Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.

The glycinocins are a class of calcium-dependent, acidic cyclolipopeptide antibiotics structurally related to the clinically approved daptomycin. Herein, we describe a divergent total synthesis of glycinocins A-C, which differ in the structure of a branched α,β-unsaturated fatty acyl moiety. The three natural products exhibited calcium-dependent antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MICs ranging from 5.5 to 17 μM.

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