4-Thiophenoxy-2-trichloromethyquinazolines display in vitro selective antiplasmodial activity against the human malaria parasite Plasmodium falciparum

Verhaeghe, Pierre; Dumètre, Aurélien; Castera‐Ducros, Caroline; Hutter, Sébastien; Laget, M.; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Rault, Syl­vain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine

doi:10.1016/j.bmcl.2011.06.113

Cited by 32 publications

(14 citation statements)

References 9 publications

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“…In view of the ineffectiveness of this synthetic route, we changed tactics and started from 4-chloro-2-trichloromethylquinazoline ( 4 ), previously described [ 13 ] and used by our team in S N Ar reactions with various nucleophilic reagents [ 10 , 14 , 15 ] or Suzuki-Miyaura cross-coupling reactions [ 9 ]. Thus, commercial benzamide was deprotonated using NaH in DMF and reacted with chlorimine ( 4 ) in DMF, leading to the target compound ( 5 ) in 60% yield ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

et al. 2020

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From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

et al. 2020

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“…A series of 4-thiophenoxy-2-trichloromethyquinazolines derivatives ( 95a-b ) were evaluated for their antiplasmodial activity against the human malarial parasite Plasmodium falciparum was determined [ 84 ]. Compounds 95a and 95b showed good activity against K1 Plasmodium falciparum (IC 50 = 1.9 μ M and 0.9 μ M, resp.…”

Section: Biological Importance Of Quinazoline Derivativesmentioning

confidence: 99%

Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives

Asif

2014

International Journal of Medicinal Chemistry

123

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The heterocyclic fused rings quinazoline and quinazolinone have drawn a huge consideration owing to their expanded applications in the field of pharmaceutical chemistry. Quinazoline and quinazolinone are reported for their diversified biological activities and compounds with different substitutions bring together to knowledge of a target with understanding of the molecule types that might interact with the target receptors. Quinazolines and quinazolinones are considered as an important chemical for the synthesis of various physiological significance and pharmacological utilized molecules. Quinazolines and quinazolinone are a large class of biologically active compounds that exhibited broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities and other activities. Being considered as advantaged scaffold, the alteration is made with different substituent.

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“…1). Concerning the research for new kinase inhibitors, it was reported that quinazolines bearing an heteroarylamino moiety at position 4 were promising ALK5 (Activin A receptor type 2-Like Kinase) inhibitors ( Among of our research activities centered on the synthesis of original molecules with anti-infective properties, [2][3][4] we developed various series of new quinazolines bearing an aryl-, 5 anilino-, 6 phenoxy-, 7 thiophenoxy-, 8 or sulfonamide substituents 9 at position 4 of the quinazoline ring. Through all studied series, the lead-compound belonged to the 4-anilinosubstituted one, presenting an inhibitory concentration 50% (IC 50 ) value of 0.4 µM on the W2 multi-resistant Plasmodium falciparum strain, an cytotoxic concentration 50% (CC 50 ) of 16 µM on the human HepG2 cell line and thus, a corresponding selectivity index (SI) of 40 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring

et al. 2014

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We report herein a new methodology for synthesizing quinazoline derivatives bearing an heteroarylamino moiety at position 4 of the quinazoline ring. As an alternative to the Buchwald-Hartwig cross-coupling reaction which appears, until now, as the only efficient way to react 4chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol% of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2substitued-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest.

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4-Thiophenoxy-2-trichloromethyquinazolines display in vitro selective antiplasmodial activity against the human malaria parasite Plasmodium falciparum

Cited by 32 publications

References 9 publications

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives

A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring

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