C6–O-alkylated 7-deazainosine nucleoside analogues: Discovery of potent and selective anti-sleeping sickness agents

Abstract

African trypanosomiasis, a deadly infectious disease caused by the protozoan Trypanosoma brucei spp., is spread to new hosts by bites of infected tsetse flies. Currently approved therapies all have their specific drawbacks, prompting a search for novel therapeutic agents. T. brucei lacks the enzymes necessary to forge the purine ring from amino acid precursors, rendering them dependent on the uptake and interconversion of host purines. This dependency renders analogues of purines and corresponding nucleosides an interesting source of potential anti-T. brucei agents. In this study, we synthesized and evaluated a series of 7-substituted 7-deazainosine derivatives and found that 6-O-alkylated analogues in particular showed highly promising in vitro activity with EC50 values in the mid-nanomolar range. SAR investigation of the O-alkyl chain showed that antitrypanosomal activity increased, and also cytotoxicity, with alkyl chain length, at least in the linear alkyl chain series. However, this could be attenuated by introducing a terminal branch point, resulting in the highly potent and selective analogues, 36, 37 and 38. No resistance related to transporter mediated-uptake could be identified, earmarking several of these analogues for further in vivo follow-up studies.

4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma brucei

“…A range of tubercidin analogues (Figure 1) was synthetized as part of a campaign to find novel hits with enhanced selective potency against T. brucei compared to tubercidin [19][20][21]. Experimental details regarding their synthesis are described [19][20][21]. The synthesis of analogue 4 is described in Supplementary method S1.…”

“…Substitution of C-7 with a bromide, trifluoromethyl, or pyridin-2-yl group led to compounds 3-5, with the latter showing sub-micromolar activity in vitro [19]. Compounds 6-9 are 7-substituted 7-deazainosine analogues [21].…”

“…A combination of structural elements of tubercidin and cordycepin resulted in the development of 3 -deoxy-7-deazaadenosine nucleosides, with 3 -deoxytubercidin (2) as the most promising candidate for late-stage sleeping sickness [20]. Likewise, the screening of a series of 7-substituted 7-deazainosine derivatives provided several 6-O-alkylated analogues (6)(7)(8)(9) with nanomolar in vitro potency and is thus interesting for further in vivo evaluation [21]. Another advantage of nucleoside analogues is their high likelihood to cross the blood-brain barrier due to the various purine transporters lining this barrier [22].…”

“…Sufficient compound exposure in the central nervous system is essential for efficacy against stage-II of the disease and is a requirement in the current target product profile [23]. 9)) [20], (TH1003 (31), FH6367, TH1008 ( 13)) [19], (FH8446 (23), FH9531 (36), FH9528 (24), FH10664 (28)) [21].…”

First Total Synthesis of 5′-O-α-d-Glucopyranosyl Tubercidin

“…Since then, 7-deazapurine has been recognized as a privileged scaffold in developing new antitumor and antiviral nucleosides [ 8 ]. Consequently, many 7-deazapurine nucleosides have been synthesized and their biological activities have been screened in the past 50 years [ 9 , 10 , 11 ]. Among them, several promising lead compounds have been discovered [ 12 , 13 , 14 ].…”