Structure–Activity Relationship Exploration of 3′-Deoxy-7-deazapurine Nucleoside Analogues as Anti-Trypanosoma brucei Agents

Abstract

Human African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3'-deoxytubercidin 5, a lead compound with activity against central nervous stage human African trypanosomiasis, we investigate the structure-activity relationship of the purine and ribofuranose ring. The purine ring tolerated only modifications at C7, while from the many alterations of the 3'-deoxyribofuranosyl moiety only the arabino analogue 48 showed pronounced antitrypanosomal activity. Profiling of the most potent analogues against resistant T. brucei strains (resistant to pentamidine, diminazene and isometamidium) showed reduced dependence on uptake mediated by the P2 aminopurine transporter compared to 5. The introduction of a 7-substituent confers increased affinity for the P1 nucleoside transporter up to 10-fold, while generally retaining high affinity for P2. Four of the most promising analogues were found to be metabolically stable, earmarking them suitable back-up analogues for lead 5.

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

“…They can inhibit the PSP enzymes or they can become toxic (e.g. cordycepin, tubercidin) when activated by these enzymes 2 – 5 . Several PSP enzymes (i.e.…”

6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy

“…Removal of the chloro-substituent (26) led to a substantial activity drop, indicating the importance of para substitution. Several alternative substituents resulted in less potent analogues (27)(28)(29)(30)(31)(32)(33)(34)(35), including 4-F ( 27), 4-CF 3 (28) and 4-Me (32) that retained low micromolar anti-T. cruzi activity, similar to BZ. Shifting the halogen to the meta (36,37) or ortho (38) position reduced the anti-T. cruzi activity, in line with previous SAR observations with the 6-amino analogues.…”

“…Finally, we investigated the effect of 3'-deoxygenation (Table 3), previously shown to significantly improve antitrypanosomal activity. [25,[32][33] However, the 3'-deoxy analogue 54 Table 1. < Activity of 7-(para-chlorophenyl) nucleoside analogues with modifications in pyrimidine moieties against intracellular T. cruzi amastigotes.…”

“…To gain access to a 3'-deoxyribofuranose analogue, a Vorbrüggen reaction was performed involving 4-chloro-5-iodopyrrolo [2,3-d]pyrimidine [43] and 1-O-acetyl-2,5-di-O-benzoyl-3deoxy-α/β-D-ribofuranose [25,[32][33] to give 81 [33] (Scheme 6). A magnesium-iodine exchange with the Knochel reagent (iPrMgCl .…”

“…. [33] 4-chloro-5-iodo-7H-pyrrolo [2,3-d]pyrimidine (500 mg, 1.79 mmol) was placed in a 100 mL twoneck round bottom flask, after which the flask was purged with N 2 gas. Anhydrous MeCN (15 mL, 7.5 mL/mmol of SM) was added.…”