Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives

Guillon, Jean; Cohen, Anita; Boudot, Clotilde; Valle, A. M.; Milano, Vittoria; Das, Rabindra Nath; Guédin, Aurore; Moreau, Stéphane; Ronga, Luisa; Savrimoutou, Solène; Demourgues, Maxime; Reviriego, Elodie; Rubio, Sandra; Ferriez, Sandie; Agnamey, Patrice; Pauc, Cécile; Moukha, Serge; Dozolme, Pascale; Nascimento, Sophie Da; Laumaillé, Pierre; Bouchut, Anne; Azas, Nadine; Mergny, Jean‐Louis; Mullié, Catherine; Sonnet, Pascal; Castro, Bertrand

doi:10.1080/14756366.2019.1706502

Cited by 17 publications

(12 citation statements)

References 48 publications

(56 reference statements)

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“…[34,35] We found that sugar conjugated naphthalene diimides previously shown to be G4 ligands [36] also bind G4s found exclusively in T. brucei and present very notable antiparasitic activity. [33,37,38] Eventually, other quadruplex ligands such as quarfloxin, CX-5461 [39] and compounds based on stiff stilbene, [40] naphthalene diimide, [41] perylene diimide, [42] phenantroline, [43,44] quinoxaline [45] and quinoline scaffolds [46] have been reported with antitrypanosomal and antiplasmodial activity. [47] In this work, we studied the presence of PQS in the genome of Trypanosoma cruzi and carried out biophysical studies confirming that some of these frequent PQS actually form stable quadruplex structures.…”

Section: Introductionmentioning

confidence: 99%

DNA G‑Quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: dithienylethene ligands as effective antiparasitic agents

Pérez-Soto,

Ramos-Soriano,

Peñalver

et al. 2024

Preprint

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Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 putative quadruplex forming sequences per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds 3 and 4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 μM, SI =25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.

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Section: Introductionmentioning

confidence: 99%

DNA G‑Quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: dithienylethene ligands as effective antiparasitic agents

Pérez-Soto,

Ramos-Soriano,

Peñalver

et al. 2024

Preprint

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“…Interestingly, a number of recent papers describe the discovery and development of G4‐ligands with anti‐parasitic activity. [ 16a , 18 ] Among the different molecular scaffolds, 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline,[ 18c , 18g ] napthalene diimide,[ 16c , 18d , 18f , 18h , 18i ] and quinazoline [18e] derivatives have been reported to show promising in vitro anti‐trypanosomal activity and selectivity (Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

“… Representative examples of G4‐ligands with reported anti‐trypanosomal activity and selectivity: 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline, [18c] carbohydrate conjugated naphthalene diimide, [16a] and 2,4‐bis[(substituted‐aminomethyl)phenyl]quinazoline. [18e] …”

Section: Introductionmentioning

confidence: 99%

G‐Quadruplexes as Key Transcriptional Regulators in Neglected Trypanosomatid Parasites

Monti

Antonio

2023

ChemBioChem

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G‐quadruplexes (G4s) are nucleic acid secondary structures that have been linked to the functional regulation of eukaryotic organisms. G4s have been extensively characterised in humans and emerging evidence suggests that they might also be biologically relevant for human pathogens. This indicates that G4s might represent a novel class of therapeutic targets for tackling infectious diseases. Bioinformatic studies revealed a high prevalence of putative quadruplex‐forming sequences (PQSs) in the genome of protozoans, which highlights their potential roles in regulating vital processes of these parasites, including DNA transcription and replication. In this work, we focus on the neglected trypanosomatid parasites, Trypanosoma and Leishmania spp., which cause debilitating and deadly diseases across the poorest populations worldwide. We review three examples where G4‐formation might be key to modulate transcriptional activity in trypanosomatids, providing an overview of experimental approaches that can be used to exploit the regulatory roles and relevance of these structures to fight parasitic infections.

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“…Heterocyclic rings with nitrogen and sulfur are therapeutically and pharmacologically reported active and are of particular interest [ 18 ]. Quinazoline derivatives are heterocyclic molecules with nitrogen fixed in the ring that exhibit antiviral, antidiabetic, antimalarial, antioxidant, and anti-inflammation characteristics, to mention a few [ 3 , 6 , 10 , 14 , 20 ]. In recent years, several medications, such as 2-anilino 4-amino substituted quinazolines, have shown antimalarial efficacy [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target

Ibrahim

Uzairu

Shallangwa

et al. 2022

Egypt J Med Hum Genet

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Background The processes of drug development and validation are too expensive to be subjected to experimental trial and errors. Hence, the use of the insilico approach becomes imperative. To this effect, the drug-likeness and pharmacokinetic properties of the ten (10) previously designed derivatives of 2-anilino 4-amino substituted quinazolines were carried out. Their predicted ligand binding interactions were also carried out by docking them against the Plasmodium falciparum dihydroorotate dehydrogenase (Pf-DHODH) protein target, and the stability of the complex was determined through dynamic simulations. The drug-likeness and pharmacokinetic characteristics were estimated using the online SwissADME software, while the Molegro Virtual Docker (MVD) software was used for molecular docking. And the dynamic simulation was performed for the duration of 100 ns to verify the stability of the docked complex, with the aid of a Schrödinger program, Desmond. Results The designed derivatives were all found to pass the Lipinski test of drug likeness, while the pharmacokinetic studies result that the skin permeability and molar refractivity values of the derivatives are both within the limits. In addition, except for derivative C-01, most of the derivatives have strong gastrointestinal absorptions and lack Pgp substrate. Furthermore, no derivative inhibited CYP1A2, CYP2C9, or CYP2C19. The docking studies show the better binding affinities between the ligands and Pf-DHODH than those between the atovaquone or chloroquine standards. The derivative C-02, {5-((6,7-dimethoxy-4-((3-nitrobenzyl)amino)quinazolin-2-yl)amino)-2-fluorobenzaldehyde} was found to be the most stable derivative, with a re-rank docking score of − 173.528 kcal/mol and interaction energy of − 225.112 kcal/mol. The dynamic simulation analysis shows that the derivative C-02 forms a stable complex with the protein target over the simulation time. Conclusions The ability of these ligands to form hydrogen bonds, as well as various other interactions, was cited as a factor responsible for their better binding affinity. These findings could aid further the development of enhanced antimalarial drugs.

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Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives

Abstract: Courtioux (2020) Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substitutedaminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4bis[(substituted-aminomethyl)phenyl]quinazoline derivatives,

Cited by 17 publications

References 48 publications

DNA G‑Quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: dithienylethene ligands as effective antiparasitic agents

DNA G‑Quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: dithienylethene ligands as effective antiparasitic agents

G‐Quadruplexes as Key Transcriptional Regulators in Neglected Trypanosomatid Parasites

Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target

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