Synthesis and structure-activity relationships of 2-phenyl-1-[(pyridinyl- and piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 2, 2009, Pages 301-304

  Giraud, Francis ^a   Guillon, Rémi ^a   Logé, Cédric ^a   Pagniez, Fabrice ^a   Picot, Carine ^a   Borgne, Marc Le ^a   Pape, Patrice Le ^a  

^a UNIVERSITÉ DE NANTES   (France)

Author keywords

Antifungal agents; Candida albicans; CYP51 inhibitors; Docking; H bond acceptor; Homology model; Triazole

Indexed keywords

2 PHENYL 1 [(PIPERIDINYLMETHYL)AMINO] 3 (1H 1,2,4 TRIAZOL 1 YL)PROPAN 2 OL; 2 PHENYL 1 [(PYRIDINYL)AMINO] 3 (1H 1,2,4 TRIAZOL 1 YL)PROPAN 2 OL; ANTIFUNGAL AGENT; STEROL 14ALPHA DEMETHYLASE; UNCLASSIFIED DRUG;

ANTIFUNGAL ACTIVITY; ARTICLE; BINDING SITE; CANDIDA ALBICANS; CONTROLLED STUDY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME INHIBITION; HYDROGEN BOND; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANTIFUNGAL AGENTS; CANDIDA ALBICANS; MICROBIAL SENSITIVITY TESTS; MODELS, MOLECULAR; PROPANOLS; STRUCTURE-ACTIVITY RELATIONSHIP;

CANDIDA ALBICANS;

EID: 57849127112     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.11.101     Document Type: Article

References (13)

1. Xiao L., Madison V., Chau A.S., Loebenberg D., Palermo R.E., and McNicholas P.M. Antimicrob. Agents Chemother. 48 (2004) 568
2. Chen S.H., Sheng C.Q., Xu X.H., Zhang W.N., and He C. Biol. Pharm. Bull. 30 (2007) 1246
3. Sheng C., Zhang W., Ji H., Zhang M., Song Y., Xu H., Zhu J., Miao Z., Jiang Q., Yao J., Zhou Y., Zhu J., and Lu J. J. Med. Chem. 49 (2006) 2512
4. Giraud F., Logé C., Pagniez F., Crepin D., Le Pape P., and Le Borgne M. Bioorg. Med. Chem. Lett. 18 (2008) 1820
5. +).
6. aliph.), 3472 (υ O{single bond}H).
7. aliph.).
8. aliph.), 3422 (υ O{single bond}H and υ N{single bond}H). MS m/z 484.0 (M+H), 384.2 (M-Boc).
9. aliph.), 3422 (υ O{single bond}H and υ N{single bond}H). MS m/z 384.4 (M+H).
10. +).
11. Pagniez F., and Le Pape P. J. Mycol. Med. 11 (2001) 73
12. Giraud, F. Ph.D. Thesis, Université de Nantes, Nantes Atlantique Universités, October 2007. Briefly, the structure of CYP51 from Mycobacterium tuberculosis complexed with fluconazole (PDB code, 1EA1) was used as the template for the homology model of CYP51-C. albicans. Multiple alignment of the CYP51-Mycobacterium tuberculosis sequence with those of CYP51-C. albicans (PIR code, P10613) and CYP51-A. fumigatus (PIR code, Q9P8R0) was performed using ClustalW. This alignment was further checked by comparing a secondary structure elements prediction for CYP51-C. albicans, obtained through the PSIPRED protein structure prediction server (UCL, Department of Computer Science, Bioinformatics Group, London), with the experimental secondary structure assignments for CYP51-M. tuberculosis deduced from the PDB file. The 3D model of CYP51-C. albicans was then constructed by the Nest program from the protein structure modeling package JACKAL (Honig Lab, Columbia University, New York). The resulting model was further subjected to an energy minimization using Powell's method available in Maximin2 procedure with the MMFF94 force field and a dielectric constant of 4.0 until the gradient value reached 0.1 kcal/mol Å. During the optimization procedure, the structure was checked periodically by Verify-3D and Ramachandran plots. If present, improper geometries were manually corrected and the structure minimized again with the above procedure.
13. Lebouvier, N. Ph.D. Thesis, Université de Nantes, Nantes Atlantique Universités, October 2004.