Design, synthesis and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis

RAVASCHINO, ESTEBAN LUIS; DOCAMPO, ROBERTO; RODRIGUEZ, JUAN BAUTISTA

Canela, RS, Brasil

Congreso; 11th Brazilian Meeting on Organic Synhesis; 2005

The Brazilian Chemical Society

INTRODUCTION   American trypanosomiasis (Chagas' disease) is a major infectious disease that affect around 18 million individuals.1 Chemotherapy for the treatment of this disease is still deficient; therefore, efforts have been conducted in the search for new molecular targets, which led to the development of more specific drugs against its etiological agent: the protozoan Trypanosoma cruzi. In this context, trypanothione biosynthesis provides a very interesting molecular target: trypanothione synthase  (TryS). This enzyme, which is unique in parasites of the order Kinetoplastida, catalyzes the last step of trypanothione biosynthesis and it is not present in mammals.2 The uniqueness of this enzyme makes it specially attractive for the developement of highly selective inhibitors of the corresponding enzymatic activity.   RESULTS AND DISCUSSION   In this work, we report the synthesis and biological evaluation of a set of phosphinopeptides structurally related to glutathion. These compounds, where a phosphinic acid moiety replaces the respective terminal carboxylate, mimic the tetrahedral transition state of TryS, a typical C:N ligase3 (Figure 1). Figure 1. Phosphinopeptides designed as enzymatic inhibitors of trypanothione synthase.     All of these compounds have been prepared using a convergent synthetic approach, and were characterized by 1H, 13C and 31P NMR, and ESI-HMRS. The pharmacological action for these phosphinopeptides have been carried out in in vitro assays against the epimastigote and amastigote forms of T. cruzi. The cellular activity exhibited by these compounds against T. cruzi was exceptionally encouraging. For example, compounds 4, 5, 6 and 7, were very effective agaisnt amastigotes, the clinically more relevant form of the parasite. In addition, these showed no toxic effect against mammalian cells.   CONCLUSION   Seven phosphinopeptides have been synthesized, characterized and biologically evaluated against T. cruzi. The potency of compound 5 was comparable with that found by a well-known antiparasitic agent 4-phenoxyphenoxyethylthiocyanate (WC-9).4  The phosphinopeptide skeleton here presented constitutes a simple pharmacophore that will be useful for the design of new and safe drugs.   ACKNOWLEDGMENTS   This work was supported by grants from the European Commission INCO-DC, Fundación Antorchas, CONICET, and the Universidad de Buenos Aires to J.B.R., and the Illinois Governor's Venture Technology Program to R.D.   [1] Moncayo, A. In: Eleventh Programme Report of the UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR). World Health Organization: Geneva, 1995, pp. 67–75. 2 Fairlamb, A.H. Annu. Rev. Microbiol. 1992, 46, 695. 3 Chen, S; Coward, J. K. J.Org. Chem, 1998, 63, 502. 4 Cinque, G; Szajnman,  S. H.; Zhong, L; Docampo, R;  Schvartzapel, A. J.; Rodriguez, J. B.; Gros, E.G. J. Med. Chem. 1998, 41, 1540.