Synthesis of novel quinoline–based 4,5–dihydro–1 H –pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents

Prada, Jonathan Ramirez; Robledo, Sara M.; Vélez, Iván Darío; Crespo, María del Pilar; Quiroga, Jairo; Abonı́a, Rodrigo; Montoya, Alba; Svetaz, Laura; Zacchino, Susana; Insuasty, Braulio

doi:10.1016/j.ejmech.2017.03.016

Cited by 108 publications

(60 citation statements)

References 55 publications

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“…The pharmacological properties of the quinoline ring illustrate the number of commercial products containing this heterocyclic system . Quinoline‐based compounds present a variety of biological actions, such as antimalarial and antileishmanial agents .…”

Section: Discussionmentioning

confidence: 99%

Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species

Tavares

Mendonça

Lage

et al. 2018

Basic Clin Pharma Tox

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In this study, a quinoline derivate, clioquinol (5-chloro-7-iodoquinolin-8-ol), was evaluated against Leishmania amazonensis and Leishmania infantum promastigotes and amastigotes. The cytotoxicity in murine macrophages and human red blood cells, as well as the efficacy in treating infected macrophages and the inhibition of infection using pre-treated parasites were also evaluated. Results showed that clioquinol inhibited L. amazonensis and L. infantum promastigotes with effective concentration 50% (EC ) values of 2.55 ± 0.25 and 1.44 ± 0.35 μg/mL, respectively, and of 1.88 ± 0.13 and 0.98 ± 0.17 μg/mL against axenic amastigotes, respectively. The cytotoxic EC concentrations of clioquinol in murine macrophages and human red blood cells were, respectively, 255 ± 23 and 489 ± 20 μg/mL. With these results, the selectivity index was calculated, showing values of 99.9 and 177.1 against promastigotes, respectively, and of 135.6 and 260.1 against axenic amastigotes, respectively. Significant reductions in the percentage of infected macrophages after treatment using clioquinol were also observed, as well as when parasites were pre-treated with clioquinol and used to infect murine macrophages. The mechanism of action of clioquinol was investigated in L. amazonensis, and results revealed morphological and biochemical alterations in the clioquinol-treated parasites, including reduction in cell volume, loss of mitochondrial membrane potential, increase in the ROS production and rupture of the plasma membrane. The externalization of phosphatidylserine (PS) at the cell surface was evaluated in treated parasites that had been doubly labelled with annexin and propidium iodide (PI). The results showed no significant difference for PS exposure when compared to the untreated control, although a significant increase in the PI/annexin V-labelled cell population was found in the treated parasites. Results suggest that clioquinol induces a discontinuity of the parasite membrane, possibly related to a characteristic event of cell death caused by necrosis. This study demonstrates, for the first time, the antileishmanial activity of clioquinol against two relevant Leishmania species and suggests that the mitochondria of the parasites may be a possible biological target leading to parasite necrosis. Our findings suggest that clioquinol may have a potential application in treatment of leishmaniasis and further studies should be performed in infected mammalian hosts.

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Section: Discussionmentioning

confidence: 99%

Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species

Tavares

Mendonça

Lage

et al. 2018

Basic Clin Pharma Tox

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“…Once we obtained the chalcone–thiazole hybrids bearing nitrogen mustard 5a–g , we performed the synthesis of diverse N ‐acetyl and N ‐formyl pyrazolines 6/7 by using reported procedures. [ 44,45 ] For the synthesis of N ‐acetyl derivatives 6a–g , chalcones 5a–g were treated with hydrazine hydrate in EtOH under reflux, resulting in the formation of the corresponding N ‐H pyrazolines, followed by addition of acetic anhydride via “one‐pot” reaction, affording the pyrazoline derivatives 6a–g in good yields (70–52%). On the basis of these results, the reaction was extended to the synthesis of N ‐formyl pyrazolines (Scheme 3) in the presence of formic acid in place of acetic anhydride and the desired products 7a–g were successfully obtained in good yields (76–52%).…”

Section: Resultsmentioning

confidence: 99%

“…According to recent papers on N ‐aryl pyrazolines, the introduction of the aryl group at the N ‐1 position of the dihydropyrazole ring leads to biological activity improvement. [ 33,45–48 ] However, chlorophenyl derivatives may enhance potency and binding efficiency compared to their unsubstituted phenyl derivatives. [ 2,49,50 ] In addition, these derivatives show an improvement in metabolic stability and pharmacokinetic profile, as recently demonstrated by Eggert et al, [ 49 ] who identified that the 3,4‐dichloro derivative (IC 50 = 0.08 μM) is more active than the corresponding 4‐chloro (IC 50 = 0.8 μM) and unsubstituted phenyl derivatives (IC 50 > 20 μM) against SMYD2 for the treatment of cancer.…”

Section: Resultsmentioning

confidence: 99%

New thiazolyl‐pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

Cuartas

Robledo

Vélez

et al. 2020

Archiv der Pharmazie

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A new series of N-substituted pyrazoline derivatives 6a-g, 7a-g, 8a-g, and 9a-g was synthetized by reaction of hydrazine derivatives and chalcone-thiazole hybrids bearing nitrogen mustard 5a-g. The chalcones 5a-g were obtained by Claisen-Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a-g. These new compounds 6/7/8/9a-g were screened for their antifungal activity against Cryptococcus neoformans, with IC 50 values of 3.9-7.8 µg/ml for the N-3, 5-dichlorophenyl pyrazolines 9e-g. Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl (6a,b) and N-formyl pyrazolines (7a, 7b, 7c, and 7g) showed inhibitory activity against methicillinsusceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycinintermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g, 8f, and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC 50 values of 11.80, 6.46, and 4.98 μM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent. K E Y W O R D S antibacterial activity, antifungal activity, antiprotozoal activity, chalcone, pyrazoline

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“…The amino tethered chalcone–quinoline hybrids 28 (Figure 6; EC 50 : 10.26–208.59 μM) showed weak to moderate activity against CQS 3D7 P. falciparum strain. [ 69–73 ] The SAR proved that the linker between chalcone and quinoline moiety was crucial for the activity, and the piperazinyl‐containing linkers were favorable to the activity. [ 74 ] Among them, hybrids 29a , b (IC 50 : 0.3–0.6 μM) were highly active against CQS D10, CQR Dd2, and W2 strains, but both of them were less potent than the reference chloroquine (IC 50 : 0.017–0.097 μM).…”

Section: Chalcone–quinoline Hybridsmentioning

confidence: 99%

Chalcone hybrids and their antimalarial activity

Cheng

Yang

Huang

et al. 2020

Archiv der Pharmazie

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Malaria, one of the most striking, re‐emerging infectious diseases caused by the genus Plasmodium, places a huge burden on global healthcare systems. A major challenge in the control and eradication of malaria is the continuous emergence of increasingly widespread drug‐resistant malaria, creating an urgent need to develop novel antimalarial agents. Chalcone derivatives are ubiquitous in nature and have become indispensable units in medicinal chemistry applications due to their diverse biological profiles. Many chalcone derivatives demonstrate potential in vitro and in vivo antimalarial activity, so chalcone could be a useful template for the development of novel antimalarial agents. This review covers the recent development of chalcone hybrids as antimalarial agents. The critical aspects of the design and structure–activity relationship of these compounds are also discussed.

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Synthesis of novel quinoline–based 4,5–dihydro–1 H –pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents

Cited by 108 publications

References 55 publications

Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species

Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species

New thiazolyl‐pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

Chalcone hybrids and their antimalarial activity

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