Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

Bioorg Med Chem Lett. 2013 Feb 13. pii: S0960-894X(13)00193-5. doi: 10.1016/j.bmcl.2013.02.019. [Epub ahead of print]

Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

Cheng G, Muench SP, Zhou Y, Afanador GA, Mui EJ, Fomovska A, Lai BS, Prigge ST, Woods S, Roberts CW, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Rice DW, McLeod R.

Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.

Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.

PMID: 23453069 [PubMed - as supplied by publisher]