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Second Generation of 2H-Benzimidazole 1,3-Dioxide Derivatives As Anti-Trypanosomatid Agents: Synthesis, Biological Evaluation, and Mode of Action Studies

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Second Generation of 2H-Benzimidazole 1,3-Dioxide Derivatives As Anti-Trypanosomatid Agents: Synthesis, Biological Evaluation, and Mode of Action Studies ARTICLE IN PRESS European Journal of Medicinal Chemistry xxx (2009) 1–8 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Original article Second generation of 2H-benzimidazole 1,3-dioxide derivatives as anti-trypanosomatid agents: Synthesis, biological evaluation, and mode of action studies Mariana Boiani a, Lucı´a Boiani a, Alicia Merlino a, Paola Herna´ndez a, Agustina Chidichimo b, Juan J. Cazzulo b, Hugo Cerecetto a,*, Mercedes Gonza´lez a,* a Departamento de Quı´mica Orga´nica, Facultad de Ciencias-Facultad de Quı´mica, Universidad de la Repu´blica, Igua 4225, 11400 Montevideo, Uruguay b Instituto de Investigaciones Biotecnolo´gicas, Universidad Nacional de General San Martı´n-CONICET, 1650 San Martı´n, Buenos Aires, Argentina article info abstract Article history: Exploring the influence of different substitution patterns of 2H-benzimidazole 1,3-dioxide derivatives Received 2 May 2009 (BzNO) we prepared fifteen new derivatives. Initially the BzNO were tested against Trypanosoma cruzi Received in revised form Tulahuen 2 strain epimastigote form rendering very potent anti-T. cruzi agents. Moreover, the BzNO were 3 June 2009 able to inhibit the growth of virulent and resistant to Benznidazole strains (CL Brener clone, Colombiana, Accepted 4 June 2009 and Y strains) and to Leishmania braziliensis. Interestingly, BzNO exhibited very high selectivity index and Available online xxx particularly the spiro-BzNO 13 provokes an important diminution of amastigotes in Vero cells. Besides, it was found a diminution of acetate and glycine as excreted metabolites but without increase of parasite Keywords: 2H-Benzimidazole 1,3-dioxide glucose uptake indicating that the glycosome is probably not involucrate in the 2H-benzimidazole 1,3- Chagas disease dioxides mechanism of action. Leishmaniasis Ó 2009 Elsevier Masson SAS. All rights reserved. Mitochondrial dehydrogenases 1. Introduction other tissues. Drugs currently used in the treatment of Chagas’ disease are two nitroaromatic heterocycles, Nifurtimox (Nfx, Parasitic diseases affect hundreds of millions people around the LampitÒ, recently discontinued by Bayer) and Benznidazole (Bnz, world, mainly in underdeveloped countries. Since parasitic RochaganÒ, Roche), introduced empirically over three decades ago protozoa are eukaryotic, they share many common features with [2]. Both drugs are active in the acute phase of the disease but its their mammalian host making the development of effective and efficacy is very low in the established chronic phase. What is more, selective drugs a hard task. Diseases caused by Trypanosomatidae, differences in drug susceptibility among different T. cruzi strains which share a similar state regarding drug treatment, include lead to varied parasitological cure rates according to the Chagas’ disease (Trypanosoma cruzi, T. cruzi) and leishmaniasis geographical area [3]. (Leishmania spp.) [1]. These trypanosomatids alone are responsible The drugs of choice for the treatment of leishmaniasis are sodium for an infected population of nearly 30 millions and more than 400 stibolgluconate (PentostamÒ), meglumine antimoniate (Glu- millions are at risk. T. cruzi presents three main morphological cantimeÒ), pentamidine and liposomal amphotericin B, but these forms in a complex life cycle. The epimastigote form replicates sometimes meet with failure [4]. Currently, WHO/TDR develops within the crop and midgut of Chagas’ disease vectors as, it is a research program with Miltefosine (Mtf), a very promising leish- released with the insect excrements as the non-dividing highly manocidal drug [5]. These awful illnesses, associated to poverty, infective metacyclic trypomastigotes that invade mammalian does not attract the pharmaceutical companies as a result of the lack tissues via wounds provoked by blood sucking action. The parasite of commercial motives; consequently, efforts to develop new and multiplies intracellularly as amastigote form which is released as safer drugs have to be carried out mainly by academic institutions. the non-dividing bloodstream trypomastigote form that invades Extensive work, in the last two decades, has helped to under- stand the molecular basis of the antichagasic activity of Nfx and Bnz. Nfx mode of action is via the reduction of the nitro group to a nitroanion radical, and for Bnz it is postulated to act via inter- * Corresponding authors. Tel.: þ598 2 525 86 18x216; fax: þ598 2 525 07 49. E-mail addresses: [email protected] (H. Cerecetto), [email protected] mediates that covalently modify bio-macromolecules [6]. Most (M. Gonza´lez). frequent side effects of these drugs include anorexia, vomiting, 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.06.014 Please cite this article in press as: M. Boiani et al., Second generation of 2H-benzimidazole 1,3-dioxide derivatives as..., European Journal of Medicinal Chemistry (2009), doi:10.1016/j.ejmech.2009.06.014 ARTICLE IN PRESS 2 M. Boiani et al. / European Journal of Medicinal Chemistry xxx (2009) 1–8 peripheral polyneuropathy and allergic dermopathy that are 2. Methods and results probably a result of oxidative or reductive damage to the host’s tissue and are thus inextricably linked to its antiparasitic activity 2.1. Chemistry [2]. However, it has been pointed out that drugs that produce oxidative stress by redox cycling may be selective, as long as they 2H-Benzimidazole 1,3-dioxide derivatives were obtained by are selectively reduced by oxidoreductases that are unique to the a simple and efficient general approach using the reaction of the parasite [7]. The same could be said for drugs that produce corresponding benzofuroxan analogues with nitroalkanes [12]. reductive damage such as Bnz. Following this reasoning, we have BzNO derivatives 8–22 were obtained in moderate to good yields by been looking for less toxic and more selective antichagasic drugs by reaction of the benzofuroxan [8] with the corresponding nitroalkane using an N-oxide moiety as the bioreductive group. Thus, benzo- in basic media at room temperature (Scheme 1). The corresponding furoxan (Bfx) derivatives (benzo[1,2-c]1,2,5-oxadizole N-oxide) benzofuroxan derivatives were prepared as previously described were described for the first time as in vitro anti-T. cruzi agents. [8a,8h]. 2-Nitropropane and nitrocyclopentane are commercially These Bfx displayed activities similar or higher than the reference available however 2-nitroheptane or 2-nitro-1-(substituted phe- drugs Nfx and Bnz (i.e. 1–3, Fig. 1) [8]. In order to study other N- nyl)propanes were prepared using nitroaldolic/reduction two-step oxide containing heterocycle we analyzed quinoxaline N,N0-dioxide procedure previously described [13]. Derivatives 8–22 are soluble in system finding derivatives that displayed very good anti-T. cruzi different organic solvents (hexane, chloroform, and acetone) as well activities, like compound 4 (Fig. 1) [9]. We also investigated as in water. All of the proposed structures were established by 1H-, different series of benzimidazole N-oxides [10] resulting 2H- 13C NMR (HMQC, HMBC) spectroscopy and MS. The purity was benzimidazole 1,3-dioxide, BzNO (i.e. 5–7, Fig. 1), the most in vitro established by TLC and microanalysis. active derivatives against to T. cruzi and Leishmania spp. Further- more, these derivatives posses in vivo activity and add to Lipinski’s 2.2. Biological characterization rules of five, have adequate topological polar surface areas, and excellent solubility in water turning them into promising candi- 2.2.1. In vitro anti-T. cruzi activity dates for drug development [11]. The new 2H-benzimidazole 1,3-dioxide derivatives were In the context of our research on the 2H-benzimidazole 1,3- initially tested in vitro against the epimastigote form of T. cruzi, dioxides pharmacochemistry, new derivatives were designed in Tulahuen 2 strain. The existence of the epimastigote form of T. cruzi order to explore the biological effects of these structural changes in as an obligate mammalian intracellular stage has been revisited and parent compounds 5–7. The new BzNO were biological evaluated confirmed [14]. The compounds were incorporated into the media against different T. cruzi strains and against Leishmania protozoa. at 25 mM and their ability to inhibit growth of the parasite was The new BzNO were obtained by modifications on positions 5 and 6 evaluated in comparison to the control (no drug added to the (series a, Fig. 1). Moieties present in parent compounds 1–4 where media) at day 5. The ID50 doses (50% inhibitory dose) were deter- used to study its effects in the 2H-benzimidazole system. In addi- mined for all of them (Table 1). Nfx and Bnz were used as the tion, position 2 modifications were planned. Firstly, 2,2-dimethyl reference trypanocidal drug. Parent compounds, 5–7, and deriva- substituents are incorporated in a cyclic structure (series b, spiro tives 8, and 12–20, were selected to study against the high virulent derivatives, Fig. 1) and secondly, one of the 2-methyl substituent is [15] CL Brener clone and the Nfx- and Bnz-partially resistant changed by arylic or alkylic moiety (series c, Fig. 1). Additionally we strains, Y and Colombiana strains [16]. In these last assays viability studied some parasites biochemical changes promoted by 2H- of T. cruzi, at day 5, was assessed colorimetrically using MTT (3-[4,5- benzimidazole 1,3-dioxides, i.e. effects on the mitochondrion dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay dehydrogenase, on the glucose uptake, and on the excreted [17]. For each derivative, the percentage of cytotoxicity (PCyt) was metabolites, trying to assess the mode of action. initially determined at 25 mM as it is indicated in Experimental Section and then in a doses-response assay, between 1.0 and 50.0 mM, the ID50 concentration was calculated (Table 2). R1 Parent compound 7 and derivatives 13, and 16 were also eval- O O uated, between 10.0 and 50.0 mM, against the bloodstream form of Cl N S R2 N T.
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