Bioorganic & Medicinal Chemistry 16 (2008) 569–577
Heteroallyl-containing 5-nitrofuranes as new anti-Trypanosoma cruzi agents with a dual mechanism of action
´a Alejandra Gerpe,a Imeria Odreman-Nunez,b Patricia Draper,a Lucı Boiani,a ˜ b a,* ´ Julio A. Urbina, Mercedes Gonzalez and Hugo Cerecettoa,*
´ ´ ´ ´ ´ Laboratorio de Quımica Organica,Facultad de Quımica/Facultad de Ciencias, Igua 4225, Universidad de la Republica, 11400 Montevideo, Uruguay b ´ ´ ´ ´ ´ Laboratorio de Quımica Biologica, Centro de Biofısica y Bioquımica, Instituto Venezolano de Investigaciones Cientıﬁcas, Caracas 1020, Venezuela
Received 24 May 2007; revised 5 July 2007; accepted 9 July 2007 Available online 21 August 2007
Abstract—New heteroallyl-containing5-nitrofuranes were synthesized as potential anti-Trypanosoma cruzi agents with a dual mechanism of action, oxidative stress and inhibition of membrane sterol biosynthesis. Some of the derivatives were found to have high and selective activity against the proliferative stages of the parasite, with IC50 values against the clinically relevant intracellular amastigote forms in the low micromolar tosub-micromolar range. Oxidative stress was veriﬁed measuring cyanide dependent respiration. Inhibition of the de novo sterol biosynthesis at the level of squalene epoxidase was conﬁrmed, using high-resolution gas– liquid chromatography coupled to mass spectrometry, by the disappearance of the parasite’s mature sterols and the concomitant accumulation of squalene. The in vitro activities of thesenovel compounds were superior to that of nifurtimox, a nitrofuran currently used in the treatment of human Chagas’ disease, and terbinaﬁne, a commercially available allylamine-based squalene epoxidase inhibitor. The results support further in vivo studies of some of these nitrofuran derivatives. Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction Chagas’ disease remains the major parasiticdisease burden in Latin America, despite recent advances in the control of its vectorial and transfusional transmission.1–3 Chemotherapy to control this parasitic infection remains unsatisfactory, despite signiﬁcant progress in our understanding of the biochemistry and physiology of its etiological agent, Trypanosoma cruzi (T. cruzi),4,5 which has resulted in the validation of several metabolicsteps essential for parasite survival as potential chemotherapeutic targets.5,6 Current speciﬁc treatments are based on old and quite unspeciﬁc drugs, associated with long-term treatments that may give rise to severe side effects. In fact, although nifurtimox (Nfx, Fig. 1) and Benznidazole (Bnz), the only two drugs available for clinical treatment of this disease, are able to eliminate patentparasitemia and to reduce serological titers in acute
Keywords: Heteroallyl nitrofuranes; Oxygen redox cycling; Sterol biosynthesis inhibitors; Squalene epoxidase; Anti-T. cruzi compounds. * Corresponding authors. Tel.: +598 2 525 86 18; fax: +598 2 525 07 49; e-mail addresses: firstname.lastname@example.org; email@example.com 0968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.bmc.2007.07.031
Figure 1. Benznidazole, nifurtimox and terbinaﬁne. Structural targets used in the design of the new series of molecules.
and early chronic infections, they are not active against all T. cruzi strains and have signiﬁcantly lower eﬃcacy in long-term chronic infections.5,6 Both drugs act via the reduction of the nitro group. In the case of Nfx, reduction generates an unstablenitro anion radical which produces highly toxic reduced oxygen species, whereas Bnz involves covalent modiﬁcation of macromolecules by nitro reduction intermediates.7 The side eﬀects of these drugs result from the oxidative
A. Gerpe et al. / Bioorg. Med. Chem. 16 (2008) 569–577
or reductive damage in the host’s tissues and are thus inextricably linked to its anti-parasitic activity....