Abstract
Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant P. falciparum strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds.
Highlights
The impact of natural products on the development of modern antimalarial therapy cannot be overstated.[1]
The discovery of the alkaloid quinine, one of the WHO Model List of Essential Medicines, inspired the development of several clinically used drugs for malaria prophylaxis and therapy, including mefloquine, the 4-aminoquinolines chloroquine and amodiaquine, and the 8-aminoquinolines primaquine and tafenoquine. Another natural product, artemisinin, and its semisynthetic analogues have been used in combination with other antimalarials as a first line treatment for P. falciparum malaria worldwide
The chemical diversity and potentially novel modes of action of natural products make them ideal targets for the development of new classes of potent antimalarials
Summary
Letter points for potential antimalarial lead compound identification; by contrast, the adociane- and amphilectane-type compounds (e.g., 4−6) are hydrophobic. With the goal of accessing ICT-like structures via simple sequences from readily available materials, we produced two isonitrile-bearing compounds from the inexpensive sesquiterpenoid sclareolide (Scheme 4) These compounds were meant to reproduce the complex cyclohexane highlighted in 1 (Figure 1); we note that the different decalin ring fusion forces the isonitrile in sclareolide-derived compounds 43 and 44 to be oriented axially, whereas those in structures 1 through 6 have their isonitriles in an equatorial disposition. The two chemical probe precursors provided confounding results, wherein analogue (±)-36, with its full set of natural features, proved an order of magnitude less active than (±)-37, in which both the C10 center is inverted, C4 bears an equatorial isonitrile, and C5 bears an equatorial hydroxyl group (note this compound differs in the C4 and C5 configurations relative to 29). Experimental procedures for the synthesis of and characterization data for all new compounds, experimental details and raw data for the antimalarial assays and information about the metabolic stability experiments for compound (±)-37 (PDF)
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