Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Desroches, Justine; Kieffer, Charline; Primas, Nicolas; Hutter, Sébastien; Gellis, Armand; El‐Kashef, Hussein; Rathelot, Pascal; Verhaeghe, Pierre; Azas, Nadine; Vanelle, Patrice

doi:10.1016/j.ejmech.2016.09.029

Cited by 22 publications

(22 citation statements)

References 48 publications

(18 reference statements)

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“…16 Some more recent modulations of the position 4 of this pharmacophore failed to achieve more active derivatives. 17,18 Here, we present a comprehensive study of the structure-activity relationships of this pharmacophore, especially focusing on the modulation of the redox potentials. Thirty one pharmacophore derivatives, substituted at positions 3, 4, 5, 6 and 7, were synthesized and their in vitro cytotoxicity and activities against L. infantum (axenic amastigotes), and T. brucei brucei (trypomastigotes) were first determined.…”

Section: Introductionmentioning

confidence: 99%

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Pedron

Boudot

Hutter

et al. 2018

European Journal of Medicinal Chemistry

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To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.

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Section: Introductionmentioning

confidence: 99%

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Pedron

Boudot

Hutter

et al. 2018

European Journal of Medicinal Chemistry

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“…Noteworthily, previous research in our laboratory led to the discovery of a series of novel indole analogs possessing excellent antimicrobial, antioxidant, and anticancer activities . Most interestingly, more recent literature survey has revealed that the incorporation of a thiophene moiety can significantly enhance the antimicrobial activity of candidate compounds …”

Section: Introductionmentioning

confidence: 99%

Antibacterial and antitubercular evaluation of dihydronaphthalenone‐indole hybrid analogs

Kumar

et al. 2017

Chem Biol Drug Des

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A new series of indole appended dihydronaphthalenone hybrid analogs (5a-t) have been synthesized through the Lewis acid catalyzed Michael addition of indoles to the arylidene/hetero arylidene ketones. All the synthesized derivatives are well characterized through the H-NMR, C-NMR, HRMS spectroscopic techniques, compound 5r was further confirmed through single crystal X-ray analysis and screened for antibacterial and antitubercular activities. Among the synthesized compounds, the minimum inhibition concentration of 5l (against Escherichia coli) and 5o & 5p (against E. coli & Staphylococcus aureus) was found to be as low as 3.12 μg/ml as compared to the standard antibacterial drug ciprofloxacin 2.5 μg/ml. In antitubercular activity, compounds 5o and 5p with minimum inhibition concentration 6.25 μg/ml were found to be comparable with that of the drugs Pyrazinamide 5 μg/ml and Streptomycin 5 μg/ml. Compounds 5i, 5j, 5m, 5n, 5q, and 5r also showed promising activity against group of organisms tested.

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“…Previously, we have shown that the CCl 3 group is mandatory to provide antiplasmodial activity [ 28 , 29 , 30 ]. To confirm the key role played by the 3-CCl 3 group of the most potent compound ( 3i ) in phenoxyquinoxaline series, the CCl 3 group was replaced by a proton ( 3u ), a CH 3 group ( 2i ), a CF 3 group ( 3v ), and a CHCl 2 group ( 3w ).…”

Section: Resultsmentioning

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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Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Cited by 22 publications

References 48 publications

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Antibacterial and antitubercular evaluation of dihydronaphthalenone‐indole hybrid analogs

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

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