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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.

CASSCF(8,8)/6-31G* and AM1-SRP direct dynamics trajectory calculations have been run on the rearrangement of 1,2,6-heptatriene to 3-methylene-1,5-hexadiene. They show that the experimental results of Roth et al. on this reaction can be explained without the need to invoke a concerted, pericyclic mechanism. Instead, bifurcation occurs at the transition state for conversion of the reactant to 2-methylenecyclohexane-1,4-diyl. Some trajectories leaving the transition state do enter the PES local minimum for the intermediate, but others, differing only in the phases of the real-frequency vibrational modes, bypass the intermediate and proceed over a second transition state to the product. A significant fraction of the trajectories that do enter the biradical local minimum proceed on to the product in <500 fs, despite the fact that the minimum is some 12 kcal/mol deep at the CASSCF level. This nonstatistical behavior seems to be due in part to a resonance between key C-H bending and C-C stretching vibrations in the intermediate.