Synthesis, Biological Evaluation and Structure-Activity Relationships of New Quinoxaline Derivatives as  Anti-Plasmodium falciparum Agents

Gil, Ana Gloria; Pabón, Adriana; Galiano, Silvia; Burguete, Asunción; Pérez‐Silanes, Silvia; Deharo, Eric; Monge, Antonio; Aldana, Ignacio

doi:10.3390/molecules19022166

Cited by 40 publications

(27 citation statements)

References 57 publications

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“…Compounds with one halogenous group substituted in position 6 and 7 provide an efficient approach for further development of antimalarial and antileishmanial agents. From a series of quinoxaline analogs of chalcones in another study, compounds 1a (IC 50 = 6.2 μM; Figure 9F ) and 2a (IC 50 = 5.8 μM; Figure 9G ) were the most active against FCR-3 P. falciparum ( Gil et al, 2014 ). SAR demonstrated the importance of an enone moiety linked to the quinoxaline ring in the search for antimalarial ligands.…”

Section: Antiprotozoal Activities Of Qdnosmentioning

confidence: 99%

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Cheng

Cao

et al. 2016

Front. Pharmacol.

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Quinoxaline 1,4-di-N-oxides (QdNOs) have manifold biological properties, including antimicrobial, antitumoral, antitrypanosomal and antiinflammatory/antioxidant activities. These diverse activities endow them broad applications and prospects in human and veterinary medicines. As QdNOs arouse widespread interest, the evaluation of their medicinal chemistry is still in progress. In the meantime, adverse effects have been reported in some of the QdNO derivatives. For example, genotoxicity and bacterial resistance have been found in QdNO antibacterial growth promoters, conferring urgent need for discovery of new QdNO drugs. However, the modes of actions of QdNOs are not fully understood, hindering the development and innovation of these promising compounds. Here, QdNOs are categorized based on the activities and usages, among which the antimicrobial activities are consist of antibacterial, antimycobacterial and anticandida activities, and the antiprotozoal activities include antitrypanosomal, antimalarial, antitrichomonas, and antiamoebic activities. The structure-activity relationship and the mode of actions of each type of activity of QdNOs are summarized, and the toxicity and the underlying mechanisms are also discussed, providing insight for the future research and development of these fascinating compounds.

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Section: Antiprotozoal Activities Of Qdnosmentioning

confidence: 99%

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Cheng

Cao

et al. 2016

Front. Pharmacol.

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“…Quinoxaline nucleus forms an important part of active pharmacophore in synthesis of wide range of biological active compounds used as antibacterial, 27,28 antiviral, 29,30 anti-HIV, 31 antimalarial, 32,33 anticancer, [34][35][36] antitubercular, 37 antileishmanial, 38 and various neurological disorders. 39,40 Based on our interest in sustainable green chemistry, herein, we have developed a methodology where complex ketones which have pharmacologically important moiety can be reduced using a cheap and easy process with D carota as the catalyst.…”

Section: Introductionmentioning

confidence: 99%

Green synthesis of enantiopure quinoxaline alcohols using Daucus carota

et al. 2019

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Green chemistry comprises a new approach in the synthesis of biologically active compounds using biocatalysts, thus diminishing the hazards for human health and environmental pollution. Asymmetric bioreduction is one of the most widely employed strategies in chemoenzymatic synthesis to produce enantiomerically pure chiral alcohols. The present study highlights the use biocatalyst Daucus carota for selective bioreduction of quinoxaline ketones 1a-6a to their corresponding optically pure alcohols 1b-6b in high yields (up to 84%) and good enantioselectivity (up to 98%). The absolute configuration of the chiral product (R)-1-(3-methyl 7-nitroquinoxalin-2-yl) ethan-1-ol 2b was confirmed by X-ray crystallography studies. The chiral R-configuration of the products obtained was confirmed by absolute configuration studies and was assigned following anti-Prelogs rule. Quinoxaline pharmacophores form a part of well-known potent drug molecules; hence, the chiral products were studied for determination of their molecular properties using SwissADME property analyser. All the chiral products show no Lipinski rule violations and are expected to have good oral bioavailability. As per the molecular properties prediction studies, the compound 6b (R)-1- (6,7-dichloro-3-methylquinoxalin-2-yl) ethanol is observed to show the best physicochemical properties to be a good lead molecule. Thus, the sustainable methodology was developed, and it confirms the synthesis of novel quinoxaline chiral alcohols in a simple, inexpensive, and eco-friendly condition using D carota.

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“…Moreover, radiolabeled chalcones have been used as PET imaging agents for in vivo imaging of the β-amyloid plaques of Alzheimer’s disease [ 17 , 18 ]. After the advent of licochalcone A with its antiplasmodial activity [ 19 ], a large number ofnovel synthetic chalcone derivatives and chalcone hybrids have been designed, synthesized and evaluated for their antiplasmodial activity [ 20 , 21 , 22 , 23 , 24 ]. Several reports suggest that chalcones’ antiplasmodial potential is due the ability to inhibit both the plasmodial aspartate protease and cysteine protease targets [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture

et al. 2018

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A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50 values of 3.0 μg/mL and 2.2 μg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.

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Synthesis, Biological Evaluation and Structure-Activity Relationships of New Quinoxaline Derivatives as Anti-Plasmodium falciparum Agents

Cited by 40 publications

References 57 publications

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Green synthesis of enantiopure quinoxaline alcohols using Daucus carota

Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture

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