Abstract
In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.
Highlights
Malaria is a devastating parasitic disease causing widespread mortality and morbidity across many parts of the developing world
A drug discovery program for the identification of novel antimalarials was initiated with the high throughput phenotypic screening (HTS) of an in-house library of protein kinase scaffolds (4731 compounds).[7]
Analogue design was directed toward improving potency and solubility and reducing the number of aromatic rings, which can have a beneficial impact on overall development characteristics including solubility.[11,12]
Summary
Malaria is a devastating parasitic disease causing widespread mortality and morbidity across many parts of the developing world. Pyridyl unit at the R3 position with aliphatic substituents was investigated to both reduce the aromatic ring count and increase the sp[3] nature.[13] Small aliphatic groups such as the cyclopropyl group of 16 were not tolerated and resulted in around a 30-fold drop in potency (Table 4). The possibility of modifying the 4-pyridyl unit with the addition of functional groups adjacent to the pyridine nitrogen was investigated, which could potentially reduce binding to human CYP isoforms while retaining suitable affinity for the unknown target of interest (Table 8). Other groups in the 3-position which would alter the electronics of the pyridine nitrogen were inactive (e.g., the CF3 group 42, EC50 = 50 μM) The effects of both electron-donating and electron-withdrawing substituents (43 and 44) were investigated, where both gave a 5- to 10-fold reduction in potency compared to the substituted pyridine 12. Despite a variety of variations on the R1 position, all modifications investigated led to a marked decrease in potency
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