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Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis

Authors:            

Lago, Eloi M. 1 ; Silva, Marcos P. 1 ; Queiroz, Talita G. 1 ; Mazlouma, Susana F. 1 ; Rodrigues, Vinicius C. 1 ; Carnauba, Paulo U. 1 ; Pinto, Pedro L. 2 ; Rocha, Jefferson A. 3 ; Ferreira, Leonardo L. G. 4 ; Andricopulo, Adriano D. 4 ; de Moraes, Josue 1


Abstract:

Background:Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases,depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidalanti-inflammatory drugs (NSAIDs) commonly used in medical and veterinaryfields were evaluated for theiranti-schistosomal properties.Methods:The efficacy of NSAIDs wasfirst tested against adultSchistosoma mansoni ex vivousing phenotypicscreening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease param-eters measured were worm and egg burden, hepato- and splenomegaly.Findings:From 73 NSAIDs,five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac)were identified to effectively kill schistosomes. These results were further supported by scanning electron mi-croscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, re-vealed to be a critical property for theex vivoactivity profile. Compounds were then testedin vivousing bothpatent and a prepatentS. mansoniinfection in a mouse model. The most effective NSAID was mefenamic acid,which highly reduced worm burden, egg production, and hepato- and splenomegaly.Interpretation:The treatment regimen used in this study is within the range for which mefenamic acid has beenused in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.


1   University of Guarulhos, Research Center for Neglected Diseases, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil

2   Adolfo Lutz Institute, Center for Research in Parasitology, São Paulo, SP, Brazil

3   Federal University of Maranhão, Research Group of Natural Science and Biotechnology, Grajaú, MA, Brazil

4   University of Sao Paulo, Sao Carlos Institute of Physics, Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, São Carlos, SP, Brazil


Link to article:    https://www.sciencedirect.com/science/article/pii/S2352396419302683?via%3D