Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

• Published in: Journal of medicinal chemistry 2001-06, Vol.44 (13), p.2080-2093
• Main Authors: Bressi, Jerome C, Verlinde, Christophe L. M. J, Aronov, Alex M, Shaw, My Le, Shin, Sam S, Nguyen, Lisa N, Suresh, Stephen, Buckner, Frederick S, Van Voorhis, Wesley C, Kuntz, Irwin D, Hol, Wim G. J, Gelb, Michael H
• Format: Article
• Language: English
• Subjects: 3T3 Cells - parasitology; Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - pharmacology; adenosine analogues; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Combinatorial Chemistry Techniques; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; glyceraldehyde-3-phosphate dehydrogenase; Glyceraldehyde-3-Phosphate Dehydrogenases - antagonists & inhibitors; Glyceraldehyde-3-Phosphate Dehydrogenases - chemistry; Leishmania mexicana; Leishmania mexicana - drug effects; Leishmania mexicana - growth & development; Medical sciences; Mice; Pharmacology. Drug treatments; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - growth & development; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - growth & development; Trypanosomatina - enzymology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000472o

In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD+ interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N 6-(1-naphthalenemethyl)-2‘-deoxy-2‘-(3-methoxybenzamido)adenosine (6e), N 6-(substituted-naphthalenemethyl)-2‘-deoxy-2‘-(substituted-benzamido)adenosine analogues were investigated. N 6-(1-Naphthalenemethyl)-2‘-deoxy-2‘-(3,5-dimethoxybenzamido)adenosine (6m), N 6-[1-(3-hydroxynaphthalene)methyl]-2‘-deoxy-2‘-(3,5-dimethoxybenzamido)adenosine (7m), N 6-[1-(3-methoxynaphthalene)methyl]-2‘-deoxy-2‘-(3,5-dimethoxybenzamido)adenosine (9m), N 6-(2-naphthalenemethyl)-2‘-deoxy-2‘-(3-methoxybenzamido)adenosine (11e), and N 6-(2-naphthalenemethyl)-2‘-deoxy-2‘-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC50's of these compounds were in the range 2−12 μM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure−activity relationships of this class of compounds, a library of 240 N 6-(substituted)-2‘-deoxy-2‘-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N6 and C2‘ substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5‘-amido substituents and found that 2‘,5‘-dideoxy-2‘-(3,5-dimethoxybenzamido)-5‘-(diphenylacetamido)adenosine (49) displays an IC50 of 60−100 μM against the three parasite GAPDH's.