Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides

• Published in: Bioorganic & medicinal chemistry letters 2013-06, Vol.23 (12), p.3551-3555
• Main Authors: Muench, Stephen P., Stec, Jozef, Zhou, Ying, Afanador, Gustavo A., McPhillie, Martin J., Hickman, Mark R., Lee, Patty J., Leed, Susan E., Auschwitz, Jennifer M., Prigge, Sean T., Rice, David W., McLeod, Rima
• Format: Article
• Language: English
• Subjects: Apicomplexa; Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - metabolism; drugs; Enoyl reductase; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - chemistry; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism; Models, Molecular; parasites; peptides; Plasmodium; Plasmodium falciparum - metabolism; solvents; Toxoplasma; Toxoplasma - metabolism; transporters; Triclosan; Triclosan - analogs & derivatives; Triclosan - chemical synthesis; Triclosan - chemistry; Triclosan - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.04.035

The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery.