title: Thymol and eugenol derivatives as potential antileishmanial agents.
abstract: In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5-10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase-expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100mg/kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl-thymol was the best inhibitor (8.67 ± 0.28 μg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of leishmaniasis.
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil; Curso de Quimica, Centro de Ciências e Tecnologia, Universidade Estadual do Ceara, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil. Electronic address: selenemaiademorais@gmail.com.
authors.forename: Selene Maia
authors.initials: SM
authors.lastname: de Morais
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Nadja Soares
authors.initials: NS
authors.lastname: Vila-Nova
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil; Laboratório de Doenças Parasitárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Claudia Maria Leal
authors.initials: CM
authors.lastname: Bevilaqua
authors.affiliation: Laboratório de Doenças Parasitárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Fernanda Cristina
authors.initials: FC
authors.lastname: Rondon
authors.affiliation: Laboratório de Biologia da Reprodução, Universidade Federal do Ceará, Av. Mister Hull s/n, Campus do Pici, 60021-970 Fortaleza, Ceará, Brazil.
authors.forename: Carlos Henrique
authors.initials: CH
authors.lastname: Lobo
authors.affiliation: Laboratório de Biologia da Reprodução, Universidade Federal do Ceará, Av. Mister Hull s/n, Campus do Pici, 60021-970 Fortaleza, Ceará, Brazil.
authors.forename: Arlindo
authors.initials: A
authors.lastname: de Alencar Araripe Noronha Moura
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Antônia Débora
authors.initials: AD
authors.lastname: Sales
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Ana Paula Ribeiro
authors.initials: AP
authors.lastname: Rodrigues
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: José Ricardo
authors.initials: JR
authors.lastname: de Figuereido
authors.affiliation: Programa de Pós-Graduação em Ciências Veterinárias, Universidade Estadual do Ceará, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil; Faculdade de Veterinária - FAVET, Avenida Paranjana 1700, Campus do Itaperi, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Claudio Cabral
authors.initials: CC
authors.lastname: Campello
authors.affiliation: Department of Internal Medicine, University of Iowa and the VA Medical Center, Iowa City, IA 52242, USA; Department of Microbiology, University of Iowa and the VA Medical Center, Iowa City, IA 52242, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Wilson
authors.affiliation: Laboratório de Protozoologia, Universidade de São Paulo, Avenida Eneas de Carvalho Aguiar, 470, 05403-000 São Paulo, SP, Brazil.
authors.forename: Heitor Franco
authors.initials: HF
authors.lastname: de Andrade
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D005054:Eugenol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008264:Macrophages / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013943:Thymol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000981:Antiprotozoal Agents; D013943:Thymol; D005054:Eugenol
keywords: Eugenol; Leishmania infatum chagasi; Thymol