Structural Optimization of Quinolon-4(1<i>H</i>)-imines as Dual-Stage Antimalarials: Toward Increased Potency and Metabolic Stability

Ressurreição, Ana S.; Gonçalves, Daniel; Sitoe, Ana R.; Albuquerque, Inês S.; Gut, Jiří; Góis, Ana; Gonçalves, Lídia; Bronze, Maria Rosário; Hänscheid, Thomas; Biagini, Giancarlo A.; Rosenthal, Philip J.; Prudêncio, Miguel; Mota, Maria M.; Lopes, Francisca; Moreira, Rui

doi:10.1021/jm4011466

Cited by 18 publications

(15 citation statements)

References 48 publications

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“…16 The design of aminoquinoline derivatives, including chloroquine, has demonstrated the possibility of modifying the structure of this class of compounds towards improving their spectrum of action. [17][18][19][20] We recently showed that organoruthenium complexes containing chloroquine in their composition presented in vitro and in vivo antimalarial activity. These organoruthenium complexes affected trophozoites by inhibiting hemozoin formation and producing reactive oxygen species (ROS) but, unlike chloroquine, they exhibited fast parasiticidal activity against blood stages and reduced viability of gametocytes.…”

Section: Introductionmentioning

confidence: 99%

Platinum(ii)–chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function

et al. 2017

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Chloroquine is an antimalarial agent with strong activity against the blood stage of Plasmodium infection, but with low activity against the parasite's liver stage. In addition, the resistance to chloroquine limits its clinical use. The discovery of new molecules possessing multistage activity and overcoming drug resistance is needed. One possible strategy to achieve this lies in combining antimalarial quinolones with the pharmacological effects of transition metals. We investigated the antimalarial activity of four platinum(ii) complexes composed of chloroquine and phosphine ligands, denoted as WV-90, WV-92, WV-93 and WV-94. In comparison with chloroquine, the complexes were less potent against the chloroquine-sensitive 3D7 strain but they were as active as chloroquine in inhibiting the chloroquine-resistant W2 strain of P. falciparum. Regarding selectivity, the complexes WV-90 and WV-93 displayed higher indexes. Unlike chloroquine, the complexes act as irreversible parasiticidal agents against trophozoites and the WV-93 complex displayed activity against the hepatic stage of P. berghei. The in vivo suppression activity against P. berghei in the Peters 4 day test displayed by the complexes was similar to that of chloroquine. However, the efficacy in an established P. berghei infection in the Thompson test was superior for the WV-93 complex compared to chloroquine. The complexes' antimalarial mechanism of action is initiated by inhibiting the hemozoin formation. While chloroquine efficiently inhibits hemozoin, parasites treated with the platinum complexes display residual hemozoin crystals. This is explained since the interaction of the platinum complexes with ferriprotoporphyrin is weaker than that of chloroquine. However, the complexes caused a loss of mitochondrial integrity and subsequent reduction in mitochondrial activity, and their effects on mitochondria were more pronounced than those in the chloroquine-treated parasites. The dual effect of the platinum complexes may explain their activity against the hemozoin-lacking parasites (hepatic stage), where chloroquine has no activity. Our findings indicate that the platinum(ii)-chloroquine complexes are multifunctional antimalarial compounds and reinforce the importance of metal complexes in antimalarial drug discovery.

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Section: Introductionmentioning

confidence: 99%

Platinum(ii)–chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function

et al. 2017

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“…Compound synthesis. The synthesis and characterization of all compounds screened has been previously reported (9,10,13,14). Stock solutions with concentrations between 10 and 20 mM were prepared by dissolving the compounds in dimethyl sulfoxide (DMSO) at room temperature and were stored at 220°C.…”

Section: Methodsmentioning

confidence: 99%

“…SQ, on the other hand, was reported to inhibit succinate dehydrogenase (complex II), an essential enzyme for Leishmania (8). Quinolin-4(1H)-imines, which can be considered tautomeric analogues of quinolines, were previously reported by some of us as potent dual-stage antiplasmodials, displaying potential to bind to the Q o ubiquinone oxidation site of cytochrome bc 1 from Plasmodium falciparum (9,10). More recently, quinolin-4(1H)imines were also disclosed as efficient antitrypanosomal agents, endowed with excellent pharmacokinetic profiles (11).…”

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confidence: 99%

Biological Evaluation and Mechanistic Studies of Quinolin-(1 H )-Imines as a New Chemotype against Leishmaniasis

Gomes‐Alves

Duarte

Cruz

et al. 2021

Antimicrob Agents Chemother

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Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, urging the need for more effective, safer, and cheaper drugs. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, L. amazonensis and L. major. Several of the screened compounds showed IC50 values against intracellular L. infantum parasites in the submicromolar range (1h: IC50 0.9 μM and 1n: IC50 0.7 μM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major, albeit in the low micromolar range. Mechanistic studies revealed that 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that 1n is a promising antileishmanial lead and emphasize the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.

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“…Basis Set 22 Quinolon-4 (1H) -imine molecules with an effective concentration (EC50) against Plasmodium falciparum W2, which causes malaria (Table 1) obtained from the publication of Ressurreição et al, [22]. The parent structure of the Quinolon-4 (1H) -imine compound is presented in Figure 1.…”

Section: Methodsmentioning

confidence: 99%

QSAR and Ab Initio studies of quinolon-4(1H)-imine derivatives as antimalarial agents

Kilo¹,

Kilo²,

Hamdiani³

2021

Acta.Chim.Asiana

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Study on antimalarial activity of 22 quinolon-4(1H)-imine derivatives by using Quantitative Structure-Activity Relationships (QSAR) has been performed. Electronic and molecular descriptors were used in Quantitative Structure-Activity Relationships (QSAR) model and it was obtained from Hartree-Fock (HF) molecular orbital calculation with 6-31G basis set. QSAR analysis has been performed by multiple linear regression (MLR) method. The best equation of QSAR model on this study is: pEC50 = -4,177 + (37,902 x qC3) + (171,282 x qC8) + (9,061 x qC10) + (125,818 x qC11) + (-149,125 x qC17) + (191,623 x qC18), with statistical parameters, n = 22; r2 = 0,910; SEE = 0,171; Fcal/Ftab = 4,510 and PRESS = 0,697. The best equation can applied to design and predict new compounds with higher antimalarial activity.

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Structural Optimization of Quinolon-4(1H)-imines as Dual-Stage Antimalarials: Toward Increased Potency and Metabolic Stability

Cited by 18 publications

References 48 publications

Platinum(ii)–chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function

Platinum(ii)–chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function

Biological Evaluation and Mechanistic Studies of Quinolin-(1 H )-Imines as a New Chemotype against Leishmaniasis

QSAR and Ab Initio studies of quinolon-4(1H)-imine derivatives as antimalarial agents

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