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, 27 (12), 2702-2707

Optimization of a Binding Fragment Targeting the "Enlarged Methionine Pocket" Leads to Potent Trypanosoma Brucei methionyl-tRNA Synthetase Inhibitors

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Optimization of a Binding Fragment Targeting the "Enlarged Methionine Pocket" Leads to Potent Trypanosoma Brucei methionyl-tRNA Synthetase Inhibitors

Wenlin Huang et al. Bioorg Med Chem Lett.

Abstract

Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the "enlarged methionine pocket" (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM.

Keywords: Human African trypanosomiasis; Methionyl-tRNA synthetase; Structure-based design; Trypanosoma brucei.

Figures

Figure 1
Figure 1
Structures of compounds 1 and 2.
Figure 2
Figure 2
Binding of compound 13 to TbMetRS. (A) TbMetRS•Compound 13 complex structure (PDB: 5V49). The protein surface and the two pockets, EMP and AP, where the inhibitor is bound are shown. Protein carbon atoms are colored grey, nitrogens blue and oxygens red. (B) Superposition of TbMetRS structures bound to compounds 13 and 2 (PDB: 5J59). Chlorine atoms are colored green, carbon atoms of compounds 13 and 2 are colored orange and cyan, respectively. (C and D) Hydrogen bond interactions in TbMetRS•compound 2 and TbMetRS•compound 13 structures are shown with dotted lines and labels for interacting residues are underlined.
Scheme 1
Scheme 1
Reagents and conditions: (a) (S)-tert-butyl piperidin-3-ylcarbamate, pyridine, MW, 100 °C, 30 min; (b) TFA, DCM, r.t. overnight; (c) Substituted benzaldehyde, DIPEA, NaBH3CN, AcOH, CH3OH, r.t., overnight.
Scheme 2
Scheme 2
Reagents and conditions: (a) tert-butyl (2-(methylamino)ethyl) carbamate, pyridine, MW, 100 °C, 30 min; (b) TFA, DCM, r.t. overnight; (c) 3,5-dichloro-2-ethoxybenzaldehyde, DIPEA, NaBH3CN, AcOH, CH3OH, r.t., overnight.
Scheme 3
Scheme 3
Reagents and conditions: (a) 2,2-dimethoxy-N-methylethanamine, pyridine, MW, 100 °C, 60 min; (b) HCl (2 M), acetone, reflux, 60 min; (c) methyl 2-amino-2-(3,5-dichlorophenyl)acetate (HCl salt), DIPEA, NaBH3CN, AcOH, CH3OH, r.t., overnight; (d) LiAlH4, THF, 0 °C, 1h; (e) NH3·H2O, r.t. overnight.
Scheme 4
Scheme 4
Reagents and conditions: Ti(OEt)4, EtOH, MW, 100 °C, 30 min; then NaBH3CN, MW, 100 °C, 8 h.
Scheme 5
Scheme 5
Reagents and conditions: DIPEA, NaBH3CN, AcOH, CH3OH, r.t., overnight.

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