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The compounds were very potent noncompetitive inhibitors of native\n            <jats:italic>L. amazonensis<\/jats:italic>\n            squalene synthase (SQS), with inhibition constants also being in the nanomolar to subnanomolar range. Growth inhibition was strictly associated with the depletion of the parasite's main endogenous sterols and the concomitant accumulation of exogenous cholesterol. Using electron microscopy, we identified the intracellular structures affected by the compounds. A large number of lipid inclusions displaying different shapes and electron densities were observed after treatment with both SQS inhibitors, and these inclusions were associated with an intense disorganization of the membrane that surrounds the cell body and flagellum, as well as the endoplasmic reticulum and the Golgi complex. Cells treated with ER-119884 but not those treated with E5700 had an altered cytoskeleton organization due to an abnormal distribution of tubulin, and many were arrested at cytokinesis. A prominent contractile vacuole and a phenotype typical of programmed cell death were frequently found in drug-treated cells. The selectivity of the drugs was demonstrated with the JC-1 mitochondrial fluorescent label and by trypan blue exclusion tests with macrophages, which showed that the IC\n            <jats:sub>50<\/jats:sub>\n            s against the host cells were 4 to 5 orders of magnitude greater that those against the intracellular parasites. Taken together, our results show that ER-119884 and E5700 are unusually potent and selective inhibitors of the growth of\n            <jats:italic>Leishmania amazonensis<\/jats:italic>\n            , probably because of their inhibitory effects on de novo sterol biosynthesis at the level of SQS, but some of our observations indicate that ER-119884 may also interfere with other cellular processes.\n          <\/jats:p>","DOI":"10.1128\/aac.01616-07","type":"journal-article","created":{"date-parts":[[2008,9,3]],"date-time":"2008-09-03T01:11:21Z","timestamp":1220404281000},"page":"4098-4114","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":77,"title":["In Vitro Activities of ER-119884 and E5700, Two Potent Squalene Synthase Inhibitors, against\n            <i>Leishmania amazonensis<\/i>\n            : Antiproliferative, Biochemical, and Ultrastructural Effects"],"prefix":"10.1128","volume":"52","author":[{"given":"Juliany Cola","family":"Fernandes Rodrigues","sequence":"first","affiliation":[{"name":"Laborato\u0301rio de Ultraestrutura Celular Hertha Meyer, Instituto de Biofi\u0301sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS, Bloco G, subsolo, Ilha do Funda\u0303o, Rio de Janeiro, RJ 21.941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Luis","family":"Concepcion","sequence":"additional","affiliation":[{"name":"Laboratorio de Enzimologia de Parasitos, Facultad de Ciencias, Universidad de los Andes, Merida, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Laborato\u0301rio de Qui\u0301mica Biolo\u0301gica, Centro de Bioqui\u0301mica y Biofi\u0301sica, Instituto Venezolano de Investigaciones Cienti\u0301ficas, Apartado 21827, Caracas 1020A, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aura","family":"Caldera","sequence":"additional","affiliation":[{"name":"Laborato\u0301rio de Qui\u0301mica Biolo\u0301gica, Centro de Bioqui\u0301mica y Biofi\u0301sica, Instituto Venezolano de Investigaciones Cienti\u0301ficas, Apartado 21827, Caracas 1020A, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio A.","family":"Urbina","sequence":"additional","affiliation":[{"name":"Laborato\u0301rio de Qui\u0301mica Biolo\u0301gica, Centro de Bioqui\u0301mica y Biofi\u0301sica, Instituto Venezolano de Investigaciones Cienti\u0301ficas, Apartado 21827, Caracas 1020A, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanderley","family":"de Souza","sequence":"additional","affiliation":[{"name":"Laborato\u0301rio de Ultraestrutura Celular Hertha Meyer, Instituto de Biofi\u0301sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS, Bloco G, subsolo, Ilha do Funda\u0303o, Rio de Janeiro, RJ 21.941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1991.44.536"},{"key":"e_1_3_2_3_2","first-page":"437","year":"1992","unstructured":"Barrett-Bee, K., and N. 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