An ICof 200 M. Attaching an more phenethyl group for the adenine ring (69) resulted in elevated potency (IC50 = 30 M). At one hundred M, compound 34 was selective over rabbit muscle PGK. Compound 34 was also tested against BSF T. brucei brucei and T. brucei rhodesiense. Screens against both subspecies gave an EC50 of 20 M, and 40 M against murine fibroblasts, representing a 2-fold selectivity.105 5.3.1.four. Hexokinase. As a third instance of a carbohydrate kinase targeted for inhibitor discovery, the T. brucei hexokinase is only 37 similar to the human homologue, suggesting the possibility of selective inhibitor style.eight Phosphorylation of glucose to glucose-6-phosphate is catalyzed by hexokinase, and many studies have shown that analogues of glucose, such as glucosamine106 and 2-C-hydroxymethyl glucose107 derivatives, inhibit the reaction. Since glucose-6-phosphate has affinity toward the active site of T. brucei hexokinase, Willson et al. tested many glucose-6-phosphate analogues against T. brucei hexokinase. Compounds 35 and 36, shown in Figure 9, showed weak inhibition against T. brucei hexokinase, with 75 inhibition at three mM for 35 and 60 inhibition at 0.2 mM for 36.Figure 9. Glucose-6-phosphate derivatives tested against T. brucei hexokinase.Figure 8. Adenosine derivatives tested against TbPGK and T. brucei.five.three.two. Trypanosoma cruzi. Protein kinase activity in T. cruzi has been studied since the late 1970s. It was located that T. cruzi’s protein kinase activity PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/21193451 was independent of cyclic nuleotides and stimulated as much as 4-fold by unique nucleosides.109 Inosine stimulated protein kinase activity at low concentration, and adenosine showed maximal stimulation at 0.1 mM.109 Deoxyadenosines inhibited protein kinase activity in T. cruzi and T. gambiense; 2 deoxyadenosine (37, Figure ten) inhibited protein kinase activity by 30 and three deoxyadenosine (38) by 75 . Each deoxyadenosides are competitive inhibitors of ATP (Ki = 0.11 mM and 0.eight mM, respectively).109 5.three.2.1. Arginine Kinase. Arginine kinase belongs for the family members of guanidine kinases. The guanidine kinases catalyze Nphosphorylated Ceruletide web guanidino compounds by the reversible transferdx.doi.org/10.1021/cr500197d | Chem. Rev. 2014, 114, 11280-Chemical ReviewsReviewFigure 10. General protein kinase inhibitors in T. cruzi.of an ATP phosphoryl group to a guanidino acceptor inside the enzyme. Phosphoarginine plays an essential role as an power reserve because of the high-energy phosphate transfer when a renewal of ATP is required.110 A correlation between enzyme activity, nutrient availability, and cell density suggests that arginine kinases function as a regulator of energy reserves beneath starvation anxiety conditions.111 T. cruzi arginine kinase is inhibited at 10 mM by the arginine analogues, agmatine (39) to 79.three , canavanine (40) to 54.6 , nitroargine (41) to 52.six , and homoarginine (42) to 38.two (Figure 11). Also,Figure 11. Inhibitors of arginine kinase in T. cruzi.canavanine and homoarginine inhibited the cell development of epimastigotes of T. cruzi by 79.7 and 55.8 at a 10 mM drug concentration, and their arginine kinase Ki values were calculated to become 7.55 and 6.02 mM, respectively. These results recommend inhibition of cell growth mediated by the inhibition on the parasite’s arginine kinase, although the extraordinarily low potency of those inhibitors leaves area for more study to confirm this.5.three.two.two. Phosphofructokinase. Phosphofructokinase (PFK) has not too long ago been identified to.