Design, synthesis and biological evaluation of novel 4-alkapolyenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents – Part III

Ronga, Luisa; Favero, Marco Del; Cohen, Anita; Soum, Claire; Pape, Patrice Le; Savrimoutou, Solène; Pinaud, Noël; Mullié, Catherine; Daulouède, Sylvie; Vincendeau, Philippe; Farvacques, Natacha; Agnamey, Patrice; Pagniez, Fabrice; Hutter, Sébastien; Azas, Nadine; Sonnet, Pascal; Guillon, Jean

doi:10.1016/j.ejmech.2014.05.037

Cited by 47 publications

(33 citation statements)

References 52 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: 97%

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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: 97%

“…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%

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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“…The reaction of 4a-d with triphosgene in toluene gave the lactams 5a-d 22 . Reduction of the nitro moiety of 6a-b with iron in hot glacial acetic acid produced the spontaneous ring closure onto the ester to afford the desired the lactams 5e-f through a one-pot reduction-cyclization step 27,25 . The lactams 5a-f were subsequently chlorodehydroxylated with phosphorous oxychloride, leading to the 4-chloropyrrolo[1,2-a]quinoxalines 7a-f.…”

Section: Chemistrymentioning

confidence: 99%

“…These compounds have been reported as key intermediates for the assembly of several heterocycles including antipsychotic agents, anti-HIV agents, adenosine A 3 receptor modulators 19 , antiparasitic agents [20][21][22][23][24][25] and antitumor agents [26][27][28][29][30] . In the course of our work devoted to discover new compounds employed in the antiparasitic chemotherapy, we previously identified some series of substituted pyrrolo[1,2-a]quinoxaline derivatives designed as interesting bioactive isosteres of quinoline derivatives [20][21][22][23][24] .Thus, taking into account our experience in the field of the synthesis of new antimalarial heterocyclic compounds based on our pyrrolo[1,2-a]quinoxaline heterocyclic core [20][21][22][23][24][27][28][29][30] , we decided to incorporate a benzyl group in position 4 of the heterocyclic skeletonof our previously described bispyrrolo [1,2-a]quinoxalines C 20 to broaden the structural diversity of these derivatives, and mainly to increase the aromatic surface of these designed compounds ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives

Guillon

Cohen

Gueddouda

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel series of bis-and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC 50 in the lM range. In attempting to investigate the large broadspectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds. ARTICLE HISTORY

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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.…”

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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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Design, synthesis and biological evaluation of novel 4-alkapolyenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents – Part III

Cited by 47 publications

References 52 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

Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

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