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Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC\n            <jats:sub>50<\/jats:sub>\n            ] &lt; 5 \u03bcM) against intracellular amastigotes of at least one\n            <jats:named-content content-type=\"genus-species\">Leishmania<\/jats:named-content>\n            species and acceptable activity (20 \u03bcM &lt; EC\n            <jats:sub>50<\/jats:sub>\n            &lt; 30 \u03bcM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the\n            <jats:italic>in vitro<\/jats:italic>\n            evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell 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 had stability superior to that of\n            <jats:italic>para<\/jats:italic>\n            -hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, 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 larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against\n            <jats:named-content content-type=\"genus-species\">Leishmania major<\/jats:named-content>\n            was tested\n            <jats:italic>in vivo<\/jats:italic>\n            . LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration.\n          <\/jats:p>","DOI":"10.1128\/aac.02419-17","type":"journal-article","created":{"date-parts":[[2018,3,6]],"date-time":"2018-03-06T09:51:49Z","timestamp":1520329909000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["Topical Treatment for Cutaneous Leishmaniasis: Dermato-Pharmacokinetic Lead Optimization of Benzoxaboroles"],"prefix":"10.1128","volume":"62","author":[{"given":"Katrien","family":"Van Bocxlaer","sequence":"first","affiliation":[{"name":"London School of Hygiene &amp; Tropical Medicine, Faculty of Infections and Tropical Diseases, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Gaukel","sequence":"additional","affiliation":[{"name":"Scynexis Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre","family":"Hauser","sequence":"additional","affiliation":[{"name":"Scynexis Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Hee","family":"Park","sequence":"additional","affiliation":[{"name":"Scynexis Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Schock","sequence":"additional","affiliation":[{"name":"Scynexis Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Yardley","sequence":"additional","affiliation":[{"name":"London School of Hygiene &amp; Tropical Medicine, Faculty of Infections and Tropical Diseases, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Randolph","sequence":"additional","affiliation":[{"name":"Scynexis Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob J.","family":"Plattner","sequence":"additional","affiliation":[{"name":"Anacor Pharmaceuticals, Inc., Palo Alto, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejal","family":"Merchant","sequence":"additional","affiliation":[{"name":"Anacor Pharmaceuticals, Inc., Palo Alto, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon L.","family":"Croft","sequence":"additional","affiliation":[{"name":"London School of Hygiene &amp; Tropical Medicine, Faculty of Infections and Tropical Diseases, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Anacor Pharmaceuticals, Inc., Palo Alto, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Wring","sequence":"additional","affiliation":[{"name":"Scynexis Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035671"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0035-9203(01)90223-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(10)70223-1"},{"key":"e_1_3_2_5_2","volume-title":"Leishmaniasis: trends in epidemiology, diagnosis and treatment","author":"Rangel EF","year":"2014","unstructured":"Rangel EF, da Costa SM, Carvalho BM. 2014. 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