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Layout of a combination experiment in a 96-well plate with the concentration ratios of drug A and drug B prepared as six solutions. When plates were prepared as described in the text, clear wells serve as aquadest, dot black wells serve as a parasite control (no drug, 0% growth inhibition), and wells labeled 1 to 6 serve as drug wells for six drug combination solution, in triplicate, with the wells in row F holding the lowest drug concentration. Both 96-well plates were prepared similarly, with row F2 representing solutions 4 to 6 in the second 96-well plate. Drug A was (1)-N-alkyl and (1)-N-benzyl-1,10-phenanthroline derivatives, drug B was either E64 or chloroquine.
Source publication
Potential new targets for antimalarial chemotherapy include parasite proteases, which are required for several cellular functions during the Plasmodium falciparum life cycle. Four new derivatives of N-alkyl and N-benzyl-1,10-phenanthroline have been synthesized. Those are (1)-N-methyl-1,10-phenanthrolinium sulfate, (1)-N-ethyl-1,10-phenanthrolinium...
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Citations
... The 1,10-phenantroline scaffolds [6,7], particularly N-benzyl-1,10-phenantrolinium salts, display great potential as antiplasmodium agents [8][9][10]. The activity of the drug is also correlated to their anion counterpart, where large anions, such as bromide or iodide, may give good antiplasmodium profile [11][12][13]. ...
This study describes the development of N-benzyl-1,10-phenantrolinium salt as an antiplasmodium agent. The salt, that is, 1-(4-ethoxy-3-methoxybenzyl)-1,10-phenanthrolin-1-ium bromide, was prepared using vanillin as the starting material in four simple synthetic steps. First, the alkylation of vanillin using diethyl sulfate produced 4-ethoxy-3- methoxybenzaldehyde in 79% yield. Second, the reduction of the protected vanillin by NaBH4 through the grinding method allowed us to obtain 4-ethoxy-3-methoxybenzyl alcohol in 96% yield. Next, the bromination of the benzyl alcohol under solvent-free condition led to the formation of the corresponding benzyl bromide, which in turn underwent bimolecular nucleophilic substitution with 1,10-phenanthroline to produce the desired product, that is, 1-(4-ethoxy-3- methoxybenzyl)-1,10-phenanthrolin-1-ium bromide, in 58% yield. The evaluation of N-benzyl-1,10-phenantrolinium salt as an antiplasmodium agent was conducted through heme polymerization inhibitory activity (HPIA) assay. The results showed that the phenantroline salt and chloroquine displayed the HPIA half maximal inhibitory concentrations of 3.63 and 4.37 mM, respectively. Therefore, 1-(4-ethoxy-3-methoxybenzyl)-1,10-phenanthrolin-1-ium bromide displays desirable HPIA and has a great potential to be further developed as an antiplasmodium.
... Some bioactive antiprotozoal phenanthrolines based on this structure have been described such as 4,7-phenanthrolines C and D ( Figure 1) [18], 4-chloro-2-methyl-3-vinyl-1,10-phenanthroline E ( Figure 1) [19], 4-methoxy-11-methyl-3H-pyrrolo [3,2-c] [1,10]phenanthroline F (Figure 1) [20], and N-benzyl-1,10phenanthrolinium iodide G ( Figure 1) [21,22]. This phenanthroline moiety could also be considered as a bioisoster of the phenanthrene heterocycle found in the halofantrine's structure [5]. ...
... Moreover, previous studies on in vitro antiplasmodial activity of diaza phenanthrene analogs indicated that the 1,10-phenanthroline skeleton represents an interesting and potential antimalarial lead compound. A few bioactive antimalarial phenanthrolines based on this skeleton have been described such as 4,7-phenanthrolines C and D (Figure 1) [17], 4chloro-2-methyl-3-vinyl-1,10-phenanthroline E (Figure 1) [18], 4-methoxy-11-methyl-3Hpyrrolo [3,2-c] [1,10]phenanthroline F (Figure 1) [19], and N-benzyl-1,10-phenanthrolinium iodide G (Figure 1) [20,21]. Moreover, the study of the trypanocidal activity of new anilinophenanthrolines H-J against Trypanosoma cruzi has also been reported [22]. ...
A series of novel 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Pharmacological results showed antiprotozoal activity with IC50 values in the sub and μM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline 1l was identified as the most potent antimalarial derivative with a ratio of cytotoxic to antiparasitic activities of 505.7 against the P. falciparum CQ-resistant strain W2. Against the promastigote forms of L. donovani, the phenanthrolines 1h, 1j, 1n and 1o were the most active with IC50 from 2.52 to 4.50 μM. The phenanthroline derivative 1o was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on T. brucei brucei strain. FRET melting and native mass spectrometry experiments evidenced that the nitrogen heterocyclic derivatives bind the telomeric G-quadruplexes of P. falciparum and Trypanosoma. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma could be considered to be possible targets of this kind of nitrogen heterocyclic derivatives, their potential ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.
... Wijayanti et al. [21] reported a strong antiproliferative effect of 1,10phenanthroline derivatives against Plasmodium falciparum with IC 50 values ranging from 260.42 to 465.38 nM. Four hundred compounds of the Open Access Malaria Box were evaluated against the cysteine proteases, cruzipain, by Pereira et al. [22] and 70 of them inhibited this enzyme by at least 50% at 5 μM. ...
Chagas disease is present in Latin America, North America, Europe, and Asia, where between 6 and 7 million people are infected. This illness is transmitted mainly by the insect vector during blood feeding and by oral transmission. Chagas disease is treated with benznidazole and its effectiveness depends on which phase of the disease the treatment starts. Therefore, the identification of new compounds with anti-Chagas activities is important. Protozoan parasites present cysteine proteases, important for host cell infection and differentiation, which have been explored as valid targets against pathogenic parasites. In the present study, the effects of 10 new 1,10-phenanthroline derivatives were evaluated on T. cruzi. Three of them were effective against amastigotes (IC50 from 0.5 to 3 μM), epimastigotes (IC50 from 0.5 to at least 10 μM) and trypomastigotes (and LD50 from 1 to 10 μM), and they were not toxic to mammalian cells (CC50 ≥ 20 μM). These compounds also promoted the formation of autophagosomes, alter the level of heterochromatin condensation, caused the loss of kDNA topology, and the elongated cell body shape. Apart from ultrastructural alterations, an increased generation of ROS and decreased mitochondrial membrane potential were observed. Therefore, these drugs revealed potential trypanocidal effects and warrant further antiparasitic studies against Chagas disease.
... Previous studies have showed that during intraerythrocytic development, the phospholipid content of the parasite increases significantly as the latter accumulates membranes needed for growth and division 33 . Though some of the lipids are synthesized in the apicoplast, the bulk of the lipids are scavenged from the host. ...
Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline–oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3′4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.
... Meanwhile, it showed high selectivity on P. falciparum proteases with very high IC 50 value on Vero cells [103] . In addition, in vivo investigation showed clearance of parasitemia 4 days after treatment of P. berghei-infected mice [104] . To identify the mechanism of action, a third study was conducted by comparing the in vitro and in vivo results with those obtained using chloroquine and E-64. ...
... The agent used in this study was FEN, which derivatives of Nalkyl and N-benzyl-1-10-phenanthroline ( Fig. 1). FEN has been synthesized and modified by Setiawati et al. [15] and Wijayanti et al. [17], obtained from the faculty of mathematics and natural sciences of Universitas Gadjah Mada, Yogyakarta, Indonesia. This compound was dissolved to a concentration of 1000 mg/mL in dimethyl sulfoxide (DMSO; Sigma-Aldrich, Missouri, USA) and stored at À20 8C. ...
The therapy for invasive candidiasis related to biofilms infection remains a difficult medical problem. To overcome this problem, efforts have been made to search for novel antibiofilm agents from various sources. This study investigated the in vitro antibiofilm activity of (1)-N-2-methoxybenzyl-1,10-phenanthrolinium bromide (FEN) against Candida albicans. The minimum biofilm inhibitory concentration (MBIC) and minimum biofilm reduction concentration (MBRC) were determined using the MTT (3-(4-5-dimethylthiazol-2-yl)2,5-dyphenyl tetrazolium bromide) reduction assay. Biofilms on surfaces were visualized using scanning electron microscopy (SEM). This new compound inhibited the growth of C. albicans biofilms by 80 % with an MBIC80 range from 0.5-2.0μg/mL. The ability of FEN to reduce 50 % of a preformed biofilm was demonstrated by defining a MBRC50 range from 6.25--12.5μg/mL. To reduce 80 % of a preformed biofilm required higher concentrations >200μg/mL. In addition, SEM images showed disruption of C. albicans biofilms matrix exposed to FEN. These results indicated that (1)-N-2-methoxybenzyl-1,10-phenanthrolinium bromide has the potential to be developed as a new antibiofilm agent against C. albicans.
... The 1,10-phenanthroline is one of these heteroaromatic scaffolds that is considered as diaza-analog of phenanthrene with two nitrogen atoms at C-1 and C-10 positions and quinoline analog with a fused pyridine ring. Therefore, considering the side effects, high cost, and unreliable absorption of HAL, the researchers synthesized its diaza-analogs by the replacement of phenanthrene with 1,10-phenanthroline and evaluated their antiplasmodial activities in both in vitro and in vivo tests ( Figure 1) (14)(15)(16)(17)(18)(19)(20). ...
... In the present study, with regard to the spread of resistance to quinoline antiplasmodial drugs, their disadvantages, and the great potential of 1,10phenanthroline (14)(15)(16)(17)(18)(19), four new phenanthroline derivatives were synthesized and evaluated for the first time against Plasmodium berghei (ANKA strain). Similar to the available antiplasmodial drugs, these derivatives were composed of aliphatic side chain containing tertiary amine. ...
... Previous studies have shown that phenanthroline derivatives have antiplasmodial activity (14)(15)(16)(17)(18)(19)(20). For instance, the derivatives of N-benzyl-1,10-phenanthroline (1 and 2) have been demonstrated to have good activity against FCR-3 strain with the IC50 values of 0.1 and 0.18 µM, respectively after 72-hr incubation ( Figure 1) (16). ...
Objective(s)
Due to the rapid increased drug resistance to Plasmodium parasites, an urgent need to achieve new antiplasmodial drugs is felt. Therefore, in this study, the new synthetic phenanthroline derivatives were synthesized with antiplasmodial activity.
Materials and Methods
A series of 1,10-phenanthroline derivatives containing amino-alcohol and amino-ether substituents were synthesized via facile procedures, starting with 5,6-epoxy-1,10-phenanthroline. Their antiplasmodial activity was then evaluated using Peter’s 4-day suppressive test against Plasmodium berghei-infected mice (ANKA strain). Furthermore, the mean survival time of the mice treated with synthetic compounds was compared with the negative control group.
Results
The results demonstrated that the compounds 6-(3-(dibutylamino)propylamino)-5,6-dihydro-1,10-phenanthroline-5-ol(7b) at the dose of 150 mg/kg/day and 4-(1,10-phenanthroline-5-yloxy)-N, N-dipropylbutan-1-amine (8b) at the dose of 15 mg/kg/day have 90.58% and 88.32% suppression, respectively. All synthetic compounds prolonged the mean survival time of treated mice in comparison with negative control groups, indicating the in vivo antiplasmodial activity of these new compounds.
Conclusion
The present study is the first attempt to achieve new, effective synthetic compounds based on phenanthroline scaffold with the antiplasmodial activity. However, more research is needed to optimize their antimalarial activity.
... The stock solutions were stored frozen at −70 o C until the day of the test. The final concentrations of dimethyl sulfoxide (DMSO) were 1% in all assays [14]. ...
Metal-based drugs, such as 1,10-phenanthroline, have demonstrated anticancer, antifungal and antiplasmodium activities. One of the 1,10-phenanthroline derivatives compounds (1)-N-2-methoxybenzyl-1,10-phenanthrolinium bromide (FEN), which has been demonstrated an inhibitory effect on the growth of Candida spp. This study aimed to explore the in vitro antifungal activity of FEN and its effect on the membrane integrity of Candida albicans. The minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of FEN against planktonic C. albicans cells were determined using the broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines. Cell membrane integrity was determined with the propidium iodide assay using a flow cytometer and were visualized using scanning electron microscopy (SEM). Planktonic cells growth of C. albicans were inhibited by FEN, with an MIC of 0.39–1.56 µg/mL and a MFC that ranged from 3.125 to 100 µg/mL. When C. albicans was exposed to FEN, the uptake of propidium iodide was increased, which indicated that membrane disruption is the probable mode of action of this compound. There was cells surface changes of C. albicans when observed under SEM.
... The activity of the 20S subunit of the proteasomes can be exclusively inhibited by binding between the proteasome proteins and the 20S β-subunit (27). E64, a specific inhibitor of lysosomes, inhibits the activity of cysteine proteinases in the lysosome and affects the degradation of the substrate (28). ...
The aim of this study was to investigate the effect of lysosomal and ubiquitin-proteasome system dysfunction on the abnormal aggregation of α-synuclein, and to analyze its role in the pathogenesis of Parkinson's disease (PD). PC12 cells subjected to nerve growth factor-induced differentiation were used as the cell model to study the dopaminergic neurons, and the lysosomal and proteasomal inhibitors trans-epoxysuccinyl-L-leucylamido-(4-guanidino) butane (E64) and, respectively, were used exclusively and in combination to treat the PC12 cells. The viability and metabolic state of the cells was assessed using the MTT assay; flow cytometry was used to measure the rate of cell apoptosis; and the double immunofluorescence method was applied to observe the formation of thioflavin S- and α-synuclein protein-positive aggregates and inclusion bodies in the PC12 cells. In addition, the Hoechst 33258 staining method was used to observe the apoptosis of the α-synuclein protein and thioflavin-S double-labeled cells. Following the administration of the lysosomal and proteasomal pathway inhibitors, the cell viability decreased in a concentration-dependent manner and the cell apoptosis rate increased. The proportion of PC12 cells with α-synuclein protein-positive aggregates and inclusion bodies in the E64 group was 7.94%, compared with 20.33 and 36.77% in the lactacystin and combination treatment groups, respectively. Statistical analysis indicated that the number of inclusion body-positive cells in the treatment groups was significantly higher than that in the control group (3.78%) (P<0.05). Apoptosis was evident in the double-positive cells with α-synuclein protein-positive inclusion bodies (17.29±1.54%). In conclusion, lysosomal and proteasomal dysfunction may play an important role in the pathogenesis of PD through the induction of abnormal α-synuclein protein aggregation in dopaminergic neurons.
