Synthesis and Antitrypanosomal Activity of 6-Substituted 7-Methyl-7-deazapurine Nucleosides

Abstract

Human African Trypanosomiasis caused by Trypanosoma brucei species is one of the most damaging neglected tropical diseases. While the number of newly diagnosed cases per year is record low, there is still high interest in the development of new antitrypanosomal agents in case of resistance to currently used drugs and their combinations, and to replace drugs with serious side effects. We report a series of 7-methyl-7-deazapurine (5-methyl-pyrrolo­[2,3-d]­pyrimidine) ribonucleosides bearing alkyl, methylsulfanyl, methylamino, or diverse alkoxy groups at position 6 that was prepared through glycosylation of 6-chloro-7-methyl-7-deazapurine followed by nucleophilic substitutions or cross-coupling reactions at position 6 and deprotection. Most of the title nucleosides displayed significant activity against Trypanosoma brucei brucei and T. b. gambiense at submicromolar or nanomolar concentrations and low cytotoxicity and thus represent promising candidates for further development.

Competing interests during the key N-glycosylation of 6-chloro-7-deaza-7-iodopurine for the synthesis of 7-deaza-2′-methyladenosine using Vorbrüggen conditions

“…A notable alternative would thus either be substituting acetonitrile, for example, with 1,2-dichloroethane ( Smith et al, 2004 ), or performing the reaction without DBU. As mentioned earlier, Cho has recently reported the same coupling using BSA and TMSOTf ( Cho et al, 2020 ) which has also been used for N -glycosylation reactions with other 7-deazapurine analogs, as reported by Seela and Ming (2007 ) and Ingale et al ( 2018 ) and the Hocek group ( Nauš et al, 2015 ; Perlíková et al, 2021 ) for non- C 2 -branched peracylated pentoses. In our hands, however, the same side-reaction occurred on repeating Cho’s protocol.…”

Adamantane-Substituted Purine Nucleosides: Synthesis, Host–Guest Complexes with β-Cyclodextrin and Biological Activity

“…A wide range of significant biological effects have recently been described for synthetically prepared purine nucleosides or their bioisosteres. For example, they can act as adenosine receptor ligands [ 2 ], plant growth regulators [ 3 ], or antiviral [ 3 , 4 , 5 , 6 ], antitumor [ 5 , 6 , 7 , 8 ], and antiprotozoal agents [ 9 , 10 , 11 , 12 ]. From a synthetic point of view, purine nucleosides represent an interesting class of compounds with structural diversity and nearly unrestricted possibilities for modifying the purine ring, especially at positions C2, C6, and N9 [ 13 , 14 ].…”

Exploration of 6-methyl-7-(Hetero)Aryl-7-Deazapurine ribonucleosides as antileishmanial agents

“…brucei and T. b. gambiense. [24] Remarkably, the hit rate against Leishmania is comparatively low. 7-Deazapurine nucleoside analogues that do show in vitro antileishmanial activity include the 7-(3,4dichlorophenyl) analogue 10, [16] and the 6-methyl-7-3,6-(dihydro-2H-pyranyl) analogue 11 (Figure 1C).…”