title: Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G.
abstract: Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.
authors.affiliation: Laborat&#243;rio de Parasitologia Humana, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. eduarda_c.costa@hotmail.com.
authors.forename: Eduarda C
authors.initials: EC
authors.lastname: Costa
authors.affiliation: Laborat&#243;rio de S&#237;ntese e Qu&#237;mica Medicinal-LASQUIM, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. tatibortolo@gmail.com.
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Cassamale
authors.affiliation: Laborat&#243;rio de S&#237;ntese e Qu&#237;mica Medicinal-LASQUIM, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. diegob.carvalho@hotmail.com.
authors.forename: Diego B
authors.initials: DB
authors.lastname: Carvalho
authors.affiliation: Laborat&#243;rio de Parasitologia Humana, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. lauri.bosqui@gmail.com.
authors.forename: Lauriane S S
authors.initials: LS
authors.lastname: Bosquiroli
authors.affiliation: Laborat&#243;rio de Biologia Molecular e Culturas Celulares, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. mariahojeda@live.com.
authors.forename: Mariáh
authors.initials: M
authors.lastname: Ojeda
authors.affiliation: Laborat&#243;rio de Biofisiofarmacologia, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. thalitario@hotmail.com.
authors.forename: Thalita V
authors.initials: TV
authors.lastname: Ximenes
authors.affiliation: Laborat&#243;rio de Biologia Molecular e Culturas Celulares, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. matosmfc@gmail.com.
authors.forename: Maria F C
authors.initials: MF
authors.lastname: Matos
authors.affiliation: Laborat&#243;rio de Biofisiofarmacologia, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. monica.kadri@ufms.br.
authors.forename: Mônica C T
authors.initials: MC
authors.lastname: Kadri
authors.affiliation: Laborat&#243;rio de S&#237;ntese e Qu&#237;mica Medicinal-LASQUIM, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. adrianobaroni@hotmail.com.
authors.forename: Adriano C M
authors.initials: AC
authors.lastname: Baroni
authors.affiliation: Laborat&#243;rio de Parasitologia Humana, Centro de Ci&#234;ncias Biol&#243;gicas e da Sa&#250;de, Universidade Federal de Mato Grosso do Sul, 79090-900 Campo Grande-MS, Brazil. carla.arruda@ufms.br.
authors.forename: Carla C P
authors.initials: CC
authors.lastname: Arruda
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry; D005663:Furans / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D007891:Leishmania / Q000187:drug effects / Q000472:pathogenicity; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D017705:Lignans / Q000008:administration & dosage / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects; D009569:Nitric Oxide / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D005663:Furans; D017705:Lignans; D009569:Nitric Oxide; C018674:tetrahydrofuran; C084077:galgravin; C074346:grandisin
keywords: biological activity; cytotoxicity; neglected diseases; neolignan derivatives; synthetic compounds