Tetramethylpiperidine‐substituted phenazines as novel anti‐plasmodial agents

Makgatho, Marema Ephraim; Anderson, Ronald; O’Sullivan, John; Egan, Timothy J.; Freese, Janet A.; Cornelius, Nicolene; Rensburg, C. E. J. Van

doi:10.1002/1098-2299(200006)50:2<195::aid-ddr10>3.3.co;2-k

Cited by 9 publications

(12 citation statements)

References 7 publications

(7 reference statements)

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“…Taken together, the inhibition caused by clofazimine at these concentrations was irreversible. The IC 50 s of clofazimine for Babesia and Theileria parasites reported in the present study were lower than those for P. falciparum (12,21) (Table 1). In addition, clofazimine was more effective against Babesia and Theileria species than against Leishmania donovani (22).…”

Section: Discussioncontrasting

confidence: 69%

Clofazimine Inhibits the Growth of Babesia and Theileria Parasites In Vitro and In Vivo

Tuvshintulga

AbouLaila

Davaasuren

et al. 2016

Antimicrob Agents Chemother

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The present study evaluated the growth-inhibitory effects of clofazimine, currently used for treating leprosy, against Babesia bovis, B. bigemina, B. caballi, and Theileria equi in in vitro culture and against Babesia microti in mice. The 50% inhibitory concentrations (IC 50 s) of clofazimine against the in vitro growth of B. bovis, B. bigemina, B. caballi, and T. equi were 4.5, 3, 4.3, and 0.29 M, respectively. In mice infected with B. microti, treatment with 20 mg/kg of body weight of clofazimine administered orally resulted in a significantly lower peak parasitemia (5.3%) than that in the control group (45.9%), which was comparable to the subcutaneous administration of 25 mg/kg diminazene aceturate, the most widely used treatment for animal piroplasmosis. Although slight anemia was observed in both clofazimine-and diminazene aceturate-treated infected mice, the level and duration of anemia were lower and shorter, respectively, than those in untreated infected mice. Using blood transfusions and PCR, we also examined whether clofazimine completely killed B. microti. On day 40 postinfection, when blood analysis was performed, parasites were not found in blood smears; however, the DNA of B. microti was detected in the blood of clofaziminetreated animals and in several tissues of clofazimine-and diminazene aceturate-treated mice by PCR. The growth of parasites was observed in mice after blood transfusions from clofazimine-treated mice. In conclusion, clofazimine showed excellent inhibitory effects against Babesia and Theileria in vitro and in vivo, and further study on clofazimine is required for the future development of a novel chemotherapy with high efficacy and safety against animal piroplasmosis and, possibly, human babesiosis.

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Section: Discussioncontrasting

confidence: 69%

Clofazimine Inhibits the Growth of Babesia and Theileria Parasites In Vitro and In Vivo

Tuvshintulga

AbouLaila

Davaasuren

et al. 2016

Antimicrob Agents Chemother

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“…5 Macrolactone synthesized from benzo [a] phenazine shows good activity against mycobacterium tuberculosis. 6 In general, natural and synthetic phenazines find useful applications against malaria 7 and hepatitis C viral replication. 8 The biological activity of phenazines is due to their redox reactions leading to the formation of toxic radicals.…”

mentioning

confidence: 99%

pH Dependent Electrochemical Characterization, Computational Studies and Evaluation of Thermodynamic, Kinetic and Analytical Parameters of Two Phenazines

Shah

Zaid

Shah

et al. 2014

J. Electrochem. Soc.

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The electrochemical response of two biologically important phenazine derivatives was examined by using cyclic, differential pulse and square wave voltammetry in a wide pH range of 2.0 -12.0. Cyclic voltammetry was employed for the determination of heterogeneous electron transfer rate constant and diffusion coefficient of the analytes. The value of electron transfer rate constant was used for evaluation of Gibbs free energy, enthalpy and entropy changes of redox reactions of the compounds. Differential pulse voltammetry was used for the determination of number of protons and electrons involved in the redox processes. Limits of detection and quantification were assessed by square wave voltammetry. The detailed pH dependent redox mechanisms of the compounds were proposed on the basis of experimental results which were further supported by theoretical calculations. These redox mechanistic pathways are expected to play a key role in understanding the necessary aspects of structure-activity relationships and exploring the hidden routes by which this class of compounds exert its biochemical actions. Phenazines have broad range applications in biology and chemistry.1 This class constitutes a large group of nitrogen containing heterocyclic compounds, the members of which differ in their chemical and physical properties on the basis of type and position of functional groups present. Naturally, phenazines are produced by limited genera of bacteria including Pseudomonas, Burkholderia and Brevibacterium.2 Starting from different parent materials, phenazines can be synthesized by various reactions including oxidative condensation, electrochemical reduction, reductive cyclization and photochemical reactions.From the last 50 years, phenazines are the subject of extensive research investigations because of their broad range applications in pharmaceutical and clinical research.3 Such compounds have been reported for their wide variety of biological activities such as antitumor, anti-parasitic and antibiotic activities. Benzo [a] phenazine acts as efficient DNA intercalating ligand with antitumor activity in leukaemia and solid tumors. 4 1-Hydroxyphenazine has been reported to have promising antifungal activity against various microbes such as aspergillus fumigatus and candida albicans.5 Macrolactone synthesized from benzo [a] phenazine shows good activity against mycobacterium tuberculosis. 6 In general, natural and synthetic phenazines find useful applications against malaria 7 and hepatitis C viral replication. 8The biological activity of phenazines is due to their redox reactions leading to the formation of toxic radicals. 9 Different functional groups attached to phenazine determine their redox potential and solubility. The redox behavior and concomitant modulation of biological activities of phenazines by changing the nature and position of substituents attached to their aromatic rings have been reported by several research groups.10-12 Phenazines can alter cellular redox states and act as transporters of electrons to altern...

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“…The colourless reaction product was reduced with Zn/water and, after the usual workup, was submitted to silica gel column chromatography using hexane/ethyl acetate (95:5) as eluent. Pure 2 (179 mg; 0.52 mmol, 52% yield) was obtained as a colourless crystalline product (melting point 162-163 o C) that was shown to be identical to an authentic sample of 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione (2) by mixed melting point and TLC (cochromatography). All of the physico-chemical data of 2 were in full accordance with those previously published.…”

Section: Methodsmentioning

confidence: 99%

“…Preparation of 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione (2). Yellow solution of lapazine, was prepared as described 4,9 (1; 314 mg; 1.0 mmol) in 20 mL of methylene chloride, treated with ozone at -5.0 o C until all substrate had reacted (1h).…”

Section: Methodsmentioning

confidence: 99%

“…O efeito de substituintes localizados no anel diidropirânico das fenazinas, no caso C2'-OH, C2'-Br e C2'-I, em reações de oxidação com MCPBA, foi também investigado.The benzophenazine from β-lapachone was submitted to ozonolysis under conditions that selectively furnished the corresponding rigid macrocyclic lactone 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione in an yield of 52%. The effect of substituents located at the dihydropyrane moiety of the phenazines, namely C2'-OH, C2'-Br and C2'-I, in the oxidation with MCPBA, was also investigated.…”

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confidence: 99%

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The preparation of a 10-membered ring macrolactone by selective ozonolysis and the role of the dihydropyran-substituent on the MCPBA-oxidation reaction profile of beta-lapachone phenazines

Silva¹,

Guimarães²,

Teixeira³

et al. 2005

J. Braz. Chem. Soc.

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A benzofenazina derivada da β-lapachona foi submetida a ozonólise em condições que forneceram seletivamente a lactona macrocíclica 7,7-dimetil-7,8,9,10-tetrahidro-5H-benzo[3,4]oxecino [5,6-b]quinoxalina-5,10-diona, com rendimento de 52%. O efeito de substituintes localizados no anel diidropirânico das fenazinas, no caso C2'-OH, C2'-Br e C2'-I, em reações de oxidação com MCPBA, foi também investigado.The benzophenazine from β-lapachone was submitted to ozonolysis under conditions that selectively furnished the corresponding rigid macrocyclic lactone 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione in an yield of 52%. The effect of substituents located at the dihydropyrane moiety of the phenazines, namely C2'-OH, C2'-Br and C2'-I, in the oxidation with MCPBA, was also investigated.Keywords: β-lapachone, ozonolysis, 10-membered ring macrolide, selectivity, effect of substituent IntroductionIn general, natural and synthetic phenazines have attracted considerable attention because of their interesting biological activities, 1 including broad-spectrum antibiotic, 2 antimalarial, 3,4 trypanocidal 5 along with anti hepatitis C viral replication activities.6 Benzo[a]phenazines are also efficient DNA intercalating ligands, exhibiting antitumor activity in leukaemia and solid tumors.7 They have also been described as dual inhibitors of topoisomerase I and II. 8 In our search for preparing new derivatives, for synthetic purposes and biological screening, we recently reported 9 that peroxidation of the b-lapachone-derived benzophenazine, named lapazine (1), with m-ClC 6 H 4 CO 2 H/CH 2 Cl 2 generated, unexpectedly, a macrocyclic lactone 2 with a rigid 10-membered ring (27% yield), the corresponding N-oxide 3 (13% yield), and the dihydrobenzophenazine-5-one 4 (35% yield) (Figure 1). Macrocyclic compounds 2 and 3 were formed via oxidative cleavage of the aromatic double bond at the site of fusion of the dihydropyran moiety with the phenazine component. This region (rings C/E, in 1) (Figure 1) would behave as a conjugated enol ether, which, after the expected epoxide formation and fragmentation would lead to 2 and 3 (further oxidation). An acid-catalysed epoxide-acetal or α-hydroxy hemiacetal would furnish 4. 9Compounds 2 and 3 belong to the class of macrolides, an important group of biologically active compounds, especially recognized as antibiotics. 10Among 10-membered macrolactones, the antibiotic activity of apicularen A and B was reported. 11In the present work, considering 2 and 3, the presence of diaza heterocyclic groups close to the ion-binding macrolactone moiety constitutes attractive molecular features.In searching for a more general application of the oxidative cleavage by MCPBA, 9 we have analysed the role of substituent, at C-2', in the dihydropyrane moiety of lapazine, namely -OH (5), -Br (6) and -I (7) (Figure 1). 1075 The Preparation of a 10-Membered Ring Macrolactone Vol. 16, No. 5, 2005 Additionally, in an attempt to develop a more selective and simpler method by...

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Tetramethylpiperidine‐substituted phenazines as novel anti‐plasmodial agents

Cited by 9 publications

References 7 publications

Clofazimine Inhibits the Growth of Babesia and Theileria Parasites In Vitro and In Vivo

Clofazimine Inhibits the Growth of Babesia and Theileria Parasites In Vitro and In Vivo

pH Dependent Electrochemical Characterization, Computational Studies and Evaluation of Thermodynamic, Kinetic and Analytical Parameters of Two Phenazines

The preparation of a 10-membered ring macrolactone by selective ozonolysis and the role of the dihydropyran-substituent on the MCPBA-oxidation reaction profile of beta-lapachone phenazines

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