Design, synthesis, and structure-activity relationship of trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents

Journal of Medicinal Chemistry

Volumn 54, Issue 5, 2011, Pages 1276-1287

  Ding, Dazhong ^a   Meng, Qingqing ^a   Gao, Guangwei ^a   Zhao, Yaxue ^a   Wang, Qing ^a   Nare, Bakela ^c   Jacobs, Robert ^c   Rock, Fernando ^d   Alley, Michael R K ^d   Plattner, Jacob J ^d   Chen, Guoqiang ^b   Li, Dawei ^a   Zhou, Huchen ^a  

^a SHANGHAI JIAO TONG UNIVERSITY   (China)

^b SHANGHAI JIAO TONG UNIVERSITY SCHOOL OF MEDICINE   (China)

^c SCYNEXIS Inc   (United States)

^d PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YL N CYCLOHEXYLCARBAMATE; 6 (2 FLUOROBENZYLOXY) 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 (2 METHOXYETHOXY) 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 (2,2 DIMETHOXYETHOXY) 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 (3 HYDROXYPROPYL) 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 (PYRIDIN 2 YLMETHOXY) 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 BENZYLOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 BUTOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 CYCLOHEXYLMETHOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 ETHOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 HYDROXYL 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 ISOPROPOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 PROPOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 6 QUINOLIN 2 YLOXY 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; 7 (3 HYDROXYPROPYL) 1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROLE; [2 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YLOXYL)]ACETALDEHYDE; [2 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YLOXYL)]ACETIC ACID; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YL) 1 PHENYL]PROPENONE; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YL)]ACRYLIC ACID ETHYL ESTER; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YL)]PROPIONIC ACID ETHYL ESTER; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YLOXYL)PROPYL]ISOINDOLE 1,3 DIONE; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 7 YL) 1 PHENYL]PROPENONE; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 7 YL)]ACRYLIC ACID ETHYL ESTER; [3 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 7 YL)]PROPIONIC ACID ETHYL ESTER; ANTITRYPANOSOMAL AGENT; LEUCINE TRANSFER RNA LIGASE INHIBITOR; LIGASE INHIBITOR; N TERT BUTYL 2 (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YLOXY)ACETAMIDE; TERT BUTYL N (1,3 DIHYDRO 1 HYDROXY 2,1 BENZOXABOROL 6 YL)ETHYLCARBAMATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL CELL; ANTIPROTOZOAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; IC 50; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; TRYPANOSOMA BRUCEI;

ANIMALS; BORONIC ACIDS; CELL LINE; DRUG DESIGN; LEUCINE-TRNA LIGASE; MICE; MODELS, MOLECULAR; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRYPANOCIDAL AGENTS; TRYPANOSOMA BRUCEI BRUCEI;

EID: 79952262238     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101225g     Document Type: Article

References (16)

1. Hotez, P. J.; Molyneux, D. H.; Fenwick, A.; Kumaresan, J.; Sachs, S. E.; Sachs, J. D.; Savioli, L. Control of neglected tropical diseases N. Engl. J. Med. 2007, 357, 1018-1027 (Pubitemid 47367081)
2. Croft, S. L.; Barrett, M. P.; Urbina, J. A. Chemotherapy of trypanosomiases and leishmaniasis Trends Parasitol. 2005, 21, 508-512 (Pubitemid 41447021)
3. Renslo, A. R.; McKerrow, J. H. Drug discovery and development for neglected parasitic diseases Nat. Chem. Biol. 2006, 2, 701-710 (Pubitemid 44764212)
4. Pink, R.; Hudson, A.; Mouries, M. A.; Bendig, M. Challenges in antiparasitic drug discovery Nat. Rev. Drug Discovery 2005, 4, 727-740
5. Hurdle, J. G.; O'Neill, A. J.; Chopra, I. Prospects for aminoacyl-tRNA synthetase inhibitors as new antimicrobial agents Antimicrob. Agents Chemother. 2005, 49, 4821-4833 (Pubitemid 41778891)
6. Kim, S.; Lee, S. W.; Choi, E. C.; Choi, S. Y. Aminoacyl-tRNA synthetases and their inhibitors as a novel family of antibiotics Appl. Microbiol. Biotechnol. 2003, 61, 278-288 (Pubitemid 36683523)
7. Hendrickson, T. L.; Schimmel, P. Transfer RNA-Dependent Amino Acid Discrimination by Aminoacyl-tRNA Synthetases. In Translation Mechanisms; Lapointe, J.; Brakier-Gingras, L., Eds.; Kluwer Academic and Plenum Publishers: New York, 2003.
8. Green, L. S.; Bullard, J. M.; Ribble, W.; Dean, F.; Ayers, D. F.; Ochsner, U. A.; Janjic, N.; Jarvis, T. C. Inhibition of methionyl-tRNA synthetase by REP8839 and effects of resistance mutations on enzyme activity Antimicrob. Agents Chemother. 2009, 53, 86-94
9. Rock, F. L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Crepin, T.; Zhou, H.; Zhang, Y. K.; Hernandez, V.; Akama, T.; Baker, S. J.; Plattner, J. J.; Shapiro, L.; Martinis, S. A.; Benkovic, S. J.; Cusack, S.; Alley, M. R. K. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site Science 2007, 316, 1759-1761 (Pubitemid 46988553)
10. Lincecum, T. L.; Tukalo, M.; Yaremchuk, A.; Mursinna, R. S.; Williams, A. M.; Sproat, B. S.; Eynde, W. V. D.; Link, A.; Calenbergh, S. V.; Grotli, M.; Martinis, S. A.; Cusack, S. Structural and mechanistic basis of pre- and posttransfer editing by leucyl-tRNA synthetase Mol. Cell 2003, 11, 951-963 (Pubitemid 36566317)
11. Zhou, X. L.; Zhu, B.; Wang, E. D. The CP2 domain of leucyl-tRNA synthetase is crucial for amino acid activation and post-transfer editing J. Biol. Chem. 2008, 283, 36608-36616
12. Sukuru, S. C. K.; Crepin, T.; Milev, Y.; Marsh, L. C.; Hill, J. B.; Anderson, R. J.; Morris, J. C.; Rohatgi, A.; O'Mahony, G. O.; Grotli, M.; Danel, F.; Page, M. G. P.; Hartlein, M.; Cusack, S.; Kron, M. A.; Kuhn, L. A. Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change J. Comput.-Aided Mol. Des. 2006, 20, 159-178 (Pubitemid 44269786)
13. Ye, L.; Ding, D.; Feng, Y.; Xie, D.; Wu, P.; Guo, H.; Meng, Q.; Zhou, H. Convenient and versatile synthesis of formyl-substituted benzoxaboroles Tetrahedron 2009, 65, 8738-8744
14. Ding, D.; Zhao, Y.; Meng, Q.; Xie, D.; Nare, B.; Chen, D.; Bacchi, C. J.; Yarlett, N.; Zhang, Y. K.; Hernandez, V.; Xia, Y.; Freund, Y.; Abdulla, M.; Ang, K. H.; Ratnam, J.; McKerrow, J. H.; Jacobs, R. T.; Zhou, H.; Plattner, J. J. Discovery of novel benzoxaborole-based potent antitrypanosomal agents ACS Med. Chem. Lett. 2010, 1, 165-169
15. Seiradake, E.; Mao, W.; Hernandea, V.; Baker, S. J.; Plattner, J. J.; Alley, M. R. K.; Cusack, S. Crystal structures of the human and fungal cytosolic leucyl-tRNA synthetase editing domains: a structural basis for the rational design of antifungal benzoxaboroles J. Mol. Biol. 2009, 390, 196-207
16. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291