N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase

Abstract

A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important.

Evaluation of Nucleoside Hydrolase Inhibitors for Treatment of African Trypanosomiasis

“…The efficacy of inhibition further decreased when the purine ring was replaced by an aminobenzothiazole ring (yielding UAMC-00311; K i ϭ 560 nM) or a quinoline ring (yielding UAMC-00115; K i ϭ 446 nM). Taken together, these results suggest that, with respect to the aglycone part, structure-activity relationships for TbbIAG-NH inhibition seem to differ substantially from what was observed earlier for TvIAG-NH (4,22). The same set of compounds was also tested with TbbIG-NH.…”

“…The design and synthesis of the N-arylmethyl-substituted iminoribitol derivatives has been discussed extensively elsewhere (4,22,23). These compounds are potent inhibitors of TvIAG-NH and discriminate against hPNP (Table 1).…”

“…The synthesis of compound UAMC-00363 has been described previously (22), but minor changes in the last reaction step and purification were made: iminoribitol ⅐ HCl (0.15 g [0.887 mmol]), sodium acetate (NaOAc; 0.08 g [0.975 mmol]), and 37% aqueous formaldehyde (0.073 ml [0.975 mmol]) were dissolved in H 2 O-dioxane (4:1 [2 ml/mmol]). The reaction mixture was stirred at 95°C for 1.5 h. 9-Deazaadenine (0.242 g [0.975 mmol]) was added to the solution, and the mixture was stirred at 95°C for an additional hour.…”

“…Excess HCl was removed by evaporation under reduced pressure, and the crude mixture was adsorbed onto silica gel, which was then evaporated to dryness under reduced pressure. Purification by column chromatography (dichloromethane/methanol/NH 4 (22).…”

“…Consequently, this target has been investigated during the past decade, and potent inhibitors of NH have been developed. The immucillins (20,29) and N-arylmethyl-substituted iminoribitol derivatives (4,22,23,39) (Fig. 2) are the strongest inhibitors of T. vivax IAG-NH (TvIAG-NH) and T. b. brucei IAG-NH (TbbIAG-NH) known to date, with K i values in the low nanomolar range.…”