Open AccessHit-to-Lead Development of the Chamigrane Endoperoxide Merulin A for the Treatment of African Sleeping Sickness
Author(s) -
Gabriel Navarro,
Supchar Chokpaiboon,
Géraldine De Muylder,
Walter M. Bray,
Sean C. Nisam,
James H. McKerrow,
Khanitha Pudhom,
Roger G. Linington
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0046172
Subject(s) - african trypanosomiasis , trypanosoma brucei , antiparasitic , natural product , chemistry , ic50 , pharmacology , biology , medicine , trypanosomiasis , biochemistry , virology , in vitro , gene , pathology
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. Significance 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.