title: Hit-to-lead development of the chamigrane endoperoxide merulin A for the treatment of African sleeping sickness.
abstract: BACKGROUND
  Human African trypanosomiasis (HAT) is an infectious disease with a large global health burden occurring primarily in Central and Eastern Africa. Most current treatments have poor blood brain barrier (BBB) penetration, which prevent them from targeting the most lethal stage of the infection. In addition, current therapeutics suffer from a variety of limitations ranging from serious side effects to difficulties with treatment administration. Therefore it is of crucial importance to find new treatments that are safe, affordable, and effective against both sub-species of Trypanosoma brucei.
  
  
  METHODS
  Semi-synthetic derivatization of the fungally-derived natural product merulin A (1) has led to the discovery of new development candidates for the protozoan parasite T. brucei, the causative agent of HAT. Creation of an initial SAR library based around the merulin scaffold revealed several key features required for activity, including the endoperoxide bridge, as well as one position suitable for further derivatization. Subsequent synthesis of a 20-membered analogue library, guided by the addition of acyl groups that improve the drug-like properties of the merulin A core, resulted in the development of compound 12 with an IC(50) of 60 nM against T. brucei, and a selectivity index greater than 300-fold against HeLa and immortalized glial cells.
  
  
  CONCLUSIONS
  We report the semi-synthetic optimization of the merulin class of endoperoxide natural products as development candidates against T. brucei. We have identified compounds with low nM antiparasitic activities and high selectivity indices against HeLa cells. These compounds can be produced economically in large quantities via a one step derivatization from the microbial fermentation broth isolate, making them encouraging lead candidates for further development.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarro
authors.forename: Supchar
authors.initials: S
authors.lastname: Chokpaiboon
authors.forename: Geraldine
authors.initials: G
authors.lastname: De Muylder
authors.forename: Walter M
authors.initials: WM
authors.lastname: Bray
authors.forename: Sean C
authors.initials: SC
authors.lastname: Nisam
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Khanitha
authors.initials: K
authors.lastname: Pudhom
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
mesh_terms: D000818:Animals; D001487:Basidiomycota / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D009457:Neuroglia / Q000187:drug effects; D010545:Peroxides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: D001688:Biological Products; D010545:Peroxides; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; C550059:merulin A