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Background: Near to 5-7 million people are infected with T. cruzi in the world, and about 10,000 people per year die of problems associated with this disease. Method: Herein, the synthesis, antitrypanosomal and antimycobacterial activities of seventeen coumarinic N-acylhydrazonic derivatives have been reported. Results: These compounds were synthesized using methodology with reactions global yields ranging from 46%-70%. T. cruzi in vitro effects were evaluated against trypomastigote and amastigote, forming M. tuberculosis activity towards H37Rv sensitive strain and resistant strains. Discussion: Against T. cruzi, the more active compounds revealed only moderate activity IC50/96h~20 μM for both trypomastigotes and amastigotes intracellular forms. (E)-2-oxo-N'- (3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide showed meaningful activity in INH resistant/RIP resistant strain. Conclusion: These compound acting as multitarget could be good leads for the development of new trypanocidal and bactericidal agents.

Ortho-Quinones represent a special class of redox active compounds associated with a spectrum of pronounced biological activities, including selective cytotoxicity and antimicrobial actions. The modification of the quinone ring by simple nitrogen and sulphur substitutions leads to several new classes of compounds with their own, distinct redox behaviour and equally distinct activities against cancer cell lines and Trypanosoma cruzi. Some of the compounds investigated show activity against T. cruzi at concentrations of 24.3 and 65.6 μM with a selectivity index of around 1. These results demonstrate that simple chemical modifications on the ortho-quinone ring system, in particular, by heteroatoms such as nitrogen and sulphur, transform these simple redox molecules into powerful cytotoxic agents with considerable “potential”, not only in synthesis and electrochemistry, but also, in a broader sense, in health sciences.

In this paper, we describe the synthesis and the action against of the trypomastigote form of Trypanosoma cruzi of a new class of nitroimidazole-2-carbaldehyde O-benzyloximes. These derivatives were designed through the application of molecular hybridization concept between two potent antiprotozoal compounds, the 5-nitrothiophene-2-carbaldehyde O-oxime 6 and the trypanocidal piperidinyl-4-carbaldehyde O-benzyloxime 7 with the intention of reaching two distinct molecular targets of T. cruzi. The activity of these benzyl ether derivatives was tested against the infective trypomastigote forms of T. cruzi, and the derivative (E)-1-methyl-5-nitro-1H-imidazole-2-carbaldehyde O-(4-nitrobenzyl) oxime (1) presented moderate trypanocidal activity (IC50 = 12.7 μM) when compared with the standard drug benznidazole, which showed to be a good starting point for the design of more effective trypanocide agents.

Phenazinic ligands and Ru(II)-based complexes were synthesized from natural products lapachol and lawsone and evaluated against T. cruzi, the etiological agent of Chagas disease. These new ruthenium compounds could provide promising trypanocidal drugs. Besides synthesis and trypanocidal activity, this paper reports photophysical features and computational details of the compounds. The fluorescent trypanocidal substances are promising derivatives for further studies aiming to find molecules active against parasites associated with neglected diseases.

The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 ¼ 5.4 mM) and amastigote (IC50 ¼ 12.0 mM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 ¼ 8.8 and 8.7 mM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11 were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size and p-p interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzinitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our design strategy was capable of generating novel and active Bnz analogs.

BACKGROUND Only benznidazole (Bnz) (1) and nifurtimox (Nfx) (2) are licensed for the treatment of Chagas disease although their safety and efficacy profile are far from ideal. Farmanguinhos from Fiocruz has developed seven nitroimidazole compounds (4-10) analogs of megazol (3). OBJECTIVES To evaluate whether the genotoxic effect of 3 was abolished in the seven nitroimidazoles (4-10) analogs using the in vitro alkaline comet assay (CA) and the in vitro cytokinesis-block micronucleus assay (CBMN) in whole human blood cells (WHBC) and correlate this effect with their trypanocidal activity using bloodstream trypomastigote forms of Trypanosoma cruzi. METHODS The toxicity of 3-10 to WHBC in the in vitro CA was determined using the fluorescein diacetate/ethidium bromide assay. DNA damage in the in vitro CA was evaluated according to tail size in four classes (0-3) and methyl methane-sulfonate (MMS) was used as a positive control. The cytotoxicity of 3-10 to WHBC in the CBMN was measured using the cytokinesis-block proliferation index and the replication index. The number of the micronucleate cells in 2,000 binucleate cells by experimental group was determined. Mitomycin C and N-deacetyl-N-methylcolchicine were used as positive controls. FINDINGS Compound 3 showed a significant DNA strand break effect through the in vitro CA and highly significant clastogenic and/or aneugenic effect in the CBMN. Compounds 5, 6, 8, 9 and 10 showed negative results in the CBMN and positive results in the in vitro CA, while the inverse effect was observed for 4 and 7. MAIN CONCLUSIONS Compound 10 was the most promising to proceed with the development as a drug candidate in the treatment of Chagas disease showing absence of chromosomal cytogenetic damage and high activity against T. cruzi, about two times higher than 3 and the clinical drug 1.

Naphthoquinones are of key importance in organic synthesis and medicinal chemistry. In the last few years, various synthetic routes have been developed to prepare bioactive compounds derived or based on lapachones. In this sense, this review is mainly focused on the synthetic aspects and strategies used for the design of these compounds on the basis of their biological activities for the development of drugs against the neglected diseases leishmaniases and Chagas disease and also cancer. Three strategies used to develop bioactive quinones are discussed and categorized: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Framed within these strategies for the development of naphthoquinoidal compounds against T. cruzi. Leishmania and cancer, reactions including copper-catalyzed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, C-H activation reactions, Ullmann couplings and heterocyclisations reported up to July 2019 will be discussed. The aim of derivatisation is the generation of novel molecules that can potentially inhibit cellular organelles/processes, generate reactive oxygen species and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against leishmaniases, Chagas disease and cancer.

Background:: Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes. Objective:: We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi. Methods: These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole. Results:: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 μM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 μM), which were almost equipotent to benznidazole (IC50=10.26 μM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice. Conclusion:: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.

Quinonoid compounds based on 5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles were synthesized using simple methodologies and evaluated against T. cruzi, the etiological agent of Chagas disease, and cancer cell lines PC3, HCT-116, HL-60, MDA-MB-435 and SF-295. The cytotoxic potential of the lapachones was also assayed against peripheral blood mononuclear cells (PBMC). Two compounds 6 and 12 were identified as potential hits against T. cruzi. β-Lapachone-based 1,5-disubstituted-1,2,3-triazole (12) displayed an IC50/24 h = 125.1 μM, similar to benznidazole, the standard drug. Compound 12 was also more active than the precursor β-lapachone against the cancer cell lines. These compounds acting as multitarget quinoidal systems could provide promising new leads for the development of trypanocidal and/or anticancer drugs.

Background: Approximately, 5-7 million people are infected with T. cruzi in the world, and approximately 10,000 people per year die of complications linked to this disease. Method: This work describes the construction of a new family of hidrazonoyl substituted derivatives, structurally designed exploring the molecular hybridization between megazol and nitrofurazone. Results and Discussion: The compounds were evaluated for their in vitro activity against bloodstream trypomastigotes of Trypanosoma cruzi, etiological agent of Chagas disease, and for their potential toxicity to mammalian cells. Conclusion: Among these hydrazonoyl derivatives, we identified the derivative (4) that showed trypanocidal activity (IC50/24 h = 15.0 µM) similar to Bz, the standard drug, and low toxicity to mammalian cells, reaching an SI value of 18.7.

We report herein a straightforward and efficient one-step reaction to prepare new nor-β-lapachone derivatives tethered with phenylthio groups at position 3 of the furan ring. We have screened the compounds 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 (IC50/24h from 9.2 to 182.7 μM), higher than the original quinone (391.5 μM) and four of them higher than standard drug benznidazole (103.6 μM). The most active was compound 13b (9.2 μM), being 11 times active than benznidazole and the less toxic derivative to heart muscle cells.

Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and cytotoxic properties have been attributed to the presence of the nitro group. However, we synthesised nitroimidazoles with activity against the trypomastigotes of Trypanosoma cruzi, but that were not genotoxic. Herein, nitroimidazoles (11-19) bearing different substituent groups were investigated for their potential induction of genotoxicity (comet assay) and mutagenicity (Salmonella/Microsome assay) and the correlations of these effects with their trypanocidal effect and with megazol were investigated. The compounds were designed to analyse the role played by the position of the nitro group in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable groups at N-1 as an anion receptor group and the role of a methyl group at C-2. Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to those bearing NO 2 at C-5. However, when there was a CH3 at C-2, the position of the NO2 group had no influence on the genotoxic activity. Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3 at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4-NO2; N-CH2OHCH2Cl) and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on genotoxicity. This study contributes to the future search for new and safer prototypes and provide.

In our continued search for novel trypanocidal compounds, arylamine, chalcone, triazolic, triazole– carbohydrate and chalcogenium derivatives containing a naphthoquinone scaffold were prepared; in addition to electrochemical studies, these compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Among the thirty-eight compounds herein evaluated, six were found to be more potent against trypomastigotes than the standard drug benznidazole, with IC50/24 h values between 52.9 and 89.5 mM.

Thirty four halogen and selenium-containing quinones, synthesized by rhodium-catalyzed C-H bond activation and palladium-catalyzed cross-coupling reactions, were evaluated against bloodstream trypomastigotes of T. cruzi. We have identified fifteen compounds with IC50/24 h values of less than 2 μM. Electrochemical studies on A-ring functionalized naphthoquinones were also performed aiming to correlate redox properties with trypanocidal activity. For instance, (E)-5-styryl-1,4-naphthoquinone 59 and 5,8-diiodo-1,4-naphthoquinone 3, which are around fifty fold more active than the standard drug benznidazole, are potential derivatives for further investigation. These compounds represent powerful new agents useful in Chagas disease therapy.

Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC50 = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC50, being considered a good starting point for the development of new anti-Chagas drug candidates.

The biological activities of the naphthoquinones lapachol and its cyclization product beta-lapachone, extracted from trees of the genus Tabebuia, have been intensively studied. Given continuity to the studies about heterocyclic derivatives obtained from the reaction of these naphtoquinones with amino-containing reagents, 22 derivatives of beta-lapachone, nor-beta-lapachone and lapachol were synthesised and their activities against trypomastigote forms of T. cruzi were evaluated. The compounds were grouped as oxazolic, imidazolic, phenoxazinic, indolic, pyranic and cyclopentenic derivatives. The variability of the new structures is based on the great electrophilicity of 1,2-quinoidal carbonyls towards reagents containing nitrogen or carbon as nucleophilic centres. In relation to the trypanocidal activity of the synthesised compounds, in view of their structural diversity, tendencies only could be verified. Among the cyclofunctionalised products the oxazolic and imidazolic derivatives showed +/- 1.5 to 34.8 times higher activity than crystal violet, the standard drug for the sterilization of stored blood. These results corroborate the tendency of trypanocidal activity in imidazolic skeletons, and indicate that this moiety could be used as a guide for architectural delineation of molecules with potential value for the chemotherapy of Chagas disease.

Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major “neglected” diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives.

In continuing our screening program of naphthoquinone activity against Trypanosoma cruzi, the aetiological agent of Chagas' disease, new beta-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-beta-lapachones, 3-alkoxy-nor-beta-lapachones and imidazole anthraquinones were synthesised and evaluated against bloodstream trypomastigote forms of the parasite. Compounds 2,2-dimethyl-3-(2,4-dibromophenylamino)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, IC(50)/24h 24.9+/-7.4 and 4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione with 23.4+/-3.8 microM showed a trypanosomicidal activity higher than benznidazole. These results demonstrate the potential of naphthoquinone derivatives as novel structures for the development of alternative drugs for Chagas' disease.

Despite ongoing efforts, the current treatment for Chagas disease is still unsatisfactory, mainly because of the severe side effects and variable efficacy of the available nitroheterocycles. Our group has been assaying natural quinones isolated from Brazilian flora, and their derivatives, as alternative chemotherapeutic agents against Trypanosoma cruzi. From C-allyl lawsone three naphthofuranquinones were synthesized, which were active against trypomastigotes and epimastigotes. Here, we further investigated the activity and the mechanisms of action of these quinones. They exhibited powerful effects on intracellular amastigotes, presenting low toxicity to the host cells. Ultrastructural analyses of treated epimastigotes and trypomastigotes indicated a potent effect of the three naphthofuranquinones on the parasite mitochondrion, which appeared drastically swollen and with a washed-out matrix profile. Fluorescence-activated cell sorting analysis of rhodamine 123-stained T. cruzi showed that the three naphthofuranquinones caused a potent dose-dependent collapse of the mitochondrial membrane potential, especially in the epimastigote form. Naphthofuranquinones also decreased specifically mitochondrial complex I–III activity in both epimastigotes and trypomastigotes, parallel to a reduction in succinate-induced oxygen consumption. Mitochondrial hydrogen peroxide formation was also increased in epimastigotes after treatment with the naphthofuranquinones. Our results indicate that the trypanocidal action of the naphthofuranquinones is associated with mitochondrial dysfunction, leading to increased reactive oxygen species generation and parasite death.

Megazol is a highly active compound against Trypanosoma cruzi, and has become a core structure for the design of new trypanocidal agents. Recently, we have identified the new potent trypanocide agent Brazilizone A, which presents an IC(50) twofold more potent than the prototype megazol. This result has encouraged us to further explore structurally-related 1,3,4-thiadiazole-2-arylhydrazone derivatives, in order to get a better understanding of their structural and antiprotozoal activity relationships. Herein we report the synthesis and trypanocidal profile of thirteen new Brazilizone A analogues, which supported the construction of 3D-QSAR models used for its structural optimization.

The chemical composition of ethanol extracts from samples of Brazilian propolis (EEPs) determined by HPLC and their activity againstTrypanosoma cruzi,Staphylococcus aureus,Streptococcus pneumoniae,Klebisiella pneumoniae,Candida albicans,Sporothrix schenckiiandParacoccidioides brasiliensiswere determined. Based on the predominant botanical origin in the region of samples' collection, the 10 extracts were separated into three groups: A (B. dracunculifolia+Auraucariaspp), B (B. dracunculifolia) and C (Araucariaspp). Analysis by the multiple regression of all the extracts together showed a positive correlation, higher concentrations leading to higher biological effect, ofS. aureuswithp-coumaric acid (PCUM) and 3-(4-hydroxy-3-(oxo-butenyl)-phenylacrylic acid (DHCA1) and of trypomastigotes ofT. cruziwith 3,5-diprenyl-4-hydroxycinnamic acid derivative 4 (DHCA4) and 2,2-dimethyl-6-carboxyethenyl-2H-1-benzopyran (DCBEN). When the same approach was employed for each group, due to the small number of observations, the statistical test gave unreliable results. However, an overall analysis revealed for group A an association ofS. aureuswith caffeic acid (CAF) and dicaffeoylquinic acid 3 (CAFQ3), ofS. pneumoniaewith CAFQ3 and monocaffeoylquinic acid 2 (CAFQ2) and ofT. cruzialso with CAFQ3. For group B, a higher activity againstS. pneumoniaewas associated DCBEN and forT. cruziwith CAF. For group C no association was observed between the anitmicrobial effect and any component of the extracts. The present study reinforces the relevance of PCUM and derivatives, especially prenylated ones and also of caffeolyquinic acids, on the biological activity of Brazilian propolis.

L-Amino acid methyl esters, such as L-leucine methyl ester (Leu-OMe), have been identified as agents targeting the lysosomal system of Leishmania amazonensis amastigotes, by a mechanism that involves ester hydrolysis by parasite enzymes located inside megasomes. We have here analyzed the effect of Leu-OMe on all three evolutive forms of Trypanosoma cruzi, in a search for potential targets of the compound in this protozoan. Treatment of epimastigote forms resulted in dose-dependent growth inhibition, with IC50/1 day = 0.55 +/- 0.21 mM. Incubation with 4-8mM/1 day led to 100% cell death. Treatment of bloodstream trypomastigotes resulted in cell lysis, with an IC50/1 day = 1.46 +/- 0.16 mM. Furthermore, infected macrophages treated with 0.125-1mM Leu-OMe showed a dose- and time-dependent decrease in the percent of amastigote infection. Morphological changes in macrophages were observed only at concentrations above 8mM, at the third day of treatment. Analysis of treated parasites by transmission electron microscopy demonstrated severe morphological alterations in cell shape, mitochondrion and nucleus, while kinetoplast and reservosomes (pre-lysosomal compartments) appeared to be not affected. Lysis of bloodstream trypomastigotes and intracellular amastigotes indicated that lysosomes of T. cruzi are the main target for the drug, since reservosomes occur only in epimastigote forms. The presence of lysosomes in T. cruzi epimastigotes was demonstrated by using ultrastructural cytochemistry.

Phamacological activities of a standard ethanol extract G1 from Brazilian green propolis, typified as BRP1, was evaluated in mouse models of pain and inflammation. Intraperitoneal injection ( I. P.) of G1 inhibited acetic acid-induced abdominal constrictions with an ID (50) = 0.75 +/- 0.05 mg/kg, and in the formalin test the ID (50) values were 0.85 +/- 0.07 mg/kg and 13.88 +/- 1.12 mg/kg, respectively, for the neurogenic and inflammatory phases. The extract was ineffective when assessed in the hot-plate assay. In serotonin-induced paw edema, G1 led to a maximal inhibition (MI) of 51.6 % after 120 min when administered I. P. and of 36 % after 15 min by the oral route ( O. R.). When the inflammatory agent was complete Freund's adjuvant, inhibition of paw edema was also observed after administration of the extract by both routes. In the capsaicin-induced ear edema the ID (50) values were 1.09 +/- 0.08 mg/kg ( I. P.) and 10.00 +/- 0.90 mg/kg ( O. R.). In the acute carrageenan-induced inflammatory reaction induced by carrageenan, G1 reduced the number of neutrophils in the peritoneal cavity with IC (50) values of 0.72 +/- 0.08 mg/kg and 4.17 +/- 0.50 mg/kg, by I. P. or O. R. administration, with a preferential migration of polymorphonuclear neutrophils. IN VITRO, G1 decreased nitric oxide production in LPS-stimulated RAW 264.7 cells (IC (50) = 41.60 microg/mL), and also the luciferase activity in TNF-alpha-stimulated HEK 293 cells transfected with NF-kappaB-luciferase reporter gene driven by the nuclear factor kappaB (NF-kappaB) (IC (50) = 200 microg/mL). This extract, which at low concentrations induces anti-inflammatory and analgesic effects in mouse models, presents a high content of flavonoids, known to inhibit inducible NOS (iNOS) activity. These data taken together led us to reinforce the hypothesis in the literature that the anti-inflammatory effect of propolis may be a due to inhibition of iNOS gene expression, through interference with NF-kappaB sites in the iNOS promoter.

Received 14 January 2005; returned 15 May 2005; revised 24 May 2005; accepted 7 October 2005Objectives: Investigation of the mode of action of the naphthoimidazole N1, obtained from the reaction ofb-lapachonewithbenzaldehyde,whichamong45semi-syntheticderivativesofnaphthoquinonesisolatedfrom Tabebuia sp. was one of the most active compounds against Trypanosoma cruzi trypomastigotes.Methods: Quantification of the effect of N1 against the proliferative forms of T. cruzi, and investigation ofpotential targets in the parasite using electron microscopy and flow cytometry techniques.Results:N1presentedthefollowingorderofactivity:amastigotes>trypomastigotes>epimastigotes.Theeffectonintracellularformswas 25timeshigherthanonmacrophagesandheartmusclecells.N1-treatedparasites presented an abnormal chromatin condensation and mitochondrial damage. In epimastigotes,alterations of reservosomes were observed, and in trypomastigotes, a decrease in the electron density ofacidocalcisomeswasobserved.Inepimastigotes,thenaphthoimidazoleinhibitedtheactivityofsuccinatecytochrome c reductase. Labelling with rhodamine 123 or Acridine Orange was decreased in both formstreated with N1.Conclusions:Theresultssuggestthatepimastigotes,reservosomes,mitochondrion,andnucleuscontainN1 targets. In trypomastigotes, in which reservosomes are absent, the organelles affected by thecompound were also the mitochondrion and nucleus, as well as acidocalcisomes, in which the decreasein electron density could be due to the use of polyphosphate as an alternative energy supply.Keywords: T. cruzi, chemotherapy, naphthoquinones, parasites

Objectives Investigation of the antiproliferative synergy of the lysophospholipid analogues (LPAs) edelfosine, ilmofosine and miltefosine with the ergosterol biosynthesis inhibitor ketoconazole against Trypanosoma cruzi. Methods The effect of LPAs, ketoconazole and their combination was evaluated against epimastigotes and intracellular amastigotes by the parameter IC50 leading to construction of isobolograms, for determination of a synergic effect. For epimastigotes, ultrastructural damage induced by these treatments was evaluated by transmission and scanning electron microscopy. Results Synergy was confirmed against both epimastigotes and amastigotes of the parasite. Edelfosine or ketoconazole alone induced morphological alterations in the plasma membrane and reservosomes of the parasites, while in combination, they also led to severe mitochondrial damage, formation of autophagic structures and multinucleation. Scanning electron microscopy confirmed the effect at the plasma membrane and also revealed alterations in the shape of the parasites. Conclusions Our results describe the synergic anti-proliferative effect of LPAs and ketoconazole against epimastigotes and intracellular amastigotes and suggest that in epimastigotes, plasma membrane, reservosomes and mitochondria are targets of these drugs, possibly by interference with lipid metabolism.

In this work we reported the synthesis and the trypanocidal profile of new 1,3,4-thiadiazole-2-arylhydrazone derivatives of nitroimidazole series (4) or phenyl series (5), designed by exploring the molecular hybridization approach between megazol (2) and guanyl hydrazone derivative (3). The evaluation of the activity against bloodstream trypomastigote forms of Trypanosoma cruzi forms lead us to identify a new potent trypamomicide prototype, that is, brazilizone A (4k), which present an IC50/24 h=5.3 microM.

Objectives: Analysis of the effect of edelfosine, ilmofosine and miltefosine on Leishmania amazonensis and of potential targets of these lysophospholipid analogues. Methods: Quantification and ultrastructural analysis of the effect of lysophospholipid analogues on promastigote forms and on infected peritoneal macrophages, and flow cytometry analysis of treated promastigotes labelled with propidium iodide and rhodamine 123 (Rh123). Results: The lysophospholipid analogues presented potent antiproliferative activity with IC50/3 days of 1.9‐3.4mM for promastigotes and 4.2‐9.0mM for intracellular amastigotes. Treatment with these analogues in Schneider medium for 1 day led to a dose-dependent decrease in Rh123 fluorescence, an effect more accentuated in edelfosine-treated parasites, suggesting interference with the potential of the mitochondrial membrane. In both forms of L. amazonensis, edelfosine induced extensive mitochondrial damage, multinucleation and, in promastigotes, also led to plasma membrane alterations, formation of autophagic structures and membranous arrangements inside the flagellar pocket. Conclusions: The alkylglycerophosphocholines edelfosine and ilmofosine were more active than the alkylphosphocholine miltefosine against promastigotes and intracellular amastigotes of L. amazonensis, and ultrastructural and flow cytometry data indicate the mitochondrion as a target of edelfosine.

Acetone and ethanol extracts of two Bulgarian propolis samples (Bur and Lov) were investigated by high temperature high resolution gas chromatography coupled to mass spectrometry (HT-HRGC-MS), and their activity against Trypanosoma cruzi was evaluated. The ethanol extracts--Et-Bur and Et-Lov--showed similar composition, with a high content of flavonoids, and strong inhibitory activity against T. cruzi proliferative epimastigotes, which were more susceptible than trypomastigotes. In the presence of blood, the activity of Et-Bur or Et-Lov against trypomastigotes was similar to that of the standard drug, crystal violet. Both extracts also showed similar and significant activity against Staphylococcus aureus and Candida albicans, while being inactive against Escherichia coli. The acetone extract, Ket-Bur, was more active than Et-Bur against both forms of T. cruzi.

Chagasic patients with cardiomyopathy have low levels of selenium (Se), a fundamental trace element. We evaluated the effect of supplementing infected mice with Se (0.25-16 ppm). Supplementation with 0.25 or 1 ppm Se led to parasitaemia and survival curves similar to those of the control group. Mice treated with 4-16 ppm showed a dose-dependent decrease of parasitaemia, significant for the highest concentration. This was probably due to a direct effect on the parasites, which were lysed after in vitro incubation with Se. Survival rates did not change significantly; however, heart damage was reduced in infected mice supplemented with 4 ppm Se, as indicated by a lower cardiac isoform of creatine kinase levels. Our results imply that Se supplementation does not lead to a general protection during infection, but may help protect the heart from inflammatory damage. The effect of Se supplementation in the course of T. cruzi infection depends on the host-parasite pair employed.

Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7.

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Trypanosoma cruzi, the causative agent of Chagas' disease in humans, is an intracellular protozoan parasite with the ability to invade a wide variety of mammalian cells by a unique and remarkable process in cell biology that is poorly understood. Here we present evidence suggesting a role for the host phosphatidylinositol (PI) 3-kinases during T. cruzi invasion. The PI 3-kinase inhibitor wortmannin marked inhibited T. cruzi infection when macrophages were pretreated for 20 min at 37 degrees C before inoculation. Infection of macrophages with T. cruzi markedly stimulated the formation of the lipid products of the phosphatidylinositol (PI) 3-kinases, PI 3-phospate, PI 3,4-biphosphate, and PI 3,4,5-triphosphate, but not PI 4-phosphate or PI 4,5-biphosphate. This activation was inhibited by wortmannin. Infection with T. cruzi also stimulated a marked increase in the in vitro lipid kinase activities that are present in the immunoprecipitates of anti-p85 subunit of class I PI 3-kinase and anti-phosphotyrosine. In addition, T. cruzi invasion also activated lipid kinase activity found in immunoprecipitates of class II and class III PI 3-kinases. These data demonstrate that T. cruzi invasion into macrophages strongly activates separated PI 3-kinase isoforms. Furthermore, the inhibition of the class I and class III PI 3-kinase activities abolishes the parasite entry into macrophages. These findings suggest a prominent role for the host PI 3-kinase activities during the T. cruzi infection process.

Creatine kinase (CK total and CK-MB) were studied as markers of lesion progression induced by Trypanosoma cruzi infection. After 3 weeks mice infected with 10(4) parasites showed an increase in both enzyme levels and in their frequency distribution. A trend to increase was already detected in the 2nd week. A short duration per os treatment with benznidazole (Bz) prevented the occurrence of tissue lesions, since no changes were observed in enzymes. However, in the 4th week, about 40% of Bz-treated mice showed an increase in CK-MB, as did those that survived until the 8th week. Long-term treatment with Bz in drinking water of mice infected with 10(2) parasites showed, after 32 weeks, a partial reversion of the occurrence of high CK-MB levels from 85.7% to 50%. We found a positive correlation between inflammatory infiltrates and CK-MB levels, indicating that this marker could be useful to monitor the occurrence of experimental chagasic myocarditis.

myo-inositol is a growth factor for mammalian cells as well as for the pathogenic protozoa Trypanosoma cruzi. Most of the cell surface molecules in this organism rely on myo-inositol as the biosynthetic precursor for phosphoinositides and glycosylated phosphatidylinositols. The aim of this work was to investigate the process of myo-inositol translocation across the parasite cell membrane. myo-Inositol uptake was concentration-dependent in the concentration range 0.1-10 microM with maximal transport obtained at 8 microM. Using sodium-free buffers, where Na+ was replaced by choline or K+, myo-inositol uptake was inhibited by 50%. Furosemide, an inhibitor of the ouabain-insensitive Na+-ATPase, inhibited the Na+-dependent and Na+-independent myo-inositol uptake by 68 and 33%, respectively. In contrast, ouabain, an (Na++/K+) ATPase inhibitor, did not affect transport. Part of the myo-inositol uptake is mediated by active transport as it was inhibited when energy metabolism inhibitors such as carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (34%), 2,4-dinitrophenol (50%), KCN (71%) and NaN3 (69%) were added to the medium, or the temperature of the medium was lowered to 4 degrees C. The addition of glucose (5-50 mM) or mannose (10 mM) did not change the myo-inositol uptake, whereas the addition of 10 mM nonlabeled myo-inositol totally inhibited this transport, indicating that the transporter is specific for myo-inositol. Phloretin (0.3 mM) and phoridzin (5 mM), but not cytochalasin B, were efficient inhibitors of myo-inositol uptake. A portion of the accumulated myo-inositol is converted to inositol phosphates and phosphoinositides. These data show that myo-inositol transport in T. cruzi epimastigotes is mediated by at least two specific transporters - one Na+-dependent and the other Na+-independent.

Propenamine derivatives 3-(4′-bromo-[1,1′-biphenyl]-4-yl)-3-(4- X -phenyl)- N,N -dimethyl-2-propen-1-amine (where X =H or Br) were tested in experimentally infected mice with Trypanosoma cruzi (Y strain). When a daily dose of 20 mg kg −1 of the bromo ( X =Br) derivative for 9 consecutive days was used, no parasite by optical microscopy was found. Significant parasitemic decrease was also observed with a single dose (100 mg kg −1 ) of this compound. Moreover, both treatment schemes displayed a strong protective effect characterized by decreased of mortality. On the other hand, similar treatment schedules using the unsubstituted ( X =H) derivative led to parasitemic and mortality curves similar to the control group. These results indicate that the bromo derivative has a remarkable activity against T. cruzi infection. Due to the potentiality of this derivative, further investigation of this class of compounds as chemotherapeutic agents for Chagas’ disease is of prime importance.

Naphthoquinones are considered privileged structures in medicinal chemistry due to their structural properties and biological activities. Recently, we have described the synthesis, trypanocidal and leishmanicidal activity of lapachone-based 1,2,3-triazoles. 3 In this context, herein we describe the synthesis and evaluation against T. cruzi of 1,2,3-triazole substituted paraand orthonaphthoquinones.

The available treatment for the prevention and cure of Chagas disease, caused by the protozoan Trypanosoma cruzi, is still unsatisfactory. Thus, there is an urgent need to develop new drugs. In the last few years, our research group has focused on finding a new chemical entity able to target the infectious bloodstream trypomastigotes. In this study, we assayed 16 β-lapachone analogous with modifications in the pyran and aromatic ring to find a new prototype with high trypanocidal activity. Interestingly, two ortho-naphthoquinones presented the best trypanocidal profile (8c and 8d with an IC 50 /24 h of 26.9 ± 1.3 and 23.5 ± 2.5 μM, respectively), which were 4 to 17 times more effective than β-lapachone (391.5 ± 16.5 μM) and the standard drug benznidazole (103.6 ± 0.6 μM). The introduction of a hydroxyl group on the compounds’ aromatic ring modulated their biological profile by increasing their activity not only for cancer cells (MDAMB435), as previously described in literature, but also against T. cruzi. The Structure-Activity Relationship (SAR) study indicated that this introduction modulated HOMO and MEP parameters, improving the trypanocidal activity.

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17–24, 28–30 and 36–38 are described herein for the first time. Three of these novel compounds (28–30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8μM. Analysis of the toxicity to heart muscle cells led to LC50/24h of

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Extracts from different samples of Brazilian propolis were obtained by Soxhlet extraction or maceration at room temperature using ethanol, water, and accombination of both solvents. Analysis of their composition using HPLC revealed that no major differences were seen when a propolis sample was subject to different extraction methods. The activity of the 15 extracts was assayed against bloodstream trypomastigotes of Trypanosoma cruzi, the etiologic agent of Chagas' disease. Multivariate analysis was applied to evaluate the efficiency of the different extracts and the trypanocidal activity. The extracts could be divided into two groups. In the first, in which, extracts were obtained by reflux in Soxhlet using 100% ethanol, there was a lower content of bioactive compounds and consequently lower trypanocidal activity. Extract 136-Et100 stands out in this group, since it had the highest levels of bioactive compounds together with highest activity against the parasite when compared with all other extracts. The second group comprises extracts with intermediate levels of bioactive compounds and higher activity against T. cruzi.

We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action.

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-β-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC(50)/24h values in the range of 10.9-101.5 μM. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies.

The naphthoquinone analogues of β-lapachone are obtained from methylene and aryl o-quinone methides, generated in situ by Knoevenagel condensation of lawsone (I) with paraformaldehyde (II) or aryl aldehydes (IX), followed by hetero Diels—Alder reaction with different dienophiles.

The available chemotherapy for Chagas disease, caused by Trypanosoma cruzi, is unsatisfactory; therefore, there is an intense effort to find new drugs for the treatment of this disease. In our laboratory, we have analyzed the effect on bloodstream trypomastigotes of 16 new naphthoquinone analogues of β-lapachone modified in the pyran ring, aiming to find a new prototype with high trypanocidal activity. The new compounds presented a broad spectrum of activity, and five of them presented IC(50)/24 h in the range of 22-63 μM, whereas β-lapachone had a higher value of 391.5 ± 16.5 μM.

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America, which current treatment presents variable efficacy and serious side effects. A previous screening of naphthoquinone derivatives pointed to the naphthoimidazoles N1, N2 and N3 as the most active compounds against T. cruzi. In this study, a proteomic approach was employed to identify proteins involved in the N1, N2 and N3 trypanocidal activity. In epimastigotes, the naphthoimidazoles are involved in multiple mechanisms: (a) redox metabolism; (b) energy production; (c) ergosterol biosynthesis; (d) cytoskeleton assembly; (e) protein metabolism and biosynthesis; and (f) chaperones modulation. They induce an imbalance in crucial pathways of the parasite, leading to the loss of metabolic homeostasis and T. cruzi death.

In order to elucidate the effect on mammal systems of new derivatives from 2-hydroxy-3-allyl-naphthoquinone, á-iodinated naphthofuranquinone (NPPN-3223), â-iodinated naphthofuranquinone (NPPN-3222) and â-methyl naphthofuranquinone (NPPN-3226) synthesized as possible trypanocidal agents, their effect on rat liver microsomal lipid peroxidation was investigated. They (a) inhibited NADPH-dependent, iron-catalyzed microsomal rat liver lipid peroxidation; (b) did not inhibit the tert-butyl hydroperoxide-dependent lipid peroxidation; (c) did not inhibit ascorbate?lipid peroxidation with the exception of NPPN-3226 which did inhibit it; (d) stimulated NADPH oxidation and microsomal oxygen uptake; (e) increased superoxide anion formation by NADPH-supplemented microsomes and (f) stimulated ascorbate oxidation. The three drugs were reduced to their seminaphthofuranquinone radical by the liver NADPH?P450 reductase system, as detected by ESR measurements. These results support the hypothesis that naphthofuranquinones reduction by microsomal NADPH?P450 reductase and semiquinone oxidation by molecular oxygen diverts electrons, preventing microsomal lipid peroxidation. In addition, hydroquinones and/or semiquinones formed by naphthofuranquinones reduction would be capable of lipid peroxidation inhibition and on interacting with the lipid peroxide radicals can lead to an antioxidant effect as we suggested for NPPN-3226 in close agreement to the inhibition of ascorbate?lipid peroxidation. Due to the properties of these molecules and their incoming structure developments, naphthofuranquinones would be considered as potentially promising therapeutic agents, mainly against Chagas disease. Fil: Elingold, Igal. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Taboas, Melisa Ivana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Casanova, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Galleano, Mónica Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina Fil: Silva, Raphael S.F.. Universidade Federal do Rio de Janeiro; Brasil Fil: Menna Barreto, Rubem F.S.. Fundación Oswaldo Cruz; Brasil Fil: Ventura Pinto, Antonio. Universidade Federal do Rio de Janeiro; Brasil Fil: de Castro, Solange L.. Fundación Oswaldo Cruz; Brasil Fil: Costa, Lidia Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina Fil: Dubin, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina

Naphthoquinones are compounds present in several families of higher plants. Their molecular structures confer redox properties, and they are involved in multiple biological oxidative processes. In folk medicine, especially among Indian populations, plants containing naphthoquinones have been employed for the treatment of various diseases. The biological redox cycle of quinones can be initiated by one electron reduction leading to the formation of semiquinones, unstable intermediates that react rapidly with molecular oxygen, generating free radicals. Alternatively, the reduction by two electrons, mediated by DT-diphorase, leads to the formation of hydroquinone. Lapachol, alpha-lapachone and beta-lapachone, which are isolated from the heartwood of trees of the Bignoniaceae family, are examples of bioactive naphthoquinones. In this review, we will discuss studies investigating the activity of these natural products and their derivatives in the context of the search for alternative drugs for Chagas disease, caused by Trypanosoma cruzi, a neglected illness that is endemic in Latin America.

[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.

New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas’ disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from α-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas’ disease.

[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.