In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine

Taleli, Lebusetsa; Kock, Carmen de; Smith, Peter J.; Pelly, Stephen C.; Blackie, Margaret A.L.; Otterlo, Willem A. L. van

doi:10.1016/j.bmc.2015.06.044

Cited by 15 publications

(7 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, compound 15 with the 4‐amino functionality showed better activity at both concentrations than 14 lacking a 4‐amino functionality. This finding agrees with previous reports, suggesting the importance of the 4‐amino group for the antimalarial activity of quinoline‐based compounds [19,24,29,30] …”

Section: Resultssupporting

confidence: 93%

“…Compound 2 was synthesised using the previously reported procedure [17] while compound 6 , though also reported in the literature, [18] was synthesised here using a new procedure. In addition, azidoquinoline 6 was synthesised to maintain the 4‐amino functionality of the quinoline [19] and to increase the flexibility of the linker (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

“…This finding agrees with previous reports, suggesting the importance of the 4-amino group for the antimalarial activity of quinoline-based compounds. [19,24,29,30] Reported properties of existing compounds that have been used as RAs established the importance of the presence of aromatic rings, even though it increases the molecular weight of compounds. This study unambiguously supports this finding, highlighting a marked reduction in the antiplasmodial activity of hybrids 13 a-c, when the aromatic ring is replaced with the methyl group at position 4 of the DHPM.…”

Section: Structure-activity Relationship Studymentioning

confidence: 99%

See 2 more Smart Citations

Rational Optimization of Dihydropyrimidinone‐Quinoline Hybrids as Plasmodium falciparum Glutathione Reductase Inhibitors

2022

View full text Add to dashboard Cite

A series of dihydropyrimidinone‐based antimalarial compounds were designed and synthesised based on the previously identified amide‐based quinoline hybrids which showed good resistance reversal ability against the resistant strain of Plasmodium falciparum. The aromatic ring on the dihydropyrimidinone of the original hits was exchanged for a methyl group to bring the molecular weights below 500 Da and also determine the effect of the aromatic ring count on the resistance reversal ability of the hybrids. Apart from the previously used amide bond, the hybrid linker was also extended to the triazole linker. Although the triazole linker is synthetically easier to access, the use of an amide linker seems to have an activity advantage. The synthesised compounds in addition to the previously identified hits were subjected to molecular docking particularly targeting the orthosteric site of Plasmodium falciparum glutathione reductase (PfGR) protein. The ligand with the best binding interaction was rationally optimised to increase its suitability as a competitive inhibitor against the cofactor of the PfGR. Two of the optimised ligands showed better binding affinities than the cofactor while one of the two ligands displayed hydrophobically packed correlated hydrogen‐bond which is very important in maintaining the ligand stability within the protein. In silico ADME predictions of the synthesised compounds indicate that these compounds possess good pharmacokinetic properties.

show abstract

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Structure-activity Relationship Studymentioning

confidence: 99%

See 1 more Smart Citation

Rational Optimization of Dihydropyrimidinone‐Quinoline Hybrids as Plasmodium falciparum Glutathione Reductase Inhibitors

2022

View full text Add to dashboard Cite

show abstract

“…% formic acid) at a 0.4 mL/min flow rate. 4-(2-Azidoethyl)morpholine 1a , 4-(3-azidopropyl)morpholine 1b , 1-[3′,5′- O -(tetraisopropyldisiloxan-1,3-diyl)-β- d -ribofuranosyl]-5-iodouracil 4 and 3-ethynylperylene were synthesized according to literature [ 28 , 34 , 50 ]. An aqueous solution of 2,3-dimethylbenzo[ d ]thiazol-3-ium iodide [ 51 ] was eluted through a column filled with Bio-Rad AG ® MP-1M Anion Exchange Resin (chloride form, 10 eq.)…”

Section: Methodsmentioning

confidence: 99%

Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo

et al. 2022

View full text Add to dashboard Cite

Perylene-based compounds are attracting significant attention due to their high broad-spectrum antiviral activity against enveloped viruses. Despite unambiguous results of in vitro studies and high selectivity index, the poor water solubility of these compounds prevented in vivo evaluation of their antiviral properties. In this work, we synthesized a series of compounds with a perylene pharmacophore bearing positively charged substituents to improve the aqueous solubility of this unique type of antivirals. Three types of charged groups were introduced: (1) quaternary morpholinium salts (3a–b); (2) a 2′-O-l-valinyl-uridine hydrochloride residue (8), and (3) a 3-methylbenzothiazolium cation (10). The synthesized compounds were evaluated based both on antiviral properties in vitro (CHIKV, SARS-CoV-2, and IAV) and on solubility in aqueous media. Compound 10 has the greatest aqueous solubility, making it preferable for pre-evaluation by intragastrical administration in a mouse model of lethal influenza pneumonia. The results indicate that the introduction of a positively charged group is a viable strategy for the design of drug candidates with a perylene scaffold for in vivo studies.

show abstract

“…The quinoline‐triazole hybrids 43 (Figure ; IC 50 : 8.9‐5330 nM) showed considerable activity against CQS NF54 and CQR Dd2 strains, and some of them were more active than CQ (IC 50 : 12.1 and 245 nM) against CQS NF54 and CQR Dd2 strains . The RI for a significant part of them was around 1, and lower than CQ (RI: 20.2).…”

Section: Quinoline Hybridized With Novel Antimalarial Pharmacophores mentioning

confidence: 99%

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Feng

Chang

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

Malaria is a tropical disease, leading to around half a million deaths annually. Antimalarials such as quinolines are crucial to fight against malaria, but malaria control is extremely challenged by the limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum which are resistant toward almost all currently accessible antimalarials. To tackle the growing resistance, new antimalarial drugs are needed urgently. Hybrid molecules which contain two or more pharmacophores have the potential to overcome the drug resistance, and hybridization of quinoline privileged antimalarial building block with other antimalarial pharmacophores may provide novel molecules with enhanced in vitro and in vivo activity against drug-resistant (including multidrug-resistant) P falciparum. In recent years, numerous of quinoline hybrids were developed, and their activities against a panel of drug-resistant P falciparum strains were screened. Some of quinoline hybrids were found to possess promising in vitro and in vivo potency. This review emphasized quinoline hybrid molecules with

show abstract

In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine

Cited by 15 publications

References 46 publications

Rational Optimization of Dihydropyrimidinone‐Quinoline Hybrids as Plasmodium falciparum Glutathione Reductase Inhibitors

Rational Optimization of Dihydropyrimidinone‐Quinoline Hybrids as Plasmodium falciparum Glutathione Reductase Inhibitors

Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Contact Info

Product

Resources

About