Studies on the trypanocidal activity of semi-synthetic pyran[b-4,3]naphtho[1,2-d]imidazoles from β-lapachone

Moura, Kelly C. G. de; Salomão, Kelly; Menna-Barreto, Rubem F.S.; Emery, Flávio da Silva; Pinto, Maria do Carmo F. R.; Pinto, Antônio V.; Castro, Solange L. de

doi:10.1016/j.ejmech.2004.02.015

Cited by 68 publications

(18 citation statements)

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“…Several classes of compounds were synthesized from β-lapachone, and among them, the naphthoimidazoles N1, N2 and N3 presented the highest activity against T . cruzi [12,15,16] in terms of efficacy against the three forms of the parasite [13,14]. …”

Section: Discussionmentioning

confidence: 99%

“…The naphthoimidazoles were obtained from a reaction of β-lapachone with aromatic aldehydes in the presence of ammonium acetate and acetic acid, leading to 4,5-dihydro-6,6-dimethyl-6H-2-(phenyl)-pyran[ b -4,3]naphth[1,2-d]imidazole) (N1), 4,5-dihydro-6,6-dimethyl-6H-2-(3´-indolyl)-pyran[ b -4,3]naphth[1,2-d]imidazole (N2) and 4,5-dihydro-6,6-dimethyl-6H-2-(4´-methylphenyl)-pyran[ b -4,3]naphth[1,2-d]imidazole) (N3), as previously described [12,15,16]. …”

Section: Methodsmentioning

confidence: 99%

“…Among all the screened compounds, three naphthoimidazoles derived from β-lapachone N1, N2 and N3 (Fig 1) were the most promising [12–16]. The mechanisms of action of N1, N2 and N3 were previously assessed by cell biology techniques, and they exhibited cell cycle blockage, the inhibition of succinate cytochrome c reductase activity in epimastigotes as well as ultrastructural evidence of mitochondrial swelling, the abnormal condensation of nuclear chromatin, kinetoplast disruption and plasma membrane blebbing in bloodstream trypomastigotes.…”

Section: Introductionmentioning

confidence: 99%

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Differential Gel Electrophoresis (DIGE) Evaluation of Naphthoimidazoles Mode of Action: A Study in Trypanosoma cruzi Bloodstream Trypomastigotes

et al. 2016

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BackgroundThe obligate intracellular protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a neglected illness affecting millions of people in Latin America that recently entered non-endemic countries through immigration, as a consequence of globalization. The chemotherapy for this disease is based mainly on benznidazole and nifurtimox, which are very efficient nitroderivatives against the acute stage but present limited efficacy during the chronic phase. Our group has been studying the trypanocidal effects of naturally occurring quinones and their derivatives, and naphthoimidazoles derived from β-lapachone N1, N2 and N3 were the most active. To assess the molecular mechanisms of action of these compounds, we applied proteomic techniques to analyze treated bloodstream trypomastigotes, which are the clinically relevant stage of the parasite.Methodology/Principal FindingsThe approach consisted of quantification by 2D-DIGE followed by MALDI-TOF/TOF protein identification. A total of 61 differentially abundant protein spots were detected when comparing the control with each N1, N2 or N3 treatment, for 34 identified spots. Among the differentially abundant proteins were activated protein kinase C receptor, tubulin isoforms, asparagine synthetase, arginine kinase, elongation factor 2, enolase, guanine deaminase, heat shock proteins, hypothetical proteins, paraflagellar rod components, RAB GDP dissociation inhibitor, succinyl-CoA ligase, ATP synthase subunit B and methionine sulfoxide reductase.Conclusion/SignificanceOur results point to different modes of action for N1, N2 and N3, which indicate a great variety of metabolic pathways involved and allow for novel perspectives on the development of trypanocidal agents.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential Gel Electrophoresis (DIGE) Evaluation of Naphthoimidazoles Mode of Action: A Study in Trypanosoma cruzi Bloodstream Trypomastigotes

et al. 2016

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“…Since the 90s, our group has been studying the anti- T. cruzi activity of this class of chemicals [114]. An initial screening was performed on 60 derivatives obtained through the reaction of several naphthoquinones with common reagents from heterocyclic chemistry, leading to 14 oxazolic, 30 imidazolic, and 10 other related heterocyclic compounds [115–119]. Comparing the activity of the original naphthoquinones and their derivatives, we concluded that minor structural features involved with an increase in lipophilicity, such as the furane moiety, the presence of a methoxyl group, and an aliphatic side chain, led to an increase in the effect on T. cruzi .…”

Section: Parasite Targets and Lead Compounds For New Drugsmentioning

confidence: 99%

“…As shown for naphthoquinones, a lipophilic characteristic, introduced by this appendage, and the presence of a methoxyl or a phenyl group increased the trypanocidal activity. A characteristic of the synthesised naphthoimidazoles was that most of them had aromatic groups containing electron-releasing or electron-withdrawing groups attached to the imidazole ring, and the most active compounds against T. cruzi were obtained from β -lapachone (see Section 2.3) [115, 119]. …”

Section: Parasite Targets and Lead Compounds For New Drugsmentioning

confidence: 99%

Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

Castro

Batista

et al. 2011

Molecular Biology International

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Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

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