SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF ANALOGS OF 2'-DEOXY-2'-(3-METHOXYBENZAMIDO)ADENOSINE, A SELECTIVE INHIBITOR OF TRYPANOSOMAL GLYCOSOMAL GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE

In continuation of a project aimed at the structure-based design of dr ugs against sleeping sickness, analogs of 2'-deoxy-2'-(3-methoxybenzam ido)adenosine (1) were synthesized and tested to establish structure-a ctivity relationships for inhibiting glycosomal glyceraldehyde-3-phosp hate dehydrogenase (GAPDH). Compound 1 was recently designed using the NAD: GAPDH complexes of the human enzyme and that of Trypanosoma bruc ei, the causative agent of sleeping sickness. In an effort to exploit an extra hydrophobic domain due to Val 207 of the parasite enzyme, sev eral new 2'-amido-2'-deoxyadenosines were synthesized. Some of them di splayed an interesting improvement in inhibitory activity compared to 1. Carbocyclic or acyclic analogs showed marked loss of activity, illu strating the importance of the typical (C-2'-endo) puckering of the ri bose moiety. We also describe the synthesis of a pair of compounds tha t combine the beneficial effects of a 2- and 8-substituted adenine moi ety on potency with the beneficial effect of a 2'-amido moiety on sele ctivity. Unfortunately, in both cases, IC50 values demonstrate the inc ompatibility of these combined modifications. Finally, introduction bf a hydrophobic 5'-amido group on 5'-deoxyadenosine enhances the inhibi tion of the protozoan enzyme significantly, although the gain in selec tivity is mediocre.