Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?

For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. Parasitic protozoa lack de novo synthesis and rely entirely on the purine salvage pathway to meet their purine demands. Because of the great phylogenetic difference between parasite and host, there are often sufficient distinctions that can be exploited to design specific inhibitors for the parasitic enzymes. As a result, this pathway has been thoroughly investigated over the last twenty years. It is only quite recently that the genome studies of Trypanosoma, Leishmania and Plasmodium have been published. Based on these genomic data however, the existence of by-pass mechanisms by other enzymes and transporter systems could be suggested. Taking into account such proposition, the question might arise as to whether inhibition of a single salvage enzyme will be able or not to cause parasite death or growth arrest. In this paper, the key enzymes in the purine salvage pathways of relevant pathogenic species from the genera Trypanosoma, Leishmania and Plasmodium are reviewed. Their potential as drug targets is critically evaluated and where possible, correlated to literature data on antiparasitic activity of their inhibitors. While many studies over the past ten years have yielded contradictory results, this review attempts to clarify these findings by discussing the latest elements of progress in the field. Additionally, as part of a broader discussion on substrate analogue types of inhibitors, special attention is paid to iminoribitol derivatives, serving as transition state analogues of nucleoside-processing enzymes and comprising the most potent inhibitors reported for purine salvage enzymes. More specifically, the development of three generations of immucillins and a newer series of N-(arylmethyl-) substituted iminoribitol derivatives will be discussed. Finally, this review also covers subversive substrates of salvage enzymes: compounds that are transformed by enzymatic activity into cytotoxic agents. Although not by directly intervening in the process of purine recovery, the subversive substrate approach might deliver antiprotozoal compounds that rely on salvage enzymes for their activity.

Synthesis and biochemical evaluation of guanidino-alkyl-ribitol derivatives as nucleoside hydrolase inhibitors.

Nucleoside hydrolase (NH) is a key enzyme in the purine salvage pathway. The purine specificity of the IAG-NH from Trypanosoma vivax is at least in part due to cation-pi-stacking interactions. Guanidinium ions can be involved in cation-pi-stacking interactions, therefore a series of guanidino-alkyl-ribitol derivatives were synthesized in order to examine the binding affinity of these compounds towards the target enzyme. The compounds show moderate to good inhibiting activity towards the IAG-NH from T. vivax.

1,2,3-Triazolylalkylribitol derivatives as nucleoside hydrolase inhibitors.

A range of novel 1,2,3-triazolylalkylribitol derivatives were synthesized and evaluated as nucleoside hydrolase inhibitors. The most active compound (11a) has low micromolar potency and is structurally diverse from previously reported nucleoside hydrolase inhibitors, which, along with the simplicity of the chemistry involved in its synthesis, makes it a good lead for the further development of novel nucleoside hydrolase inhibitors.

Copper(II) complexes of pentadentate 17-membered macrocyclic diamidodiamines with N, O or S as additional donors.

The crystal structures of (2,6-dioxo-1,4,7,11,14-pentaazacycloheptadecanato)copper(II) tetrahydrate, [Cu(C(12)H(23)N(5)O(2))].4H(2)O, (I), (3,16-dioxo-1-oxa-4,8,11,15-tetraazacycloheptadecanato)copper(II) pentahydrate, [Cu(C(12)H(22)N(4)O(3))].5H(2)O, (II), and (3,16-dioxo-1-thia-4,8,11,15-tetraazacycloheptadecanato)copper(II) trihydrate, [Cu(C(12)H(22)N(4)O(2)S)].3H(2)O, (III), are reported. The coordination geometry in each case is approximately square pyramidal with two amine groups and two deprotonated amide groups in the basal plane. The apical position is occupied by an amine group, an ether O atom or a thio S atom. Trigonal distortion increases in the sequence S < O < N as apical donor. The relation between the distortion in the basal plane of the complexes and the maxima in their electronic spectra is discussed.

A potentiometric study of the complexes formed between Ni(II) and Zn(II) and 3-mercaptopropionic acid.

The composition and stability constants of the complexes formed between Ni(2+) and Zn(2+) and 3-mercaptopropionic acid (3-MPA) were studied by a potentiometric method at 25 degrees and in 0.5M KNO(3). For the system Zn(2+)/3-MPA. a mixture of the mononuclear complex BA(2) and the polynuclear complexes B(3)A(4). and B(4)A(6) was found (B means the metal ion and A the ligand). The system Ni(2+)/3-MPA can be represented by the complexes B(5)A(10), B(6)A(11) B(6)A(9) and B(6)A(12). In this series the last two complexes are predominant.