| Affiliation: | 1. Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612 (USA);2. Chicago State University, College of Pharmacy, DH 203‐3, 9501 South King Drive, Chicago, IL 60628 (USA);3. Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology, and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, IL 60637 (USA);4. Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029 (USA);5. Johns Hopkins School of Public Health, Room E5132, 615 North Wolfe Street, Baltimore MD 21205 (USA);6. School of Biomedical Sciences, University of Leeds, Leeds, LS2?9JT (UK);7. Department of Discovery, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Room 2N61, 503 Robert Grant Avenue, Silver Spring, MD 20910 (USA);8. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4?0RE (UK);9. Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield (UK) |
| Abstract: | Through our focused effort to discover new and effective agents against toxoplasmosis, a structure‐based drug design approach was used to develop a series of potent inhibitors of the enoyl‐acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well‐known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM , respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme‐based assay. With respect to their excellent in vitro activity as well as improved drug‐like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections. |
