Inhibitors of adenosine consuming parasites through polymer-assisted N-acylation of N6-substituted 5′-amino-5′-deoxyadenosines

Abstract

A series of 30 adenosine derivatives with three different substituents at the N(6)-position were prepared in order to evaluate their potential to inhibit the pathogenic protozoa Plasmodium falciparum and Trypanosoma brucei in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that N(6)-substitutents should increase stability against adenosine deaminases and allow the molecules to diffuse across parasite membranes. Starting from inosine, the new compounds were prepared as single isomers using a polymer-assisted acylation protocol enabling the straightforward isolation of the target compounds in pure form. Three of the compounds displayed anti-plasmodial and one anti-trypanosomal activity in the single digit micromolar concentration range.

1,2,4‐Trisubstituted Cyclopentanes as Platforms for Diversity

“…In order to expand on our original approach to compound library synthesis [17] it was necessary to obtain a more complete representation of the 1,2,4-trisubstituted AHCP set.…”

“…2). The key intermediate for the preparation of all of these compounds is 3-cyclopentenol, which is readily prepared from cyclopentadiene [7,17,18]. Epoxidation of 3-cyclopentenol with mCPBA led to a bicyclic alcohol with cis orientation of the epoxide ring relative to the hydroxyl function with only a trace of the trans isomer, while the benzyl ether of 3-cyclopentenol gave the cis and trans isomers in a 1:1 ratio.…”

“…As illustrated in Scheme 1 the same azide intermediates (24 and 29) can be used to synthesize 2-amino-cyclopentane-1,4-diols 7 and 8 [17] and 1,2,4-cyclopentanetriamines 18 and 19.…”

4-Aminocyclopentane-1,3-diols as platforms for diversity: synthesis of a screening library

“…10 While it is expensive and laborious to synthesize singletons for the screening in multi-step sequences, it is straightforward to prepare eight racemic trisubstituted cyclopentanoles, which were meant to display recognition motifs in a spatial arrangement aer appropriate modications via N-acylation using a polymer-assisted synthesis approach. 11 them with a limited set of interaction motifs inspired by these principles, we designed and synthesized eight trisubstituted cyclopentane monoethers, each of which were obtained as racemate (Table 1).…”