Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

Abstract

Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.

New developments in anti-malarial target candidate and product profiles

“…The initial momentum was provided by phenotypic screening of diverse compound collections. New chemical diversity has been screened in the last 4 years, including microbial metabolites from Japan, and molecules with novel chemistries such as boron [168, 169] and increased sp3 types [170]. These sources are rapidly being mined out and it is only through access to novel chemical diversity via new pharmaceutical compound libraries that new relevant compounds can be screened.…”

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

“…Subsequent optimization, guided by these stereochemical insights, led to the identification of ML238 (Fig. 3), which is potent against both the chloroquine-resistant Dd2 strain (IC 50 = 0.4 nM) and the wild-type 3d7 strain (IC 50 = 0.6 nM) of Plasmodium falciparum (Heidebrecht et al , 2012; Weiwer et al , 2010). In addition, ML238 has good water solubility and does not lyse red blood cells (EC 50 > 40,000 nM), which is important because it suggests a lack of broad cytotoxicity.…”

Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen

“…Series 1 compounds were shown to inhibit the viral transcription and replication, likely via their inhibition of the L polymerase. Diversity-oriented synthesis-derived molecules have proven to be a rich source for diverse antimicrobial inhibitors (Comer et al, 2014, Heidebrecht et al, 2012, Dandapani et al, 2014). Here we show that the Broad’s DOS libraries may also be a source for new antiviral agents, having described three unique scaffolds as potential starting points for novel therapies for RSV infections.…”