteric replacement of the pyridine with a pyrazine resulted in a cohort of potent compounds with improved ADME characteristics, leading ultimately to the identification of 3 as a preclinical candidate…”

Antimalarials in Development in 2014

“…Compound 23 was also found to be completely curative at an oral dose of 4 × 10 mg/kg (MSD > 30 days). 163 Ultimately, from the series of 3,5-diarylaminopyridines synthesized, analogue 22 (MMV390048) was chosen as a clinical candidate, and a phase I study is currently under way (www.mmv.org).…”

Efficient synthesis of differently substituted triarylpyridines with the Suzuki-Miyaura cross-coupling reaction

“…[3][4][5][6] A typical example is pyridinitril, a well-known fungicide which exhibits the ability to block the action of cytochrome P450-dependent 14α-demethylase, preventing the formation of ergosterol, an important intermediate in the construction of fungal-cell membranes. [7][8][9] Many aryl-substituted pyridines are essential building blocks of pharmaceutical agents showing anti-inflammatory, 10 antibacterial, 11 and antimalarial 12 activities. The orally administered antimalarial 3,5-diaryl substituted 2-aminopyridines show promising activity against K1 (chloroquine and drug resistant strain) and NF54 (chloroquine-susceptible strain).…”