Almiramides A-C: discovery and development of a new class of leishmaniasis lead compounds

Abstract

Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A-C (1-3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.

Figure 1

Subunits a–f and NMR connectivity for 1. Solid arrows indicate HMBC correlations. Dashed arrows indicate ROESY correlations.

Figure 2

Structurally related linear lipopeptides (areas of structural homology outlined with dashed lines).

Scheme 1

Configurational Analysis Strategy for 2 and 3

Scheme 2

Generation of Semisynthetic Derivatives 11 and 12