Synthesis and anti-Trypanosoma cruzi activity of new 3-phenylthio-nor-b-lapachone derivatives Mariana F. do Carmo Cardoso a , Kelly Salomão b , Ana Cristina Bombaça b , David R. da Rocha a , Fernando de C. da Silva a , José A. S. Cavaleiro c , Solange L. de Castro b , Vitor F. Ferreira a,⇑ a Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, 24020-150 Niterói, RJ, Brazil b Laboratório de Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, 21045-900 Rio de Janeiro, RJ, Brazil c Department of Chemistry and QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal article info Article history: Received 19 March 2015 Revised 15 May 2015 Accepted 24 May 2015 Available online 12 June 2015 Keywords: Naphthoquinone Nor-b-lapachone Thiol derivative Trypanosoma cruzi Chagas disease abstract We report herein a straightforward and efficient one-step reaction to prepare new nor-b-lapachone derivatives tethered with phenylthio groups at position 3 of the furan ring. We have screened the com- pounds on bloodstream trypomastigotes of Trypanosoma cruzi, the causative agent of Chagas disease, aimed at finding a new prototype with high trypanocidal activity. The new compounds possess a broad range of activity (IC 50 /24 h from 9.2 to 182.7 lM), higher than the original quinone (391.5 lM) and four of them higher than standard drug benznidazole (103.6 lM). The most active was compound 13b (9.2 lM), being 11 times active than benznidazole and the less toxic derivative to heart muscle cells. Ó 2015 Published by Elsevier Ltd. 1. Introduction Chagas disease is caused by the protozoan Trypanosoma cruzi and affects approximately eight million individuals in Latin America, of whom 30–40% either have or will develop cardiomy- opathy, digestive megasyndromes or both. 1 A major concern is the disease’s emergence in non-endemic areas such as North America and Europe, a phenomenon which is likely due to the immigration of infected individuals. 2,3 The available chemotherapy for Chagas disease includes two nitroheterocyclic agents, nifur- timox and benznidazole, which are effective against acute infec- tions but show poor activity in the late chronic phase, with severe collateral effects and limited efficacy against different para- sitic isolates. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. 4,5 Naphthoquinone derivatives possess diverse biological proper- ties, including virucidal, microbicidal and anticancer activities, 6,7 which have stimulated the study of these bioactive compounds in the field of medicinal chemistry. Several mechanisms have been implicated in their bioactivity, such as the two-electron reduction of quinones by NADP(H):quinone oxidoreductase 1 (NQO1), which is over expressed in a variety of tumors. 8 It is noteworthy that several quinones were approved for clini- cal use or are currently undergoing evaluation in clinical trials (Fig. 1). Among them we can highlight doxorubicin (1), which is isolated from Streptomyces coeruleorubidus, and mitomycin C (2), which is isolated from Streptomyces caespitosus or Streptomyces lavendulae, for the treatment of solid tumors. Additionally, lapachol (3) has been marketed in the past as an adjuvant in the treatment of certain cancers, and Atovaquone (4) and Buparvaquone (5). In recent years, b-lapachone (6) 9–11 has attracted considerable attention, particularly in the cancer research community, because of its ability to act as a topoisomerase inhibitor and apoptosis inductor. 12 b-Lapachone is considered to be the inspiration for the synthesis of several derivatives with improved biological activ- ities. 7,13–16 Nor-b-lapachone (7) is a smaller homolog of lapachol (3) that can be easily prepared by several procedures and can be obtained efficiently from nor-lapachol (8) by acid catalysis (Fig. 1). 17 The cyclization of nor-lapachol (8) in the presence of an elec- trophilic reagent, such as bromine, forms a cationic intermediate o-quinone methide (Scheme 1), which can react with several nucleophiles to lead to nor-b-lapachones substituted at the dihy- drofuran ring. 18,19 With this aim in mind, and as a further exten- sion of our studies in this field, we have prepared the azido derivative (10), which was further transformed into 1,2,3-1H-tria- zoles. This heterocyclic nucleus is a remarkably important http://dx.doi.org/10.1016/j.bmc.2015.05.039 0968-0896/Ó 2015 Published by Elsevier Ltd. ⇑ Corresponding author. Tel.: +55 21 26292345; fax: +55 21 26292136. E-mail address: cegvito@vm.uff.br (V.F. Ferreira). Bioorganic & Medicinal Chemistry 23 (2015) 4763–4768 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc