Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1

Abstract

Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (=7 nm), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low Km to Ki ratio (Km=25 nm and Ki=2.3 nm, respectively).

From On‐Target to Off‐Target Activity: Identification and Optimisation of Trypanosoma brucei GSK3 Inhibitors and Their Characterisation as Anti‐Trypanosoma brucei Drug Discovery Lead Molecules

“…(1)]. 33 In addition, other factors such as protein binding or the requirement for a high level of enzyme inhibition to achieve a phenotypic effect, as observed previously for other T. brucei targets, could even result in a >100-fold drop off 34. The much lower observed difference between IC 50 and EC 50 suggested that the mode of action of series 1 may not be just through inhibition of Tb GSK3.…”

3D-QSAR based pharmacophore modeling and virtual screening for identification of novel pteridine reductase inhibitors

“…R/R 1 and R 2 are the side chains of the scaffolds. The molecules selected as test set with their respective K i values are shown in bold [11][12][13][14][15][16] Recently, various rational structural techniques like structure-based drug design have been used to identify inhibitors against this enzyme [11][12][13][14][15][16][17][18]. This further necessitates exploration of the binding preferences of the known inhibitors in the context of structure activity relationship and the identification of potential novel lead molecules against PTR1.…”

Pharmacophore Mapping, In Silico Screening and Molecular Docking to Identify Selective Trypanosoma brucei Pteridine Reductase Inhibitors

“…A total of 45 inhibitory molecules comprising four different scaffolds with varying substituents were included in this study. The data collected was separated into two independent sets, training set for developing the pharmacophore model and test set for validation of the generated pharmacophore hypothesis 12–15. These sets were planned so as to cover a wide‐range of the activity values and structural diversity.…”

“…The structure elucidation of PTR1 complexes with both substrate and inhibitors from T. brucei have revealed its modes of binding and molecular recognition principles 9–12. Several structure‐based drug design approaches including virtual screening have been employed to identify inhibitors12–15 against T. brucei PTR1 ( TbPTR1 ). However, till date no compound is available with greater potency, efficacy and tolerability than the existing regime.…”