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Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.

Huang W, Zhang Z, Barros-Álvarez X, Koh CY, Ranade RM, Gillespie JR, Creason SA, Shibata S, Verlinde CLMJ, Hol WGJ, Buckner FS, Fan E
Eur J Med Chem 124 1081-1092 (2016)
Related entries: 5j58, 5j59

Cited: 14 times
EuropePMC logo PMID: 27788467

Abstract

A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC50s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).

Reviews citing this publication (4)

  1. Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases. Nie A, Sun B, Fu Z, Yu D. Cell Death Dis 10 901 (2019)
  2. Pharmacological Potential and Synthetic Approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine Derivatives. Krause M, Foks H, Gobis K. Molecules 22 E399 (2017)
  3. Polyamine-based analogs and conjugates as antikinetoplastid agents. Jagu E, Pomel S, Pethe S, Loiseau PM, Labruère R. Eur J Med Chem 139 982-1015 (2017)
  4. Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites. Nasim F, Qureshi IA. ACS Omega 8 14884-14899 (2023)

Articles citing this publication (10)

  1. Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Cryptosporidium Infection. Buckner FS, Ranade RM, Gillespie JR, Shibata S, Hulverson MA, Zhang Z, Huang W, Choi R, Verlinde CLMJ, Hol WGJ, Ochida A, Akao Y, Choy RKM, Van Voorhis WC, Arnold SLM, Jumani RS, Huston CD, Fan E. Antimicrob Agents Chemother 63 e02061-18 (2019)
  2. Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections. Faghih O, Zhang Z, Ranade RM, Gillespie JR, Creason SA, Huang W, Shibata S, Barros-Álvarez X, Verlinde CLMJ, Hol WGJ, Fan E, Buckner FS. Antimicrob Agents Chemother 61 e00999-17 (2017)
  3. Spontaneous Selection of Cryptosporidium Drug Resistance in a Calf Model of Infection. Hasan MM, Stebbins EE, Choy RKM, Gillespie JR, de Hostos EL, Miller P, Mushtaq A, Ranade RM, Teixeira JE, Verlinde CLMJ, Sateriale A, Zhang Z, Osbourn DM, Griggs DW, Fan E, Buckner FS, Huston CD. Antimicrob Agents Chemother 65 e00023-21 (2021)
  4. Optimization of a binding fragment targeting the "enlarged methionine pocket" leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors. Huang W, Zhang Z, Ranade RM, Gillespie JR, Barros-Álvarez X, Creason SA, Shibata S, Verlinde CLMJ, Hol WGJ, Buckner FS, Fan E. Bioorg Med Chem Lett 27 2702-2707 (2017)
  5. Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei. Zhang Z, Barros-Álvarez X, Gillespie JR, Ranade RM, Huang W, Shibata S, Molasky NMR, Faghih O, Mushtaq A, Choy RKM, de Hostos E, Hol WGJ, Verlinde CLMJ, Buckner FS, Fan E. RSC Med Chem 11 885-895 (2020)
  6. Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase. Torrie LS, Robinson DA, Thomas MG, Hobrath JV, Shepherd SM, Post JM, Ko EJ, Ferreira RA, Mackenzie CJ, Wrobel K, Edwards DP, Gilbert IH, Gray DW, Fairlamb AH, De Rycker M. ACS Infect Dis 6 1044-1057 (2020)
  7. Molecular basis for diaryldiamine selectivity and competition with tRNA in a type 2 methionyl-tRNA synthetase from a Gram-negative bacterium. Mercaldi GF, Andrade MO, Zanella JL, Cordeiro AT, Benedetti CE. J Biol Chem 296 100658 (2021)
  8. Physiologic Targets and Modes of Action for CBL0137, a Lead for Human African Trypanosomiasis Drug Development. Sanz-Rodríguez CE, Hoffman B, Guyett PJ, Purmal A, Singh B, Pollastri MP, Mensa-Wilmot K. Mol Pharmacol 102 1-16 (2022)
  9. Exploring Proteus mirabilis Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation. Elbaramawi SS, Eissa AG, Noureldin NA, Simons C. Pharmaceuticals (Basel) 16 1263 (2023)
  10. Synthesis of some new 2-(substituted-phenyl)imidazo[4,5-c] and [4,5-b]pyridine derivatives and their antimicrobial activities. Altaib M, Doganc F, Kaşkatepe B, Göker H. Mol Divers (2023)


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