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These compounds represent a disubstituted version of the 1\u2010chloro\u20104\u2010(monoaryl\/heteroarylhydranizyl)phthalazine that exhibited a significant response against <jats:italic>L. braziliensis<\/jats:italic> according to our previous findings. Two disubstituted phthalazines <jats:bold>3b<\/jats:bold> and <jats:bold>3f<\/jats:bold> were identified as potential antileishmanial agents against <jats:italic>L. braziliensis<\/jats:italic> parasites, exhibiting a submicromolar IC<jats:sub>50<\/jats:sub> response of 2.37 and 7.90\u2009\u00b5M on the promastigote form, and of 1.82 and 4.56\u2009\u00b5M against intracellular amastigotes, respectively. In particular, compound <jats:bold>3b<\/jats:bold> showed interesting responses against amastigote isolates from reference, glucantime\u2010resistant and clinical human strains, which were by far superior to the biological response found for the glucantime drug. With regard to the toxicity results, both <jats:bold>3b<\/jats:bold> and <jats:bold>3f<\/jats:bold> exhibited moderate LD<jats:sub>50<\/jats:sub> values against murine macrophages (BMDM), with good selectivity indexes on promastigotes and intracellular amastigotes of <jats:italic>L. braziliensis.<\/jats:italic> A comparison of biological response was established between the monosubstituted and disubstituted versions of these benzalhydrazino\u2010phthalazines. Easy synthetic procedure and significant response against amastigote strains including against resistant lines made compound <jats:bold>3b<\/jats:bold> a potential candidate for further pharmacokinetic and in vivo experiments as antileishmanial agent, and as a platform for further structural optimization. Mechanism\u2010of\u2010action studies and molecular docking simulations discarded to inhibition of superoxide dismutase as possible mode of action.<\/jats:p>","DOI":"10.1002\/ardp.201800299","type":"journal-article","created":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T07:53:31Z","timestamp":1556006011000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Antileismanial activity, mechanism of action study and molecular docking of 1,4\u2010bis(substituted benzalhydrazino)phthalazines"],"prefix":"10.1002","volume":"352","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8747-5153","authenticated-orcid":false,"given":"Angel H.","family":"Romero","sequence":"first","affiliation":[{"name":"C\u00e1tedra de Qu\u00edmica General, Facultad de Farmacia Universidad Central de Venezuela Caracas Venezuela"},{"name":"Laboratorio de Ingenier\u00eda Gen\u00e9tica Instituto de Biomedicina, Hospital Vargas Caracas Venezuela"},{"name":"Laboratorio de Qu\u00edmica Medicinal y Heterociclos, Departamento de Qu\u00edmica Universidad Sim\u00f3n Bol\u00edvar Sartenejas, Baruta Venezuela"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noris","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Laboratorio de Ingenier\u00eda Gen\u00e9tica Instituto de Biomedicina, Hospital Vargas Caracas Venezuela"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Oviedo","sequence":"additional","affiliation":[{"name":"Laboratorio de Ingenier\u00eda Gen\u00e9tica Instituto de Biomedicina, Hospital Vargas Caracas Venezuela"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sim\u00f3n E.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Florida Gainesville Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"key":"e_1_2_7_1_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2007.06.009"},{"key":"e_1_2_7_1_3_1","first-page":"255","volume":"45","author":"Sharma U.","year":"2008","journal-title":"J. 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