Antileishmanial activity, structure–activity relationship of series of 2‐(trifluoromethyl)benzo[<i>b</i>][1,8]naphthyridin‐4(1<i>H</i>)‐ones

Romero, Angel H.; López, Simón E.; Rodríguez, Noris; Oviedo, Henry

doi:10.1002/ardp.201800094

Cited by 8 publications

(10 citation statements)

References 43 publications

(23 reference statements)

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“…Furthermore, the relative exchange from the CT state to the LE state in the presence of high cesium opens the door to analyze intracellular potassium as an alkaline metal as well as an intracellular phenomenon within mammal cells like macrophage through fluorescence microscopy. It may be useful to interpret through the fluorescence profile of dye 3k some reported biological findings, including (i) the moderate toxicity on the macrophage and (ii) remarkable leishmanicidal response against intracellular amastigote of the Leishmania parasite in the infected macrophage compared to an axenic form of promastigote …”

Section: Discussionmentioning

confidence: 99%

“…It may be useful to interpret through the fluorescence profile of dye 3k some reported biological findings, including (i) the moderate toxicity on the macrophage and (ii) remarkable leishmanicidal response against intracellular amastigote of the Leishmania parasite in the infected macrophage compared to an axenic form of promastigote. 43 ■ ASSOCIATED CONTENT * sı Supporting Information…”

Section: ■ Conclusionmentioning

confidence: 99%

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Photo-Induced Partially Aromatized Intramolecular Charge Transfer

Romero

Piro

et al. 2021

J. Phys. Chem. B

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Diverse models of intramolecular charge transfer (ICT) have been proposed for interpreting the origin of the charge-transfer (CT) state in donor–acceptor (D–A) dyes. However, a large variety of fused-heterocyclic dyes containing a pseudo-aromatic ring in the rigid structure have shown to be incompatible with them. To approximate a solution within the ICT concept, we reported a novel ICT model called partially aromatized intramolecular charge transfer (PAICT). PAICT involves the generation of a CT state from an ICT that occurred within a pre-excited D–A fused-heterocyclic structure possessing a pseudo-aromatic or unstable aromatic ring as the acceptor moiety. The model was proposed from the multiple-emissive mesomeric D–A N 1 -aryl-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one, whose excited mesomeric states, which are defined by the aromatic and pseudo-aromatic forms of the pyrindin-4(1H)-one ring, led to a common partial aromatized CT state upon excitation via PAICT. The latter was supported through theoretical calculations on the excited mesomeric states, one-dimensional (1D) and two-dimensional (2D) excitation–emission measurements in different solvents, and the detection of three excited states by lifetime measurements upon 370 nm excitation. The existence of mesomerism was supposed from: (i) two overlapping bands at 370–390 (or 400–420 nm) in UV–vis spectra, (ii) the direct interaction between the pyridinic nitrogen of one molecule and the carbonylic oxygen of the other found in the solid state and, (iii) the detection of three excited states by lifetime measurements. The PAICT opens new perspectives for interpreting the charge-transfer phenomenon in fused-heterocyclic dyes, in particular, those containing a pseudo-aromatic or unstable aromatic ring as an acceptor moiety.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Photo-Induced Partially Aromatized Intramolecular Charge Transfer

Romero

Piro

et al. 2021

J. Phys. Chem. B

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“…Three simple betulin derivatives (1, 17, and 18) reduced parasite growth to less than 25%, with 18 being the most active compound, reducing promastigote growth to 3.32% compared to untreated cells. Five heterocyclic betulin derivatives (22,24,25,26,27) reduced parasite growth to less than 25%, with 26 being the most active compound, reducing promastigotes growth to 4.28%.…”

Section: Selection Of the Tool Compoundsmentioning

confidence: 99%

“…Thus, phenotypic screening that includes in vitro susceptibility tests and the macrophage-amastigote model stands out as the cornerstone of studies prior to the development of new chemotherapeutics against this disease [ 21 ]. For example, trifluoromethyl-substituted quinolones and their analogues, as well as metronidazole derivatives have emerged as an interesting platform to design agents against L. (L.) mexicana and L. (V.) braziliensis [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production

et al. 2021

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Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

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“…All these compounds were previously synthesized and evaluated against in vitro models of Trypanosome cruzi and Leishmania spp. parasites. − These parasites are responsible for Leishmaniasis and Chagas disease, respectively, and they, in conjunction with malaria, belong to the group of neglected tropical diseases . Despite the genetic and host preference differences between the trypanosomatids and the Plasmodium parasites, it is common to find antitrypanosomatid agents with good antimalarial activity. , …”

Section: Introductionmentioning

confidence: 99%

Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting β-Hematin Crystallization

et al. 2022

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The β-hematin formation is a unique process adopted by Plasmodium sp. to detoxify free heme and represents a validated target to design new effective antimalarials. Most of the β-hematin inhibitors are mainly based on 4-aminoquinolines, but the parasite has developed diverse defense mechanisms against this type of chemical system. Thus, the identification of other molecular chemical entities targeting the β-hematin formation pathway is highly needed to evade resistance mechanisms associated with 4-aminoquinolines. Herein, we showed that the highly coordinative character can be a useful tool for the rational design of antimalarial agents targeting β-hematin crystallization. From a small library consisting of five compound families with recognized antitrypanosomatid activity and coordinative abilities, a group of tetradentate 1,4-disubstituted phthalazin-aryl/heteroarylhydrazinyl derivatives were identified as potential antimalarials. They showed a remarkable curative response against Plasmodium berghei-infected mice with a significant reduction of the parasitemia, which was well correlated with their good inhibitory activities on β-hematin crystallization (IC50 = 5–7 μM). Their in vitro inhibitory and in vivo responses were comparable to those found for a chloroquine reference. The active compounds showed moderate in vitro toxicity against peritoneal macrophages, a low hemolysis response, and a good in silico ADME profile, identifying compound 2f as a promising antimalarial agent for further experiments. Other less coordinative fused heterocycles exhibited moderate inhibitory responses toward β-hematin crystallization and modest efficacy against the in vivo model. The complexation ability of the ligands with iron(III) was experimentally and theoretically determined, finding, in general, a good correlation between the complexation ability of the ligand and the inhibitory activity toward β-hematin crystallization. These findings open new perspectives toward the rational design of antimalarial β-hematin inhibitors based on the coordinative character as an alternative to the conventional β-hematin inhibitors.

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Antileishmanial activity, structure–activity relationship of series of 2‐(trifluoromethyl)benzo[b][1,8]naphthyridin‐4(1H)‐ones

Cited by 8 publications

References 43 publications

Photo-Induced Partially Aromatized Intramolecular Charge Transfer

Photo-Induced Partially Aromatized Intramolecular Charge Transfer

Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production

Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting β-Hematin Crystallization

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