Systematic Exploration of Functional Group Relevance for Anti-Leishmanial Activity of Anisomycin

Abstract

Assessment of structure-activity relationships for anti-protozoan activity revealed a strategy for preparing potent anisomycin derivatives with reduced host toxicity. Thirteen anisomycin analogs were synthesized by modifying the alcohol, amine, and aromatic functional groups. Examination of anti-protozoal activity against various strains of Leishmania and cytotoxicity against leucocytes with comparison against the parent natural product demonstrated typical losses of activity with modifications of the alcohol, amine, and aromatic meta-positions. On the other hand, the para-phenol moiety of anisomycin proved an effective location for introducing substituents without significant loss of anti-protozoan potency. An entry point for differentiating activity against Leishmania versus host has been uncovered by this systematic study.

Keywords: Leishmania; anisomycin; ribosome.

Figure 1

Anisomycin (1) and derivatives 2–7.

Scheme 1

Synthesis of methylated anisomycin analogs.

Scheme 2

Synthesis of anisomycin analogs modified on the aromatic ring.

Figure 2

Effect of O-iso-propyl ether 22a on BMDM macrophages infected with (A) L. infantum WT and (B) L. major WT for 48 h.

Figure 3

Graphical depiction of the conserved binding site of anisomycin in L. major ribosome. The 80S ribosome (8OVJ) of L. major was superimposed on the 50S ribosome of H. marismortui (PDB ID: 3CC4), and nucleotides proposed to contact anisomycin (colored in cyan) are highlighted in orange; the corresponding homologs in E. coli rRNA are presented in parentheses; pseudouridine nucleotide is indicated with Ψ symbol.