Sustainable synthesis and automated deposition: an accessible discovery screening library of fragment-like purines.

A sub-library of 88 information-rich lead-like purine derivatives were prepared and deposited in an open access academic screening facility. The rationale for the synthesis of these rigid low complexity structures was the privileged character of the purine heterocycle associated with its inherent probability of interactions with multiple adenine-related targets. Although generally expected to be weak binders in many assays, such fragment-like compounds are estimated to match diverse binding sites. It is suggested that heterocycles with many anchor points for hydrogen bonds can be anticipated to undergo very specific interactions to produce more negative enthalpies and thus provide superior starting points for lead optimization than compounds that owe their activity to entropic effects. The in vitro cytotoxicity of the small compounds on a panel of human cancer cell lines has been investigated and some of them showed marked unselective or selective toxicity. This data may be useful if these fragments are to be incorporated into drug-like structures via metabolically cleavable connections. The sub-library will be implemented as part of the ChemBioNet ( www.chembionet.info ) library, and it is open to screening campaigns of academic research groups striving for a fragment-based approach in their biological assays.

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

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.