Over 1 billion people globally are estimated to be infected with Toxoplasma gondii with severe or unknown consequences and no safe and effective therapies are available against congenital or persistent chronic infecti...Over 1 billion people globally are estimated to be infected with Toxoplasma gondii with severe or unknown consequences and no safe and effective therapies are available against congenital or persistent chronic infection. We propose that atovaquone and diclazuril synergistically protect against fetal-maternal toxoplasmosis. Methods: Programmed pregnant mice were treated with atovaquone and diclazuril monotherapy, or combined (atovaquone + diclazuril) therapy and infected with tachyzoites (0, 300, 600) and the course of infection was studied. Results: Infected dams with low dose (300) developed moderate toxoplasmosis complications and treatments were similarly effective with minor differences between monotherapies. In contrast, major differences were observed amongst varied treatments during high-dose (600) infection and severe related-toxoplasmosis complications as follows. Dams developed hydrothorax, ascities and excess weight gain. Combined therapy (P < 0.01) and to a lesser extent diclazuril monotherapy (P 0.05) protected dams from excess weight, hydrothorax, and ascities. Infected dams exhibited splenomegaly, hepatomegaly and severe hepatitis. Combined therapy synergistically normalized pathology (P < 0.001) and to a lesser degree monotherapy (diclazuril P 0.01, and atovaquone P 0.05) protected dams from hepatitis and splemomegaly. Additionally, behavioral response to pain stimuli and fetal weight and fetal numbers were significantly preserved in treated dams. Conclusions: This is the first report describing combined atovaquone and diclazuril therapy a) to be safe in pregnancy, b) to exert novel synergistic effects, and c) to protect dams and their nested fetuses against adverse effects of severe toxoplasmosis.展开更多
Tans-Atovaquone is widely used as an effective drug to treat uncomplicated malaria. But its cis-isomer is not a drug. In the present study, we report energy minimized binding pattern of trans-Atovaquone and its cisiso...Tans-Atovaquone is widely used as an effective drug to treat uncomplicated malaria. But its cis-isomer is not a drug. In the present study, we report energy minimized binding pattern of trans-Atovaquone and its cisisomer with cytochrome bc1 (cytbc1) of yeast. The new feature of this molecular docking computation is that structural parameters of the drug molecules have been determined from their crystal structures. The energy minimized structures of protein-drug complexes show that H-bond distant between His-181 of cytochrome bc1 and C=O of Atovaquone for trans-Atovaquone is 2.85 Å and 5.3 Å with the cis-isomer. The role of this H-bonding interaction in dictating drug potency is in conformity with proton-coupled electron transport mechanism of drug action.展开更多
Five novel metal-based complexes of Ag(Ⅰ)[Ag(ATV)](1),Zn(Ⅱ)[Zn(ATV)_(2)(H_(2)O)_(2)]·2H_(2)O(2),[Zn(ATV)_(2)(CH_(3)OH)_(2)]·H_(2)O(3),{Zn(ATV)_(2)}_(n)(4),and Cu(Ⅱ)[Cu(ATV)_(2)](5),with the antimalarial n...Five novel metal-based complexes of Ag(Ⅰ)[Ag(ATV)](1),Zn(Ⅱ)[Zn(ATV)_(2)(H_(2)O)_(2)]·2H_(2)O(2),[Zn(ATV)_(2)(CH_(3)OH)_(2)]·H_(2)O(3),{Zn(ATV)_(2)}_(n)(4),and Cu(Ⅱ)[Cu(ATV)_(2)](5),with the antimalarial naphthoquinone atovaquone(ATV)were synthesized and characterized.Ag(Ⅰ)and Cu(Ⅱ)complexes were thoroughly analyzed using IR,NMR,EPR,and conductivity measurements,whereas the crystal structures of the three Zn(Ⅱ)complexes were determined by single-crystal X-ray diffraction,supported by complementary analytical techniques.Depending on the metal center,ATV coordinates in either a monodentate or bidentate coordination mode,producing highly stable metal complexes both in the solid state and in DMSO solution.These metal-ATV complexes retain the potent antiplasmodial activity of ATV against chloroquine-sensitive and-resistant Plasmodium falciparum strains and introduce additional mechanisms of action.According to FT IR results,Zn(Ⅱ)complexes inhibit β-hematin formation,complex 3 accelerates ring-stage parasite killing,and complex 5 promotes intracellular copper accumulation,which correlate with enhanced antiplasmodial potency.These results demonstrate that metal coordination can fine-tune the ATV biological profile,positioning these compounds as promising leads for the design of new antimalarial drugs.展开更多
文摘Over 1 billion people globally are estimated to be infected with Toxoplasma gondii with severe or unknown consequences and no safe and effective therapies are available against congenital or persistent chronic infection. We propose that atovaquone and diclazuril synergistically protect against fetal-maternal toxoplasmosis. Methods: Programmed pregnant mice were treated with atovaquone and diclazuril monotherapy, or combined (atovaquone + diclazuril) therapy and infected with tachyzoites (0, 300, 600) and the course of infection was studied. Results: Infected dams with low dose (300) developed moderate toxoplasmosis complications and treatments were similarly effective with minor differences between monotherapies. In contrast, major differences were observed amongst varied treatments during high-dose (600) infection and severe related-toxoplasmosis complications as follows. Dams developed hydrothorax, ascities and excess weight gain. Combined therapy (P < 0.01) and to a lesser extent diclazuril monotherapy (P 0.05) protected dams from excess weight, hydrothorax, and ascities. Infected dams exhibited splenomegaly, hepatomegaly and severe hepatitis. Combined therapy synergistically normalized pathology (P < 0.001) and to a lesser degree monotherapy (diclazuril P 0.01, and atovaquone P 0.05) protected dams from hepatitis and splemomegaly. Additionally, behavioral response to pain stimuli and fetal weight and fetal numbers were significantly preserved in treated dams. Conclusions: This is the first report describing combined atovaquone and diclazuril therapy a) to be safe in pregnancy, b) to exert novel synergistic effects, and c) to protect dams and their nested fetuses against adverse effects of severe toxoplasmosis.
文摘Tans-Atovaquone is widely used as an effective drug to treat uncomplicated malaria. But its cis-isomer is not a drug. In the present study, we report energy minimized binding pattern of trans-Atovaquone and its cisisomer with cytochrome bc1 (cytbc1) of yeast. The new feature of this molecular docking computation is that structural parameters of the drug molecules have been determined from their crystal structures. The energy minimized structures of protein-drug complexes show that H-bond distant between His-181 of cytochrome bc1 and C=O of Atovaquone for trans-Atovaquone is 2.85 Å and 5.3 Å with the cis-isomer. The role of this H-bonding interaction in dictating drug potency is in conformity with proton-coupled electron transport mechanism of drug action.
基金funded by the Brazilian agencies:FAPEMIG:APQ-00201-24Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq grants 422821/2025-0 and 440227/2022-4)+7 种基金CAPES(Finance Code 001)the Direction Générale de l’Armement[grant NBC-2-B-2120]the National Research Agency under the“Investments for Future”programme[grant ANR-10-IAHU]the European Regional Development Fund(FEDER)[grant FEDER IHUPERF]support of MCT/FINEP/CT-INFRA(grant no.01/2013-REF 0633/13,coordinated by Prof.M.de Oliveira)FAPESP and the Redoxoma project(grant no.2013/07937-8)for funding the EPR instrumentationPTDC/QUI-QIN/29697/2017 and PTDC/QUI-QIN/3898/2020(2021-2024)support provided by MINDLab(https://www.mindlab.pt)。
文摘Five novel metal-based complexes of Ag(Ⅰ)[Ag(ATV)](1),Zn(Ⅱ)[Zn(ATV)_(2)(H_(2)O)_(2)]·2H_(2)O(2),[Zn(ATV)_(2)(CH_(3)OH)_(2)]·H_(2)O(3),{Zn(ATV)_(2)}_(n)(4),and Cu(Ⅱ)[Cu(ATV)_(2)](5),with the antimalarial naphthoquinone atovaquone(ATV)were synthesized and characterized.Ag(Ⅰ)and Cu(Ⅱ)complexes were thoroughly analyzed using IR,NMR,EPR,and conductivity measurements,whereas the crystal structures of the three Zn(Ⅱ)complexes were determined by single-crystal X-ray diffraction,supported by complementary analytical techniques.Depending on the metal center,ATV coordinates in either a monodentate or bidentate coordination mode,producing highly stable metal complexes both in the solid state and in DMSO solution.These metal-ATV complexes retain the potent antiplasmodial activity of ATV against chloroquine-sensitive and-resistant Plasmodium falciparum strains and introduce additional mechanisms of action.According to FT IR results,Zn(Ⅱ)complexes inhibit β-hematin formation,complex 3 accelerates ring-stage parasite killing,and complex 5 promotes intracellular copper accumulation,which correlate with enhanced antiplasmodial potency.These results demonstrate that metal coordination can fine-tune the ATV biological profile,positioning these compounds as promising leads for the design of new antimalarial drugs.
