New salicylamide and sulfonamide derivatives of quinoxaline 1,4-di-N-oxide with antileishmanial and antimalarial activities

Barea, Carlos; Pabón, Adriana; Castillo, Denis; Zimic, Mirko; Quiliano, Miguel; Galiano, Silvia; Pérez‐Silanes, Silvia; Monge, Antonio; Deharo, Eric; Aldana, Ignacio

doi:10.1016/j.bmcl.2011.05.125

Cited by 56 publications

(40 citation statements)

References 16 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: 96%

“…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).…”

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confidence: 99%

“…Quinoxaline derivatives have promising biological properties because of their privileged scaffold (13)(14)(15). Several biological effects have been reported, including anticancer (14,16,17), antimicrobial (18)(19)(20)(21)(22), antiviral (23), and anti-inflammatory and antioxidant (24,25) effects.…”

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confidence: 99%

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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: 96%

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confidence: 99%

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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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“…[14,15] Our group has vast experience in the synthesis and biological evaluation of multiple quinoxaline 1,4-di-Noxide derivatives, having identified a broad spectrum of anti-infective activities. [16][17][18][19][20][21][22][23][24][25][26] The evaluation of several libraries of compounds led us to find a series with high in vitro activity against T. cruzi. [27] This finding allowed us to establish structural features for maintaining high in vitro activity against the parasite (Scheme 1).…”

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confidence: 99%

Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

Torres

Moreno‐Viguri

Galiano

et al. 2013

European Journal of Medicinal Chemistry

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ABSTRACT. As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with 2 fluoro groups at the 6-and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups.

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“…In fact, ferrocenic pyrrolo[1,2-a] quinoxaline 138 with IC 50 of 16.6 + 1.2 nM was six times more active than chloroquine (105.3 + 16.2 nM) upon in vitro screening against chloroquine-resistant strain FcB1 [137]. Based on enormous biological activity of 1,4-di-N-oxides of quinoxaline, its benzamide 139 and sulfonamide 140 substituents were reported to possess good antimalarial activity for further study in drug design [138]. Also, N-(3-(4-(4- (7,8- as a ring-modified quinoline antimalarial agent which acted by way of inhibition of P. falciparum thioredoxin reductase (PfTrxR) [142].…”

Section: Antimalarial Activitymentioning

confidence: 96%

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

Ajani

2014

European Journal of Medicinal Chemistry

100

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New salicylamide and sulfonamide derivatives of quinoxaline 1,4-di-N-oxide with antileishmanial and antimalarial activities

Cited by 56 publications

References 16 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 quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

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