Bioorganic & Medicinal Chemistry 18 (2010) 4721–4739
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and Leishmania chagasi parasites of novel tetrahydro-1-benzazepine derivatives
Sandra Gómez-Ayala a, Julián A.Castrillón a, Alirio Palma a,*, Sandra M. Leal b, Patricia Escobar b, Alí Bahsas c
Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, A. A. 678, Bucaramanga, Santander, Colombia Centro de Investigación de Enfermedades Tropicales, Facultad de Salud, Escuela de Medicina, Departamento de Ciencias Básicas, Universidad Industrial de Santander, A.A. 678, Bucaramanga,Santander, Colombia c Laboratorio de RMN, Grupo de Productos Naturales, Departamento de Química, Universidad de los Andes, Mérida 5101, Venezuela
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Forty six new 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-benzazepine derivatives were synthesized and fully characterized. All compounds were tested in vitro against both Trypanosomacruzi and Leishmania chagasi parasites and also for cytotoxicity using Vero and THP-1 mammalian cell lines. Many of the evaluated compounds showed remarkable activity against the epimastigote and intracellular amastigote forms of T. cruzi, with IC50 values comparable with that of control drug nifurtimox, a nitrofuran derivative currently used in the treatment of Chagas’ disease. Other derivatives werefound to have good activity against L. chagasi promastigotes, with low toxicity against the mammalian cells, but neither of them was active on intracellular amastigotes of L. chagasi infecting THP-1 macrophages. Ó 2010 Elsevier Ltd. All rights reserved.
Article history: Received 2 February 2010 Revised 3 May 2010 Accepted 5 May 2010 Available online 7 May 2010 Keywords: Trypanosoma cruziLeishmania chagasi Antiparasitic activity 1,4-Epoxy-2-aryltetrahydro-1-benzazepines 2-Aryl-4-hydroxytetrahydro-1benzazepines
1. Introduction Leishmaniasis and Chagas’ disease are two parasitic infections that constitute a serious public health problem in many tropical and subtropical countries and that affect million people living mainly in poor rural areas. Leishmaniasis is a group of diseasescaused by different species and subspecies of Leishmania, and transmitted to humans by the phlebotomine sandﬂy belonged from the Phlebotumus genus. It is estimated that 12 million people are infected worldwide, particularly in the developing countries, with 2 million new incidences occurring yearly.1 For many years, the classic treatment of leishmaniasis has been based on the use of pentavalentantimonial drugs. Amphotericin B, aminosidine (paromomycin), pentamidine and miltefosine have been introduced as second-line therapy.2–7 Chagas’ disease is caused by the infection with the Trypanosoma cruzi parasite, and transmitted to humans through the feces of infected triatomines insects or by blood transfusions, organ transplantation, placental and orally routes. It is estimated that between 18 and20 million people are infected and around 40 million people are at risk of infection in almost all Latin-American
* Corresponding author. Tel./fax: +57 7 6349069. E-mail addresses: email@example.com, firstname.lastname@example.org (A. Palma). 0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2010.05.018
´ countries. The treatments of Chagas disease are basedon the use of nifurtimox and benznidazole, compounds that are effective only in the acute phase of the disease.8 Unfortunately, the current treatments against these both parasitic diseases have a number of severe limitations such as parenteral administration, poor efﬁcacy, toxic side effects, long course of treatment, high treatment cost and loss of effectiveness due to parasites resistance.8–15...
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