New hydrazine and hydrazide quinoxaline 1,4-di- N -oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity

Quiliano, Miguel; Pabón, Adriana; Ramirez-Calderon, Gustavo; Barea, Carlos; Deharo, Eric; Galiano, Silvia; Aldana, Ignacio

doi:10.1016/j.bmcl.2017.02.049

Cited by 33 publications

(13 citation statements)

References 35 publications

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“…In conclusion, our comprehensive study characterized the mechanism of reactions of Pf FNR with redox-cycling xenobiotics, which may be instrumental in the further development of redox-active antiplasmodial agents [3][4][5][6][7][8]. In terms of k cat /K m for the reduction of quinones and nitroaromatics (Table 1 and Figure 2), the reactivity of Pf FNR is considerably higher as compared to other P. falciparum flavoenzymes, glutathione reductase, thioredoxin reductase and type 2 NADH dehydrogenase [9,10].…”

Section: Discussionmentioning

confidence: 90%

“…P. falciparum is particularly vulnerable to oxidative stress, which might be caused by its lack of the antioxidant enzymes catalase and glutathione peroxidase [2]. For this reason, redox cycling compounds such as quinones, aromatic nitrocompounds and aromatic N-oxides, which frequently exhibit antiplasmodial in vitro activity at micromolar or lower concentrations, were a subject of great interest for a number of years ( [3][4][5][6][7][8] and references therein). However, only fragmental data are available on their reactions with P. falciparum redox enzymes [6,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Reactions of Plasmodium falciparum Ferredoxin:NADP+ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

Lesanavičius

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Šarlauskas

et al. 2020

IJMS

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Ferredoxin:NADP+ oxidoreductase from Plasmodium falciparum (PfFNR) catalyzes the NADPH-dependent reduction of ferredoxin (PfFd), which provides redox equivalents for the biosynthesis of isoprenoids and fatty acids in the apicoplast. Like other flavin-dependent electrontransferases, PfFNR is a potential source of free radicals of quinones and other redox cycling compounds. We report here a kinetic study of the reduction of quinones, nitroaromatic compounds and aromatic N-oxides by PfFNR. We show that all these groups of compounds are reduced in a single-electron pathway, their reactivity increasing with the increase in their single-electron reduction midpoint potential (E17). The reactivity of nitroaromatics is lower than that of quinones and aromatic N-oxides, which is in line with the differences in their electron self-exchange rate constants. Quinone reduction proceeds via a ping-pong mechanism. During the reoxidation of reduced FAD by quinones, the oxidation of FADH. to FAD is the possible rate-limiting step. The calculated electron transfer distances in the reaction of PfFNR with various electron acceptors are similar to those of Anabaena FNR, thus demonstrating their similar “intrinsic” reactivity. Ferredoxin stimulated quinone- and nitro-reductase reactions of PfFNR, evidently providing an additional reduction pathway via reduced PfFd. Based on the available data, PfFNR and possibly PfFd may play a central role in the reductive activation of quinones, nitroaromatics and aromatic N-oxides in P. falciparum, contributing to their antiplasmodial action.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Reactions of Plasmodium falciparum Ferredoxin:NADP+ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

Lesanavičius

Aliverti

Šarlauskas

et al. 2020

IJMS

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“…Indeed, several quinoxalines have already been described as promising antiplasmodial molecules, including MMV007224 (Figure 2), which was identified from the Malaria Box [10]. In addition, the 1,4-di-N-oxide quinoxaline derivative (QdNO 19) showed antiplasmodial activity against both the 3D7 chloroquine-sensitive and FCR-3 multidrugresistant strains of P. falciparum [11]. The MMV has defined requirements for the target candidate profiles (TCP) and target product profiles (TPP) [12].…”

Section: Introductionmentioning

confidence: 99%

2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

et al. 2021

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The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.

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“…Quinoxalines are an important class of nitrogen containing heterocyclic compounds because of their various applications. In recent years, substituted quinoxaline compounds have attracted much attention due to broad spectrum of interesting biological activities such as cytostatic activity, antimicrobial, antiproliferative, antimalarial, antitumor, anti‐depressant, antiplasmodial and antileishmanial activity . Specifically, NCG555879‐01 acts as BRCA1 inhibitor and antibacterial agent (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Rose Bengal Catalyzed Coupling of 1, 2 ‐ Dicarbonyls and Phenylene 1, 2 ‐Diamines: Visible‐Light Mediated Synthesis of Quinoxalines

et al. 2019

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A new approach for the formation of quinoxaline derivatives (indolo [2, 3‐b] quinoxaline or 2, 3‐Diphenyl‐quinoxaline derivatives) from several phenylene 1, 2‐diamines and 1, 2‐dicarbonyls has been developed by utilizing Rose Bengal as an organo‐ photoredox catalyst. The reported method focuses on the utilization of visible light photoredox catalysis for the formation of C−N bond in quinoxalines via radical chemistry. The developed strategy is simple, mild, exhibits excellent atom economy and is more viable toward the synthesis of biologically interesting quinoxaline frame work without the involvement of any transition metal or strong oxidant.

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New hydrazine and hydrazide quinoxaline 1,4-di- N -oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity

Cited by 33 publications

References 35 publications

Reactions of Plasmodium falciparum Ferredoxin:NADP+ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

Reactions of Plasmodium falciparum Ferredoxin:NADP+ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

Rose Bengal Catalyzed Coupling of 1, 2 ‐ Dicarbonyls and Phenylene 1, 2 ‐Diamines: Visible‐Light Mediated Synthesis of Quinoxalines

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