Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

Abstract

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

“…12), and reevaluated these compounds for antimalarial activity. 125 Biochemical assays confirmed the antimalarial potencies (300−500 nM range) of the original hits OSM-S-5 and OSM-S-6 against the 3D7 strain of P. falciparum. However, these compounds were slightly less potent than previously reported (IC 50 values of ca.…”

“…Williamson and colleagues resynthesized two GSK hits, OSM‐S‐5 and its amino‐antipyrine analog, OSM‐S‐6 (Fig. ), and reevaluated these compounds for antimalarial activity . Biochemical assays confirmed the antimalarial potencies (300−500 nM range) of the original hits OSM‐S‐5 and OSM‐S‐6 against the 3D7 strain of P. falciparum .…”

“…Various newly prepared analogs have shown high potencies along with low cytotoxicities, with some compounds, remarkably, found to be more active than the original OSM hits. Of particular note was the outstanding activity of the nontoxic compound OSM‐S‐38 against the LS, asexual blood‐stage, and late‐stage gametocytes, with inhibitory concentrations in the low nanomolar range …”

“…Xenomycin analogs F I G U R E 1 Imidazolopiperazine analogswas the outstanding activity of the nontoxic compound OSM-S-38 against the LS, asexual blood-stage, and late-stage gametocytes, with inhibitory concentrations in the low nanomolar range 125. …”

An inquiry‐based exercise in medicinal chemistry: Synthesis of a molecular library and screening for potential antimalarial and anti‐inflammatory compounds

“…In that case, the synthetic procedures and spectroscopic characterization data are also uploaded to the OSM online electronic laboratory notebook for dissemination. Notably, compounds generated at Lawrence in this project have already demonstrated antimalarial potential in testing .…”