3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

Abstract

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).

Inhibition of Cytochrome bc 1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

“…More impressively, ELQ-400 also effectively cleared asexual, blood-stage parasites with a single 1 mg/kg dose, making it the most active single-dose therapy to date, with a 20-fold to 100-fold increase in efficacy over other single-dose compounds in the developmental pipeline. [11][12][13] As with other single-dose antimalarials, we also found that ELQ-400 was capable of rapidly reducing blood-stage parasitemia in vivo. This finding was especially striking because cyt bc 1 inhibitors such as ELQ-400 have generally been classified as slow-onset antimalarials.…”

“…9,10 Several potential single-dose cure antimalarials are currently in the developmental pipeline. The ozonide OZ439, 11 the aminopyridine MMV390048, 12 and the spiroindolone NITD609 13 all effectively clear asexual, blood-stage parasites in mouse models of malaria with a single oral dose and also inhibit gametocyte development, which reduces the potential for malaria transmission. In contrast, several imidazolopiperazines, 14,15 8-aminoquinolines, 16 and antirespiratory compounds 17,18 have been identified as single-dose causal prophylactics, which inhibit the sporozoite and liverstage parasites that are responsible for the earliest stages of Plasmodium infection.…”

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

“…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). 13 Some polyarylated pyridines were found to be topoisomerase I and II inhibitors exhibiting toxicity toward human tumor cells depending on the nature of the aryl substituents. 14,15 Our previous studies in forensic chemistry were focused on the identification and synthesis of novel "route-specific" impurities, including dibenzylpyridines P1 and P2, and aryl/methylpyridines P3, and P4 ( Figure 1).…”

Characterization of Physical, Thermal and Spectral Properties of Biofield Treated 2-Aminopyridine

“…It has been used as an intermediate for the synthesis of pharmaceutical agents such as sulfapyridine, tenoxicam, and tripelennamine [4]. Recently Gonzalez Cabrera et al [7] and Younis et al [8,9] synthesized the 2-AP derivatives as potential anti-malarial candidates, and they evaluated its efficiency in Plasmodium berghei infected mouse model. Dambuza et al also reported the antimalarial properties of 3,5-Diaryl-2-aminopyridine derivatives [10].…”