A phenotypic screen of the “Malaria Box” discovered MMV008138 (1a) as an antimalarial lead that inhibits the MEP pathway of the malaria parasite Plasmodium falciparum. Independent synthesis of 1a and its three stereoisomers by Pictet-Spengler (PS) reaction of (S)- and (R)-tryptophan methyl ester (TrpOMe) with 2,4-dichlorobenzaldehyde (followed by ester hydrolysis) confirmed that (1R,3S)-configuration is critical for biological activity. PS Reaction of (S)-TrpOMe with various substituted benzaldehydes confirmed that 2',4'-dihalogen substitution confers good antimalarial activity. To further optimize antimalarial activity, we explored analogs of 1a featuring C1-substitution, by performing PS reactions of (S)-TrpOMe with various indanones and methyl aryl ketones. These reactions required Ti(Oi-Pr)4 activation, and reactions with indanones and aryl methyl ketones lacking ortho-substitution proceeded normally to give 2 and 3 after diastereomer separation and hydrolysis. However, when the aryl methyl ketone possessed an ortho substituent, the anticipated PS adduct was not found, but rather the trans- and cis-azepanes 4 and 5 were isolated. Work to optimize the yield of these products, and to deduce the mechanism of ring expansion will be presented.

Ketone Pictet-Spengler routes to spiro-, C1-methyl, and azepane analogs of an antimalarial tetrahydro-β-carboline

2019 Spring National Meeting

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