Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives

Villalobos-Rocha, Juan Carlos; Sánchez-Torres, Luvia Enid; Nogueda‐Torres, Benjamín; Segura‐Cabrera, Aldo; García-Pérez, Carlos A.; Bocanegra-García, Virgilio; Palos, Isidro; Monge, Antonio; Rivera, Gildardo

doi:10.1007/s00436-014-3850-8

Cited by 37 publications

(35 citation statements)

References 31 publications

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“…These are promising results, given that both compounds proved to be more selective for intracellular amastigotes than amphotericin B, one of the drugs of choice for the treatment of leishmaniasis (35). Previous studies reported the activities of quinoxaline derivatives against evolutionary forms of Leishmania spp., further attesting to the potential of these compounds (13,(30)(31)(32). On the other hand, the in vitro effects of LSPN329 or LSPN331 in combination with miltefosine indicate that they have indifferent interactions in promastigotes and intracellular amastigotes of L. amazonensis (data not shown).…”

Section: Discussionmentioning

confidence: 85%

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In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Kaplum

Cogo

Sangi

et al. 2016

Antimicrob Agents Chemother

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Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives against Leishmania amazonensis. The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (⌬⌿m), mitochondrial superoxide anion (O 2 · ؊ ) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated. In vivo antileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ⌬⌿m, an increase in the O 2 · ؊ concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thickness in vivo brought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.

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Section: Discussionmentioning

confidence: 85%

“…The antileishmanial activities of the quinoxaline derivatives 4-alkapolynylpyrrolo[1,2-␣]quinoxalines (29,30) and 1,4-di-N-oxide quinoxaline (13,26,31,32) have also been reported. We recently reported the activity of 2,3-disubstituted quinoxaline derivatives against Trypanosoma cruzi and L. amazonensis (33,34).…”

mentioning

confidence: 99%

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Kaplum

Cogo

Sangi

et al. 2016

Antimicrob Agents Chemother

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“…We have payed special attention to quinoline, which constitutes the central nucleus of sitamaquine (25,26), acridine (27,28), quinoxaline (29)(30)(31), and coumarins (32,33). On the other hand, nitrofuran compounds (34,35), the most relevant registered as nifurtimox, and derivatives of the benzodioxol core (36) have been selected.…”

mentioning

confidence: 99%

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Baquedano

Alcolea

Toro

et al. 2016

Antimicrob Agents Chemother

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A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED 50 ) values ranging from 0.45 to 1.27 M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3=-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

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“…Studying the in vitro anti-T. cruzi activities of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives, three compounds were discovered. However, only one was non-cytotoxic on host macrophage cells [158], and no in vivo study was presented.…”

Section: Trypanothione Reductasementioning

confidence: 99%

Efficacy and Safety of Chagas Disease Drug Therapy and Treatment Perspectives

Kawaguchi¹,

Cerqueira²,

MillanFachi³

et al. 2018

Chagas Disease - Basic Investigations and Challenges

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Chagas disease, also known as American trypanosomiasis, is a neglected disease caused by the protozoan parasite Trypanosoma cruzi. The disease affects about 6-7 million people worldwide, mostly in Latin America. Although Chagas disease was discovered more than 100 years ago, and the first treatments over 40, only 2 drugs were used to treat this pathology, it is still considered one of the neglected diseases. In this chapter, the subjects related to conventional etiological therapies, benznidazole and nifurtimox, such as the drug, the mechanism of action, the therapy schedule for treatment, efficacy and safety and their adverse effects will be discussed. Additionally, it will address alternative therapies of comorbidities related to the progression of Chagas' disease in patients with chronic disease, such as heart disease and dysfunction of the digestive system. Finally, novel pharmacological strategies and their related compounds will be reviewed accounting for their progression in pharmacological studies and their success rate.

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Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives

Cited by 37 publications

References 31 publications

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Efficacy and Safety of Chagas Disease Drug Therapy and Treatment Perspectives

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