Topical treatment for cutaneous leishmaniasis - dermato-pharmacokinetic led optimisation of benzoxaboroles

06 Mar 2018
Van Bocxlaer K, Gaukel E, Hauser D, Park SH, Schock S, Yardley V, Randolph R, Plattner JJ, Merchant T, Croft SL, Jacobs RT, Wring SA

Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania - affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focussed primarily on drug permeation and formulation optimisation as the means to increase treatment efficacy.Our approach aims to identify compounds with anti-leishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (EC50< 5 μM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 μM< EC50 <30 μM) against two more species. Benzoxaborole compounds were further prioritised based upon the in vitro evaluation of progression criteria related to skin permeation such as the partition coefficient and solubility. An MDCK-MDR1 assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but have superior stability than para-hydroxybenzoate compounds that are known skin esterase substrates. Permeation evaluation through reconstructed human epidermis showed LSH002 to be most permeable followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001 followed by LSH003 and LSH002 with a significantly higher amount of LSH001 retained in skin compared to other compounds.Finally, the efficacy of the leads (LSH001, LSH002 and LSH003) was tested in vivo against Leishmania major LSH001 suppressed lesion growth upon topical application and LSH003 reduced the lesion size following oral administration.