NOVEL 2-SUBSTITUTED 2’/3’-C-METHYL-ADENOSINE DERIVATIVES: SYNTHESIS AND BIOLOGICAL EVALUATION AGAINST TRYPANOSOMA BRUCEI

Human African trypanosomiasis (HAT), which is also known as sleeping sickness, is a devastating parasitic disease that affects more than 300000 people of sub-Saharan Africa each year. The causative agent of this affliction is the protozoan Trypanosoma brucei, which is introduced in the mammalian host by the tsetse fly. T. brucei attacks the central nervous system leading to dementia, epileptic attacks, coma, and, if left untreated, death. Current treatment for this disease, including suramin, pentamidine, melarsoprol, and difluoromethylornithine (DFMO), is often antiquated, highly toxic and frequently ineffective. Therefore, new highly effective and not toxic drugs are needed. Like most obligate intracellular parasites, T. brucei has lost the capacity to synthesize purines de novo and depends on the salvage pathway of nucleosides from the body fluids of the host. Bloodstream T. brucei can take up different types of purines and interconverts them into essential cellular nucleotides. Cordycepin (3’-deoxyadenosine) is an adenosine derivatives able to cure mice inoculated with the human pathogenic T. brucei even after parasites have penetrated into the brain, but requires co-administration with the adenosine deaminase (ADA) inhibitor coformycin to prevent deamination. However, the toxicity of coformycin has stimulated the search of adenosine analogues active against the parasite, but resistant to ADA. In our previous work, we found that the introduction of a methyl group in position 2’- or 3’- of the sugar moiety of adenosine (2’-C-methyladenosine and 3’-C-methyladenosine, respectively) confers a certain grade of resistance to ADA.(1) In fact, 3’-MeAdo is resistant to ADA, while 2’-MeAdo is deaminated by ADA even though the rate of deamination was 1/25 that observed with adenosine. Moreover, some 2, N6-disubstituted adenosine analogs have been reported to show antitrypanosomal activity.(2) Based on these findings a new series of 2-substituted-2’-C-methyl-, and 3’-C-methyl-adenosine derivatives were synthesized and tested for their antiprotozoal activity. The results of this study will be discussed. (1) Franchetti, P, et al. J Med Chem 1998, 41, 1708-1715; Franchetti, P, et al. J Med Chem 2005, 48, 4983-4989; Cappellacci, L, et al. J Med Chem 2008, 51, 4260-4269. (2) Rodenko, B, et al. Antimicrob. Agents Chemother. 2007, 51, 3796-3802.