title: Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids.
abstract: Cutaneous leishmaniasis and Chagas disease are vector-borne parasitic disease causing serious risks to million people living in poverty-stricken areas. Both diseases are a major health problem in Latin America, and currently drugs for the effective treatment of these diseases have important concerns related with efficacy or toxicity than need to be addressed. We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal and trypanocidal activities) of ten quinolone-hydrazone hybrids. The structure of the products was elucidated by spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis which is the most prevalent Leishmania species in Colombia and Trypanosoma cruzi that is the major pathogenic species to humans; in turn, cytotoxicity was evaluated against human U-937 macrophages. Compounds 6b, 6c and 8 showed activity against L. (V) panamensis with EC50 of 6.5 ± 0.8 μg/mL (21.2 μM), 0.8 ± 0.0 μg/mL (2.6 μM) and 3.4 ± 0.6 μg/mL (11.1 μM), respectively, while compounds 6a and 6c had activity against T. cruzi. with EC50 values of 1.4 ± 0.3 μg/mL (4.8 μM) and 6.6 ± 0.3 μg/mL (4.6 μM), respectively. Even compound 6a showed better activity against T. cruzi than the standard drug benznidazole with EC50 = 10.5 ± 1.8 μg/mL (40.3 μM). Analysis of the results obtained against leishmaniasis indicates that antiparasite activity is related to the presence of 2-substituted quinoline (isoquinolinic core) and the hydroxyl group in positions 3 and 4 of the aromatic ring. Although the majority of these compounds were highly cytotoxic, the antiparasite activity was higher than cytotoxicity and therefore, they still have potential to be considered as hit molecules for leishmanicidal and trypanocidal drug development.
authors.affiliation: Chemistry of Colombian Plants, Institute of Chemistry, Exact and Natural Sciences School, University of Antioquia-UdeA, Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: juancoa2@gmail.com.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Coa
authors.affiliation: Chemistry of Colombian Plants, Institute of Chemistry, Exact and Natural Sciences School, University of Antioquia-UdeA, Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: w.castrillon@hotmail.com.
authors.forename: Wilson
authors.initials: W
authors.lastname: Castrillón
authors.affiliation: Chemistry of Colombian Plants, Institute of Chemistry, Exact and Natural Sciences School, University of Antioquia-UdeA, Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: wilson.cardona1@udea.edu.co.
authors.forename: Wilson
authors.initials: W
authors.lastname: Cardona
authors.affiliation: Department of Inorganic and Organic Chemistry, Jaume I University, E-12071 Castellón, Spain. Electronic address: mcarda@qio.uji.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carda
authors.affiliation: PECET-Medical Research Institute, School of Medicine, University of Antioquia-UdeA. Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: victoriaospina@hotmail.com.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ospina
authors.affiliation: PECET-Medical Research Institute, School of Medicine, University of Antioquia-UdeA. Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: julyandru37@gmail.com.
authors.forename: July Andrea
authors.initials: JA
authors.lastname: Muñoz
authors.affiliation: PECET-Medical Research Institute, School of Medicine, University of Antioquia-UdeA. Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: ivan.velez@udea.edu.co.
authors.forename: Iván D
authors.initials: ID
authors.lastname: Vélez
authors.affiliation: PECET-Medical Research Institute, School of Medicine, University of Antioquia-UdeA. Calle 70 No. 52-21, A.A 1226 Medellín, Colombia. Electronic address: sara.robledo@udea.edu.co.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Robledo
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D018334:Leishmania guyanensis / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D006835:Hydrazones; D011804:Quinolines; C037219:quinoline
keywords: Antiprotozoal activity; Chagas disease; Cytotoxicity; Hybrids; Hydrazone; Leishmaniasis; Quinoline