|
Inhibitory concentration against Plasmodium falciparum D6 infected erythrocytes
|
Plasmodium falciparum
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum.
Year : 1994
Volume : 37
Issue : 10
First Page : 1486
Last Page : 1494
Authors : Gamage SA, Tepsiri N, Wilairat P, Wojcik SJ, Figgitt DP, Ralph RK, Denny WA.
Abstract : A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1'-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 values of 10-20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution.
|
Inhibitory concentration against Plasmodium falciparum W2 infected erythrocytes
|
Plasmodium falciparum
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum.
Year : 1994
Volume : 37
Issue : 10
First Page : 1486
Last Page : 1494
Authors : Gamage SA, Tepsiri N, Wilairat P, Wojcik SJ, Figgitt DP, Ralph RK, Denny WA.
Abstract : A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1'-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 values of 10-20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution.
|
Inhibitory concentration IC50 against Plasmodium falciparum K1 by [3H]hypoxanthine uptake over 24 hr
|
Plasmodium falciparum
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum.
Year : 1994
Volume : 37
Issue : 10
First Page : 1486
Last Page : 1494
Authors : Gamage SA, Tepsiri N, Wilairat P, Wojcik SJ, Figgitt DP, Ralph RK, Denny WA.
Abstract : A series of 9-anilinoacridines have been prepared and evaluated for their activity against a multidrug-resistant K1 strain of the malaria parasite Plasmodium falciparum in erythrocyte suspensions. 3,6-Diamino substitution on the acridine ring resulted in lower mammalian cell cytotoxicity and higher antiparasitic activity than other substitution patterns, providing compounds with the highest in vitro therapeutic indices. A new synthesis of 3,6-diamino-9-anilinoacridines, via reduction of the corresponding diazides, gives much higher yields than traditional methods. Within the subset of 3,6-diamino-9-anilinoacridines, there was considerable tolerance to substitution at the 1'-anilino position. In a sharp divergence with structure-activity relationships for high mammalian cell toxicity and anticancer effects, derivatives bearing electron-withdrawing 1'-substituents (e.g., SO2-NHR and CONHR) showed the most potent antimalarial activity (IC50 values of 10-20 nM). Representative compounds were shown to be potent inhibitors of the DNA strand-passing activity of human topoisomerase II and of the DNA decatenation activity of the corresponding parasite enzyme. The 1'-SO2NH2derivative 7n completely inhibited strand passage by Jurkat topoisomerase II at 20 microM, and an increase in linear DNA (indicative of inhibition of religation) was seen at or above 1 microM. It also inhibited the decatenating activity of the parasite topoisomerase II at 6 microM and above. In contrast, the analogous compound without the 3,6-diamino substituent was inactive in both assays up to 100 microM. Overall, there was a positive relationship between the ability of the drugs to inhibit parasite growth in culture and their ability to inhibit parasite topoisomerase II activity in an isolated enzyme assay. The 1'-SO2NH2 derivative 7n showed a high IVTI (1000) and was a potent inhibitor of both P. falciparum in vitro (IC50 20 nM) and P. falciparum-derived topoisomerase II. However, the compound was inactive against Plasmodium berghei in mice; reasons may include rapid metabolic inactivation (possibly by N-acetylation) and/or poor distribution.
|
Antimalarial activity against Plasmodium falciparum at the ring stage infected in human erythrocytes assessed as growth inhibition by microscopic analysis using giemsa staining
|
Plasmodium falciparum
|
1.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium falciparum trophozoites infected in human erythrocytes assessed as growth inhibition by microscopic analysis using giemsa staining
|
Plasmodium falciparum
|
8.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium vivax at the ring stage infected in human erythrocytes assessed as growth inhibition by microscopic analysis using giemsa staining
|
Plasmodium vivax
|
2.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium vivax trophozoites infected in human erythrocytes assessed as growth inhibition by microscopic analysis using giemsa staining
|
Plasmodium vivax
|
4.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium falciparum infected in human erythrocytes assessed as growth inhibition by microscopic analysis using giemsa staining
|
Plasmodium falciparum
|
1.92
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium vivax infected in human erythrocytes assessed as growth inhibition by microscopic analysis using giemsa staining
|
Plasmodium vivax
|
2.58
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium vivax with >50% parasites at ring stage infected in human erythrocytes assessed as growth inhibition after 30 to 50 hrs by microscopic analysis using giemsa staining
|
Plasmodium vivax
|
2.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Year : 2010
Volume : 54
Issue : 12
First Page : 5146
Last Page : 5150
Authors : Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B.
Abstract : Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
|
Antimalarial activity against Plasmodium malariae trophozoite stage infected in red blood cells in presence of AB+ human serum by drug susceptibility assay
|
Plasmodium malariae
|
7.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia.
Year : 2011
Volume : 55
Issue : 1
First Page : 197
Last Page : 202
Authors : Siswantoro H, Russell B, Ratcliff A, Prasetyorini B, Chalfein F, Marfurt J, Kenangalem E, Wuwung M, Piera KA, Ebsworth EP, Anstey NM, Tjitra E, Price RN.
Abstract : Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale. In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae, n = 46; P. ovale, n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale (P = 0.18). One patient infected with P. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC(50)s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0]; P = 0.01). The EC(50) for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times.
|
Antimalarial activity against Plasmodium malariae ring stage infected in red blood cells in presence of AB+ human serum by drug susceptibility assay
|
Plasmodium malariae
|
4.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia.
Year : 2011
Volume : 55
Issue : 1
First Page : 197
Last Page : 202
Authors : Siswantoro H, Russell B, Ratcliff A, Prasetyorini B, Chalfein F, Marfurt J, Kenangalem E, Wuwung M, Piera KA, Ebsworth EP, Anstey NM, Tjitra E, Price RN.
Abstract : Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale. In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae, n = 46; P. ovale, n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale (P = 0.18). One patient infected with P. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC(50)s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0]; P = 0.01). The EC(50) for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times.
|
Antimalarial activity against Plasmodium ovale ring stage infected in red blood cells in presence of AB+ human serum by drug susceptibility assay
|
Plasmodium ovale
|
0.72
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia.
Year : 2011
Volume : 55
Issue : 1
First Page : 197
Last Page : 202
Authors : Siswantoro H, Russell B, Ratcliff A, Prasetyorini B, Chalfein F, Marfurt J, Kenangalem E, Wuwung M, Piera KA, Ebsworth EP, Anstey NM, Tjitra E, Price RN.
Abstract : Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale. In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae, n = 46; P. ovale, n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale (P = 0.18). One patient infected with P. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC(50)s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0]; P = 0.01). The EC(50) for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times.
|
OSM: Inhibition of Plasmodium falciparum 3D7 growth. IC50 values determined from 21 point dose response curves. Avery Group Griffith.
|
Plasmodium falciparum 3D7
|
3.2
nM
|
|
Title : Open Source Malaria Deposition 1. http://malaria.ourexperiment.org
Authors : Vicky Avery (a), Jonathan Baell (b), Sanjay Batra (c), Jeremy Burrows (d), Soumya Bhattacharyya (c), Felix Calderon (e), Sue Charman(b), James R. Cronshaw (g), Sergio Wittlin (f), Matin Dean (g), Sandra Duffy (a), Sabine Fletcher (a), Javier Gamo (e), Zoe Hungerford (g), James Pham (h), Stuart Ralph (h), Murray N. Robertson (g), Matthew Tarnowski (g), Matthew H. Todd (g), Alice E. Williamson (g), Paul Willis (d), Karen White (b), Laura White (g), Paul M.Ylioja (g).
(a) Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, QLD 4111, Australia;
(b) Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia;
(c) Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow, 226 001, India;
(d) Medicines for Malaria Venture, PO Box 1826, 20 rte de Pré-Bois, 1215 Geneva 15, Switzerland;
(e) Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain;
(f) Swiss Tropical and Public Health Institute, Socinstr. 57, 4051 Basel, Switzerland;
(g) School of Chemistry, The University of Sydney, NSW 2006, Australia;
(h) Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.
Abstract : Screening of compounds synthesised and sourced by the OSDDMalaria consortium against Plasmodium falciparum and measurement of cytotoxicity.
|
Antimalarial activity against transgenic Plasmodium falciparum 3D7 GFP16B gametocytes
|
Plasmodium falciparum
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate.
Year : 2012
Volume : 55
Issue : 23
First Page : 10328
Last Page : 10344
Authors : Dechy-Cabaret O, Benoit-Vical F.
Abstract : Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development of efficient molecules against gametocytes. Knowledge of the pharmacological properties of antiplasmodials is helpful in term of using relevant molecules to treat malaria and to eradicate this dramatic public health problem. The effects of the major antiplasmodial drugs including artemisinin-based combination therapies on gametocyte load are thus reviewed herein, making the difference whenever possible between the effects on gametocytogenesis and the gametocytocidal activity. Current status on the portfolio of the most promising anti-gametocytes compounds is also presented. A close analysis of the relationship between chemical structure and antiplasmodial activity should help the design of novel antimalarial drugs targeting Plasmodium sexual stages.
|
Antimalarial activity against Plasmodium falciparum KT3 gametocytes
|
Plasmodium falciparum
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate.
Year : 2012
Volume : 55
Issue : 23
First Page : 10328
Last Page : 10344
Authors : Dechy-Cabaret O, Benoit-Vical F.
Abstract : Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development of efficient molecules against gametocytes. Knowledge of the pharmacological properties of antiplasmodials is helpful in term of using relevant molecules to treat malaria and to eradicate this dramatic public health problem. The effects of the major antiplasmodial drugs including artemisinin-based combination therapies on gametocyte load are thus reviewed herein, making the difference whenever possible between the effects on gametocytogenesis and the gametocytocidal activity. Current status on the portfolio of the most promising anti-gametocytes compounds is also presented. A close analysis of the relationship between chemical structure and antiplasmodial activity should help the design of novel antimalarial drugs targeting Plasmodium sexual stages.
|
Antimalarial activity against Plasmodium falciparum KT1 gametocytes
|
Plasmodium falciparum
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate.
Year : 2012
Volume : 55
Issue : 23
First Page : 10328
Last Page : 10344
Authors : Dechy-Cabaret O, Benoit-Vical F.
Abstract : Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development of efficient molecules against gametocytes. Knowledge of the pharmacological properties of antiplasmodials is helpful in term of using relevant molecules to treat malaria and to eradicate this dramatic public health problem. The effects of the major antiplasmodial drugs including artemisinin-based combination therapies on gametocyte load are thus reviewed herein, making the difference whenever possible between the effects on gametocytogenesis and the gametocytocidal activity. Current status on the portfolio of the most promising anti-gametocytes compounds is also presented. A close analysis of the relationship between chemical structure and antiplasmodial activity should help the design of novel antimalarial drugs targeting Plasmodium sexual stages.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 assessed as incorporation of [3H]hypoxanthine after 48 hr microdilution method
|
Plasmodium falciparum K1
|
9.1
nM
|
|
Journal : Med Chem Res
Title : Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway
Year : 2007
Volume : 16
Issue : 5
First Page : 213
Last Page : 229
Authors : Acharya BN, Kaushik MP
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 assessed as incorporation of [3H]hypoxanthine after 48 hr microdilution method
|
Plasmodium falciparum 3D7
|
5.7
nM
|
|
Journal : Med Chem Res
Title : Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway
Year : 2007
Volume : 16
Issue : 5
First Page : 213
Last Page : 229
Authors : Acharya BN, Kaushik MP
|
Antimalarial activity against gametocytic stage of Plasmodium berghei infected in blood assessed as inhibition of ookinete formation at 10 uM after 24 hrs by Giemsa staining-based microscopic analysis relative to control
|
Plasmodium berghei
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Using genetic methods to define the targets of compounds with antimalarial activity.
Year : 2013
Volume : 56
Issue : 20
First Page : 7761
Last Page : 7771
Authors : Flannery EL, Fidock DA, Winzeler EA.
Abstract : Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens.
|
Antimalarial activity against mature gametocytic stage of Plasmodium falciparum assessed as inhibition of mature gamete exflagellation at 10 uM incubated for 24 hrs prior to exflagellation induction at 21 degC measured after 20 mins by microscopic analysis relative to control
|
Plasmodium falciparum
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Using genetic methods to define the targets of compounds with antimalarial activity.
Year : 2013
Volume : 56
Issue : 20
First Page : 7761
Last Page : 7771
Authors : Flannery EL, Fidock DA, Winzeler EA.
Abstract : Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens.
|
Antimalarial activity against asexual stage of Plasmodium falciparum 3D7 after 72 hrs by image-based HTS assay
|
Plasmodium falciparum
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : Approaches to protozoan drug discovery: phenotypic screening.
Year : 2013
Volume : 56
Issue : 20
First Page : 7727
Last Page : 7740
Authors : Sykes ML, Avery VM.
Abstract : Determining the activity of a compound and the potential impact on a diseased state is frequently undertaken using phenotypic or target-based approaches. Phenotypic screens have the advantage of the whole organism being exposed to the compound and thus all the targets and biological pathways associated with it. Cell penetration and access to targets in their "natural" environment are taken into account. Unless utilizing a genetically modified organism with an additional target associated indicator, elucidation of specific target(s) of active compounds is necessary. Target discovery is desirable to allow development of chemical entities based upon knowledge of the target structure. Phenotypic drug discovery has successfully identified new molecular entities for neglected protozoan disease research. In this perspective, the phenotypic approaches used to identify chemical entities for drug discovery and for use as tools against the parasites Plasmodium falciparum, Trypanosoma brucei brucei, and Trypanosoma cruzi will be outlined.
|
Antimalarial activity against early (1 to 3) gametocytic stage of Plasmodium falciparum after 72 hrs by image-based HTS assay
|
Plasmodium falciparum
|
131.3
nM
|
|
Journal : J. Med. Chem.
Title : Approaches to protozoan drug discovery: phenotypic screening.
Year : 2013
Volume : 56
Issue : 20
First Page : 7727
Last Page : 7740
Authors : Sykes ML, Avery VM.
Abstract : Determining the activity of a compound and the potential impact on a diseased state is frequently undertaken using phenotypic or target-based approaches. Phenotypic screens have the advantage of the whole organism being exposed to the compound and thus all the targets and biological pathways associated with it. Cell penetration and access to targets in their "natural" environment are taken into account. Unless utilizing a genetically modified organism with an additional target associated indicator, elucidation of specific target(s) of active compounds is necessary. Target discovery is desirable to allow development of chemical entities based upon knowledge of the target structure. Phenotypic drug discovery has successfully identified new molecular entities for neglected protozoan disease research. In this perspective, the phenotypic approaches used to identify chemical entities for drug discovery and for use as tools against the parasites Plasmodium falciparum, Trypanosoma brucei brucei, and Trypanosoma cruzi will be outlined.
|
Cytotoxicity against HEK293 cells assessed as cell viability after 72 hrs by resazurin-based plate reader analysis
|
Homo sapiens
|
1.79
nM
|
|
Journal : J. Nat. Prod.
Title : Rotenoids, Flavonoids, and Chalcones from the Root Bark of Millettia usaramensis.
Year : 2015
Volume : 78
Issue : 12
First Page : 2932
Last Page : 2939
Authors : Deyou T, Gumula I, Pang F, Gruhonjic A, Mumo M, Holleran J, Duffy S, Fitzpatrick PA, Heydenreich M, Landberg G, Derese S, Avery V, Rissanen K, Erdélyi M, Yenesew A.
Abstract : Five new compounds, 4-O-geranylisoliquiritigenin (1), 12-dihydrousararotenoid B (2), 12-dihydrousararotenoid C (3), 4'-O-geranyl-7-hydroxyflavanone (4), and 4'-O-geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (6-17) were isolated from the CH2Cl2/MeOH (1:1) extract of the root bark of Millettia usaramensis ssp. usaramensis by chromatographic separation. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas their absolute configurations were established on the basis of chiroptical data and in some cases also by X-ray crystallography. The crude extract was moderately active (IC50 = 11.63 μg/mL) against the ER-negative MDB-MB-231 human breast cancer cell line, and accordingly compounds 6, 8, 9, 10, 12, and 16 also showed moderate to low cytotoxic activities (IC50 25.7-207.2 μM). The new natural product 1 exhibited antiplasmodial activity with IC50 values of 3.7 and 5.3 μM against the chloroquine-sensitive 3D7 and the chloroquine-resistant Dd2 Plasmodium falciparum strains, respectively, and was also cytotoxic to the HEK293 cell line.
|
Antiplasmodial activity against chloroquine-sensitive Plasmodium falciparum 3D7 assessed as inhibition of parasite growth after 72 hrs by DAPI staining-based confocal microscopic analysis
|
Plasmodium falciparum 3D7
|
3.6
nM
|
|
Journal : J. Nat. Prod.
Title : Rotenoids, Flavonoids, and Chalcones from the Root Bark of Millettia usaramensis.
Year : 2015
Volume : 78
Issue : 12
First Page : 2932
Last Page : 2939
Authors : Deyou T, Gumula I, Pang F, Gruhonjic A, Mumo M, Holleran J, Duffy S, Fitzpatrick PA, Heydenreich M, Landberg G, Derese S, Avery V, Rissanen K, Erdélyi M, Yenesew A.
Abstract : Five new compounds, 4-O-geranylisoliquiritigenin (1), 12-dihydrousararotenoid B (2), 12-dihydrousararotenoid C (3), 4'-O-geranyl-7-hydroxyflavanone (4), and 4'-O-geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (6-17) were isolated from the CH2Cl2/MeOH (1:1) extract of the root bark of Millettia usaramensis ssp. usaramensis by chromatographic separation. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas their absolute configurations were established on the basis of chiroptical data and in some cases also by X-ray crystallography. The crude extract was moderately active (IC50 = 11.63 μg/mL) against the ER-negative MDB-MB-231 human breast cancer cell line, and accordingly compounds 6, 8, 9, 10, 12, and 16 also showed moderate to low cytotoxic activities (IC50 25.7-207.2 μM). The new natural product 1 exhibited antiplasmodial activity with IC50 values of 3.7 and 5.3 μM against the chloroquine-sensitive 3D7 and the chloroquine-resistant Dd2 Plasmodium falciparum strains, respectively, and was also cytotoxic to the HEK293 cell line.
|
Antiplasmodial activity against chloroquine-resistant Plasmodium falciparum Dd2 assessed as inhibition of parasite growth after 72 hrs by DAPI staining-based confocal microscopic analysis
|
Plasmodium falciparum Dd2
|
7.51
nM
|
|
Journal : J. Nat. Prod.
Title : Rotenoids, Flavonoids, and Chalcones from the Root Bark of Millettia usaramensis.
Year : 2015
Volume : 78
Issue : 12
First Page : 2932
Last Page : 2939
Authors : Deyou T, Gumula I, Pang F, Gruhonjic A, Mumo M, Holleran J, Duffy S, Fitzpatrick PA, Heydenreich M, Landberg G, Derese S, Avery V, Rissanen K, Erdélyi M, Yenesew A.
Abstract : Five new compounds, 4-O-geranylisoliquiritigenin (1), 12-dihydrousararotenoid B (2), 12-dihydrousararotenoid C (3), 4'-O-geranyl-7-hydroxyflavanone (4), and 4'-O-geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (6-17) were isolated from the CH2Cl2/MeOH (1:1) extract of the root bark of Millettia usaramensis ssp. usaramensis by chromatographic separation. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas their absolute configurations were established on the basis of chiroptical data and in some cases also by X-ray crystallography. The crude extract was moderately active (IC50 = 11.63 μg/mL) against the ER-negative MDB-MB-231 human breast cancer cell line, and accordingly compounds 6, 8, 9, 10, 12, and 16 also showed moderate to low cytotoxic activities (IC50 25.7-207.2 μM). The new natural product 1 exhibited antiplasmodial activity with IC50 values of 3.7 and 5.3 μM against the chloroquine-sensitive 3D7 and the chloroquine-resistant Dd2 Plasmodium falciparum strains, respectively, and was also cytotoxic to the HEK293 cell line.
|
Antimalarial activity against Plasmodium falciparum NF54 harboring pfs16-LUC-GFP ring stage gametocytes after 24 hrs by MitoTracker Red staining based confocal microscopy
|
Plasmodium falciparum NF54
|
16.0
nM
|
|
Journal : J Med Chem
Title : Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.
Year : 2017
Volume : 60
Issue : 3
First Page : 1171
Last Page : 1188
Authors : Gilson PR, Tan C, Jarman KE, Lowes KN, Curtis JM, Nguyen W, Di Rago AE, Bullen HE, Prinz B, Duffy S, Baell JB, Hutton CA, Jousset Subroux H, Crabb BS, Avery VM, Cowman AF, Sleebs BE.
Abstract : Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
|
Antimalarial activity against Plasmodium falciparum NF54 harboring pfs16-LUC-GFP early stage 1 to 3 gametocytes after 48 hrs by MitoTracker Red staining based confocal microscopy
|
Plasmodium falciparum NF54
|
25.0
nM
|
|
Journal : J Med Chem
Title : Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.
Year : 2017
Volume : 60
Issue : 3
First Page : 1171
Last Page : 1188
Authors : Gilson PR, Tan C, Jarman KE, Lowes KN, Curtis JM, Nguyen W, Di Rago AE, Bullen HE, Prinz B, Duffy S, Baell JB, Hutton CA, Jousset Subroux H, Crabb BS, Avery VM, Cowman AF, Sleebs BE.
Abstract : Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 infected in human RBC after 72 hrs by DAPI staining based confocal microscopic method
|
Plasmodium falciparum 3D7
|
3.6
nM
|
|
Journal : J Nat Prod
Title : Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves.
Year : 2017
Volume : 80
Issue : 1
First Page : 114
Last Page : 125
Authors : Nyandoro SS, Munissi JJ, Gruhonjic A, Duffy S, Pan F, Puttreddy R, Holleran JP, Fitzpatrick PA, Pelletier J, Avery VM, Rissanen K, Erdélyi M.
Abstract : Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A-F (6-11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15-21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2-40 μM, and against HEK293 mammalian cells (IC50 2.7-3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03-8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum Dd2 infected in human RBC after 72 hrs by DAPI staining based confocal microscopic method
|
Plasmodium falciparum Dd2
|
7.5
nM
|
|
Journal : J Nat Prod
Title : Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves.
Year : 2017
Volume : 80
Issue : 1
First Page : 114
Last Page : 125
Authors : Nyandoro SS, Munissi JJ, Gruhonjic A, Duffy S, Pan F, Puttreddy R, Holleran JP, Fitzpatrick PA, Pelletier J, Avery VM, Rissanen K, Erdélyi M.
Abstract : Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A-F (6-11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15-21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2-40 μM, and against HEK293 mammalian cells (IC50 2.7-3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03-8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.
|
Antiplasmodial activity against chloroquine-sensitive Plasmodium falciparum 3D7 measured after 72 hrs by DAPI staining based high throughput screening assay
|
Plasmodium falciparum 3D7
|
11.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Antiplasmodial β-triketones from the flowers of the Australian tree Angophora woodsiana.
Year : 2017
Volume : 27
Issue : 11
First Page : 2602
Last Page : 2607
Authors : Senadeera SPD, Duffy S, Avery VM, Carroll AR.
Abstract : Chemical investigations of the MeOH extract of air dried flowers of the Australian tree Angophora woodsiana (Myrtaceae) yielded two new β-triketones, woodsianones A and B (1, 2) and nine known β-triketones (3-11). Woodsianone A is a β-triketone-sesquiterpene adduct and woodsianone B is a β-triketone epoxide derivative. The structures of the new and known compounds were elucidated from the analysis of 1D/2D NMR and MS data. The relative configurations of the compounds were determined from analysis of 1H-1H coupling constants and ROESY correlations. All compounds (1-11) had antiplasmodial activity against the chloroquine sensitive strain 3D7. The known compound rhodomyrtone (5) and new compound woodsianone B (2) showed moderate antiplasmodial activities against the 3D7 strain (1.84µM and 3.00µM, respectively) and chloroquine resistant strain Dd2 (4.00µM and 2.53µM, respectively).
|
Antiplasmodial activity against chloroquine-resistant Plasmodium falciparum Dd2 measured after 72 hrs by DAPI staining based high throughput screening assay
|
Plasmodium falciparum Dd2
|
18.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Antiplasmodial β-triketones from the flowers of the Australian tree Angophora woodsiana.
Year : 2017
Volume : 27
Issue : 11
First Page : 2602
Last Page : 2607
Authors : Senadeera SPD, Duffy S, Avery VM, Carroll AR.
Abstract : Chemical investigations of the MeOH extract of air dried flowers of the Australian tree Angophora woodsiana (Myrtaceae) yielded two new β-triketones, woodsianones A and B (1, 2) and nine known β-triketones (3-11). Woodsianone A is a β-triketone-sesquiterpene adduct and woodsianone B is a β-triketone epoxide derivative. The structures of the new and known compounds were elucidated from the analysis of 1D/2D NMR and MS data. The relative configurations of the compounds were determined from analysis of 1H-1H coupling constants and ROESY correlations. All compounds (1-11) had antiplasmodial activity against the chloroquine sensitive strain 3D7. The known compound rhodomyrtone (5) and new compound woodsianone B (2) showed moderate antiplasmodial activities against the 3D7 strain (1.84µM and 3.00µM, respectively) and chloroquine resistant strain Dd2 (4.00µM and 2.53µM, respectively).
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum Dd2 after 72 hrs by DAPI staining based confocal microplate imaging method
|
Plasmodium falciparum Dd2
|
140.0
nM
|
|
Journal : J Nat Prod
Title : Pimentelamines A-C, Indole Alkaloids Isolated from the Leaves of the Australian Tree Flindersia pimenteliana.
Year : 2017
Volume : 80
Issue : 12
First Page : 3211
Last Page : 3217
Authors : Robertson LP, Duffy S, Wang Y, Wang D, Avery VM, Carroll AR.
Abstract : Three members of a new class of ascorbic acid-adduct indole alkaloids (1-3), a new prenylated indole alkaloid (4), and five known compounds (5-9) were isolated from the leaves of Flindersia pimenteliana. The structures of 1-4 were elucidated on the basis of their (+)-HRESIMS and 2D NMR spectroscopic data. Antiplasmodial activity was also reported for the natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum with IC50 values ranging from 0.19 to 3.6 μM.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 after 72 hrs by DAPI staining based confocal microplate imaging method
|
Plasmodium falciparum 3D7
|
12.0
nM
|
|
Journal : J Nat Prod
Title : Pimentelamines A-C, Indole Alkaloids Isolated from the Leaves of the Australian Tree Flindersia pimenteliana.
Year : 2017
Volume : 80
Issue : 12
First Page : 3211
Last Page : 3217
Authors : Robertson LP, Duffy S, Wang Y, Wang D, Avery VM, Carroll AR.
Abstract : Three members of a new class of ascorbic acid-adduct indole alkaloids (1-3), a new prenylated indole alkaloid (4), and five known compounds (5-9) were isolated from the leaves of Flindersia pimenteliana. The structures of 1-4 were elucidated on the basis of their (+)-HRESIMS and 2D NMR spectroscopic data. Antiplasmodial activity was also reported for the natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum with IC50 values ranging from 0.19 to 3.6 μM.
|
Antiplasmodial activity against drug-sensitive Plasmodium falciparum 3D7 ring stage infected in human erythrocytes after 72 hrs by DAPI staining based method
|
Plasmodium falciparum 3D7
|
12.0
nM
|
|
Journal : J Nat Prod
Title : Antiplasmodial β-Triketone-Flavanone Hybrids from the Flowers of the Australian Tree Corymbia torelliana.
Year : 2018
Volume : 81
Issue : 7
First Page : 1588
Last Page : 1597
Authors : Senadeera SPD, Lucantoni L, Duffy S, Avery VM, Carroll AR.
Abstract : The methanol extract of the flowers of the Australian eucalypt tree Corymbia torelliana yielded six new β-triketone-flavanone hybrids, torellianones A-F (1-6), the tetrahydroxycyclohexane torellianol A (7), and known β-triketones (4 S)-ficifolidione (8) and (4 R)-ficifolidione (9), and β-triketone-flavanones kunzeanone A (10) and kunzeanone B (11). Torellianones A and B, C and D, and E and F were each isolated as inseparable diastereomeric mixtures. Exchange correlations observed in a ROESY spectrum indicated that 5 and 6 also interconverted between stable conformers. The structures of 1-7 were elucidated from the analysis of 1D/2D NMR and MS data. Relative configurations of torellianones C-F and torrellianol A were determined from analysis of ROESY data. Compounds 1-10 were tested for antiplasmodial activity against a drug-sensitive (3D7) strain of Plasmodium falciparum, with 3-6 and 8-10 showing limited antiplasmodial activity, with IC50 values ranging from 3.2 to 16.6 μM.
|
Antiplasmodial activity against 4-aminoquinoline/antifolates-resistant Plasmodium falciparum Dd2 ring stage infected in human erythrocytes after 72 hrs by DAPI staining based method
|
Plasmodium falciparum Dd2
|
18.0
nM
|
|
Journal : J Nat Prod
Title : Antiplasmodial β-Triketone-Flavanone Hybrids from the Flowers of the Australian Tree Corymbia torelliana.
Year : 2018
Volume : 81
Issue : 7
First Page : 1588
Last Page : 1597
Authors : Senadeera SPD, Lucantoni L, Duffy S, Avery VM, Carroll AR.
Abstract : The methanol extract of the flowers of the Australian eucalypt tree Corymbia torelliana yielded six new β-triketone-flavanone hybrids, torellianones A-F (1-6), the tetrahydroxycyclohexane torellianol A (7), and known β-triketones (4 S)-ficifolidione (8) and (4 R)-ficifolidione (9), and β-triketone-flavanones kunzeanone A (10) and kunzeanone B (11). Torellianones A and B, C and D, and E and F were each isolated as inseparable diastereomeric mixtures. Exchange correlations observed in a ROESY spectrum indicated that 5 and 6 also interconverted between stable conformers. The structures of 1-7 were elucidated from the analysis of 1D/2D NMR and MS data. Relative configurations of torellianones C-F and torrellianol A were determined from analysis of ROESY data. Compounds 1-10 were tested for antiplasmodial activity against a drug-sensitive (3D7) strain of Plasmodium falciparum, with 3-6 and 8-10 showing limited antiplasmodial activity, with IC50 values ranging from 3.2 to 16.6 μM.
|
Gametocytocidal activity against transgenic GFP-fused Plasmodium falciparum NF54 early stage gametocytes after 72 hrs by Mitotracker Red CMH2XRos staining based imaging method
|
Plasmodium falciparum NF54
|
29.0
nM
|
|
Journal : Eur J Med Chem
Title : One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites.
Year : 2018
Volume : 158
First Page : 801
Last Page : 813
Authors : Diedrich D, Stenzel K, Hesping E, Antonova-Koch Y, Gebru T, Duffy S, Fisher G, Schöler A, Meister S, Kurz T, Avery VM, Winzeler EA, Held J, Andrews KT, Hansen FK.
Abstract : Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC50: 4 nM; Pf Dd2 IC50: 1 nM) and P. berghei exo-erythrocytic forms (Pb EEF IC50: 25 nM) with promising parasite-specific activity (SIPf3D7/HepG2: 2496, SIPfDd2/HepG2: 9990, and SIPbEEF/HepG2: 400).
|
Antimalarial activity against Plasmodium falciparum 3D7 after 72 hrs by DAPI staining-based confocal imaging analysis
|
Plasmodium falciparum
|
7.0
nM
|
|
Journal : J Med Chem
Title : Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.
Year : 2019
Volume : 62
Issue : 2
First Page : 622
Last Page : 640
Authors : Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S.
Abstract : There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
|
Antimalarial activity against Plasmodium falciparum Dd2 after 72 hrs by DAPI staining-based confocal imaging analysis
|
Plasmodium falciparum
|
7.9
nM
|
|
Journal : J Med Chem
Title : Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.
Year : 2019
Volume : 62
Issue : 2
First Page : 622
Last Page : 640
Authors : Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S.
Abstract : There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
|
Antiplasmodial activity against drug-sensitive Plasmodium falciparum 3D7 ring stage forms assessed as inhibition of parasite growth after 72 hrs by DAPI staining-based confocal microscopic analysis
|
Plasmodium falciparum
|
8.2
nM
|
|
Journal : J Nat Prod
Title : Acrotrione: An Oxidized Xanthene from the Roots of Acronychia pubescens.
Year : 2019
Volume : 82
Issue : 4
First Page : 1019
Last Page : 1023
Authors : Robertson LP, Lucantoni L, Duffy S, Avery VM, Carroll AR.
Abstract : A new oxidized xanthene, acrotrione (1), and two known acetophenones (2 and 3) were isolated from a methanol extract of the roots of Acronychia pubescens. The structure of 1 was elucidated on the basis of its (+)-HRESIMS, 2D NMR, and ECD data. Acritrione (1) contains an unusual oxidized furo[2,3- c]xanthene moiety that has not been previously reported. Moderate antiplasmodial activity for these natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum was determined with IC<sub>50</sub> values ranging from 1.7 to 4.7 μM.
|
Antiplasmodial activity against drug-resistant Plasmodium falciparum Dd2 ring stage forms assessed as inhibition of parasite growth after 72 hrs by DAPI staining-based confocal microscopic analysis
|
Plasmodium falciparum
|
11.0
nM
|
|
Journal : J Nat Prod
Title : Acrotrione: An Oxidized Xanthene from the Roots of Acronychia pubescens.
Year : 2019
Volume : 82
Issue : 4
First Page : 1019
Last Page : 1023
Authors : Robertson LP, Lucantoni L, Duffy S, Avery VM, Carroll AR.
Abstract : A new oxidized xanthene, acrotrione (1), and two known acetophenones (2 and 3) were isolated from a methanol extract of the roots of Acronychia pubescens. The structure of 1 was elucidated on the basis of its (+)-HRESIMS, 2D NMR, and ECD data. Acritrione (1) contains an unusual oxidized furo[2,3- c]xanthene moiety that has not been previously reported. Moderate antiplasmodial activity for these natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum was determined with IC<sub>50</sub> values ranging from 1.7 to 4.7 μM.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 assessed as reduction in parasite rowth incubated for 72 hrs by DAPI staining based fluorescence assay
|
Plasmodium falciparum
|
3.6
nM
|
|
Journal : J Nat Prod
Title : A Meroisoprenoid, Heptenolides, and <i>C</i>-Benzylated Flavonoids from <i>Sphaerocoryne gracilis</i> ssp. <i>gracilis</i>.
Year : 2020
Volume : 83
Issue : 2
First Page : 316
Last Page : 322
Authors : Maeda G, Munissi JJE, Lindblad S, Duffy S, Pelletier J, Avery VM, Nyandoro SS, Erdélyi M.
Abstract : A new meroisoprenoid (<b>1</b>), two heptenolides (<b>2</b> and <b>3</b>), two <i>C</i>-benzylated flavonoids (<b>4</b> and <b>5</b>), and 11 known compounds (<b>6</b>-<b>16</b>) were isolated from leaf, stem bark, and root bark extracts of <i>Sphaerocoryne gracilis</i> ssp. <i>gracilis</i> by chromatographic separation. The structures of the new metabolites <b>1</b>-<b>5</b> were established by NMR, IR, and UV spectroscopic and mass spectrometric data analysis. (<i>Z</i>)-Sphaerodiol (<b>7</b>), (<i>Z</i>)-acetylmelodorinol (<b>8</b>), 7-hydroxy-6-hydromelodienone (<b>10</b>), and dichamanetin (<b>15</b>) inhibited the proliferation of <i>Plasmodium falciparum</i> (3D7, Dd2) with IC<sub>50</sub> values of 1.4-10.5 μM, although these compounds also showed cytotoxicity against human embryonic kidney HEK-293 cells. None of the compounds exhibited significant disruption in protein translation when assayed in vitro.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum Dd2 assessed as reduction in parasite growth incubated for 72 hrs by DAPI staining based fluorescence assay
|
Plasmodium falciparum
|
7.5
nM
|
|
Journal : J Nat Prod
Title : A Meroisoprenoid, Heptenolides, and <i>C</i>-Benzylated Flavonoids from <i>Sphaerocoryne gracilis</i> ssp. <i>gracilis</i>.
Year : 2020
Volume : 83
Issue : 2
First Page : 316
Last Page : 322
Authors : Maeda G, Munissi JJE, Lindblad S, Duffy S, Pelletier J, Avery VM, Nyandoro SS, Erdélyi M.
Abstract : A new meroisoprenoid (<b>1</b>), two heptenolides (<b>2</b> and <b>3</b>), two <i>C</i>-benzylated flavonoids (<b>4</b> and <b>5</b>), and 11 known compounds (<b>6</b>-<b>16</b>) were isolated from leaf, stem bark, and root bark extracts of <i>Sphaerocoryne gracilis</i> ssp. <i>gracilis</i> by chromatographic separation. The structures of the new metabolites <b>1</b>-<b>5</b> were established by NMR, IR, and UV spectroscopic and mass spectrometric data analysis. (<i>Z</i>)-Sphaerodiol (<b>7</b>), (<i>Z</i>)-acetylmelodorinol (<b>8</b>), 7-hydroxy-6-hydromelodienone (<b>10</b>), and dichamanetin (<b>15</b>) inhibited the proliferation of <i>Plasmodium falciparum</i> (3D7, Dd2) with IC<sub>50</sub> values of 1.4-10.5 μM, although these compounds also showed cytotoxicity against human embryonic kidney HEK-293 cells. None of the compounds exhibited significant disruption in protein translation when assayed in vitro.
|
Antiviral activity against Ebolavirus infected in human HeLa cells assessed as reduction in viral replication incubated for 48 hrs by luminescence based assay
|
Ebolavirus
|
820.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Toward the Target: Tilorone, Quinacrine, and Pyronaridine Bind to Ebola Virus Glycoprotein.
Year : 2020
Volume : 11
Issue : 8
First Page : 1653
Last Page : 1658
Authors : Lane TR, Ekins S.
Abstract : Pyronaridine, tilorone, and quinacrine were recently identified by a machine learning model and demonstrated <i>in vitro</i> and <i>in vivo</i> activity against Ebola virus (EBOV) and represent viable candidates for drug repurposing. The target for these molecules was previously unknown. These drugs have now been docked into the crystal structure of the ebola glycoprotein and then experimentally validated <i>in vitro</i> using microscale thermophoresis to generate <i>K</i> <sub>d</sub> values for tilorone (0.73 μM), pyronaridine (7.34 μM), and quinacrine (7.55 μM). These molecules were shown to bind with a higher affinity than the previously reported toremifene (16 μM). These three structures provide more insight into the structural diversity of ebola glycoprotein inhibitors which can be utilized in the discovery and design of additional inhibitors.
|
Antimalarial activity against Plasmodium falciparum NF54 early stage (1 to 3) expressing Pfs16-LUC-GFP assessed as growth inhibition by high content imaging assay
|
Plasmodium falciparum
|
53.0
nM
|
|
Journal : Eur J Med Chem
Title : Structure activity refinement of phenylsulfonyl piperazines as antimalarials that block erythrocytic invasion.
Year : 2021
Volume : 214
First Page : 113253
Last Page : 113253
Authors : Nguyen W,Dans MG,Ngo A,Gancheva MR,Romeo O,Duffy S,de Koning-Ward TF,Lowes KN,Sabroux HJ,Avery VM,Wilson DW,Gilson PR,Sleebs BE
Abstract : The emerging resistance to combination therapies comprised of artemisinin derivatives has driven a need to identify new antimalarials with novel mechanisms of action. Central to the survival and proliferation of the malaria parasite is the invasion of red blood cells by Plasmodium merozoites, providing an attractive target for novel therapeutics. A screen of the Medicines for Malaria Venture Pathogen Box employing transgenic P. falciparum parasites expressing the nanoluciferase bioluminescent reporter identified the phenylsulfonyl piperazine class as a specific inhibitor of erythrocyte invasion. Here, we describe the optimization and further characterization of the phenylsulfonyl piperazine class. During the optimization process we defined the functionality required for P. falciparum asexual stage activity and determined the alpha-carbonyl S-methyl isomer was important for antimalarial potency. The optimized compounds also possessed comparable activity against multidrug resistant strains of P. falciparum and displayed weak activity against sexual stage gametocytes. We determined that the optimized compounds blocked erythrocyte invasion consistent with the asexual activity observed and therefore the phenylsulfonyl piperazine analogues described could serve as useful tools for studying Plasmodium erythrocyte invasion.
|
Antimalarial activity against synchronous ring stage of Plasmodium falciparum 3D7 assessed as parasite growth inhibition incubated for 72 hrs by Griffith assay based fluorescence analysis
|
Plasmodium falciparum
|
7.4
nM
|
|
|
Antimalarial activity against synchronous ring stage of Plasmodium falciparum Dd2 assessed as parasite growth inhibition incubated for 72 hrs by Griffith assay based fluorescence analysis
|
Plasmodium falciparum
|
8.3
nM
|
|
