|
Antimalarial activity against drug-sensitive Plasmodium falciparum NF54 infected in human erythrocytes after 48 hrs by [3H]hypoxanthine assay
|
Plasmodium falciparum NF54
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.
Year : 2010
Volume : 53
Issue : 14
First Page : 5155
Last Page : 5164
Authors : Yeung BK, Zou B, Rottmann M, Lakshminarayana SB, Ang SH, Leong SY, Tan J, Wong J, Keller-Maerki S, Fischli C, Goh A, Schmitt EK, Krastel P, Francotte E, Kuhen K, Plouffe D, Henson K, Wagner T, Winzeler EA, Petersen F, Brun R, Dartois V, Diagana TT, Keller TH.
Abstract : The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.
|
Antimalarial activity against Plasmodium falciparum 3D7 assessed as parasite growth inhibition at 1.6 nM after24 hrs by [3H]hypoxanthin incorporation assay
|
Plasmodium falciparum
|
90.0
%
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum NF54 after 48 hrs incubation by [3H]hypoxanthin incorporation assay
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum 3D7 after 48 hrs incubation by [3H]hypoxanthin incorporation assay
|
Plasmodium falciparum
|
0.7
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against chloroquine and pyrimethamine-resistant Plasmodium falciparum K1 after 48 hrs incubation by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum K1
|
0.6
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against chloroquine and pyrimethamine-resistant Plasmodium falciparum W2
|
Plasmodium falciparum
|
0.9
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against pyrimethamine-resistant Plasmodium falciparum 7G8 after 48 hrs incubation by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum
|
1.2
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against chloroquine, mefloquine and pyrimethamine-resistant Plasmodium falciparum TM90C2A after 48 hrs incubation by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against chloroquine, mefloquine and pyrimethamine-resistant Plasmodium falciparum TM91C235 after 48 hrs incubation by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum
|
0.9
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum D6 after 48 hrs incubation by [3H]hypoxanthin incorporation assay
|
Plasmodium falciparum
|
1.0
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against chloroquine and pyrimethamine-resistant Plasmodium falciparum V1/S after 48 hrs incubation by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum
|
1.4
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Inhibition of human ERG at 30 uM
|
Homo sapiens
|
52.0
%
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Inhibition of human ERG at 30 uM by patch clamp method
|
Homo sapiens
|
44.9
%
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
0.44
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against NITD609-resistant Plasmodium falciparum Dd2 Clone1 bearing P-type ATPase4 I398F and P990R mutations after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
10.9
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against NITD609-resistant Plasmodium falciparum Dd2 Clone2 bearing P-type ATPase4 T418N and P990R mutations after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
3.7
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against NITD609-resistant Plasmodium falciparum Dd2 Clone3 bearing P-type ATPase4 D1247Y mutations after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
3.2
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against NITD678-resistant Plasmodium falciparum Dd2 Clone1 bearing P-type ATPase4 G223R mutations after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
2.8
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against NITD678-resistant Plasmodium falciparum Dd2 Clone2 bearing P-type ATPase4 A184S and P990Y mutations after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
2.8
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against NITD678-resistant Plasmodium falciparum Dd2 Clone3 bearing P-type ATPase4 I203M and I263V mutations after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
4.1
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 containing attB site inserted in parasite genome and expressing parental ATP4 after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
0.85
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 containing attB site inserted in parasite genome and using EF1-alpha promoter driven expressing wild type ATP4 after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
0.92
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 containing attB site inserted in parasite genome and using EF1-alpha promoter driven expressing ATP4 D1247Y mutant after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
1.57
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 containing attB site inserted in parasite genome and using EF1-alpha promoter driven expressing ATP4 I398F/P990R mutant after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
1.89
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 containing attB site inserted in parasite genome and using CAM promoter driven expressing ATP4 D1247Y mutant after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
3.9
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum Dd2 containing attB site inserted in parasite genome and using CAM promoter driven expressing ATP4 I398F/P990R mutant after 72 hrs by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
4.25
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antimalarial activity against Plasmodium falciparum assessed as [35S]Met/Cys incorporation by SYBR green based fluorescence assay
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Inhibition of protein synthesis in NITD609-resistant Plasmodium falciparum Dd2 Clone1 within 1 hrs by [35S]Met/Cys incorporation assay
|
Plasmodium falciparum
|
50.0
%
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Inhibition of protein synthesis in NITD609-resistant Plasmodium falciparum Dd2 Clone3 within 1 hrs by [35S]Met/Cys incorporation assay
|
Plasmodium falciparum
|
50.0
%
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Antiplasmodial activity against drug-sensitive Plasmodium falciparum 3D7
|
Plasmodium falciparum
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Recent advances in malaria drug discovery.
Year : 2013
Volume : 23
Issue : 10
First Page : 2829
Last Page : 2843
Authors : Biamonte MA, Wanner J, Le Roch KG.
Abstract : This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria.
|
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.
|
Antiplasmodial activity against blood stage form of Plasmodium falciparum NF54
|
Plasmodium falciparum
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Cell-based medicinal chemistry optimization of high-throughput screening (HTS) hits for orally active antimalarials. Part 1: challenges in potency and absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK).
Year : 2013
Volume : 56
Issue : 20
First Page : 7741
Last Page : 7749
Authors : Chatterjee AK.
Abstract : Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has been utilized by several groups to optimize weakly active antimalarial pharmacophores, such as the quinolone scaffold, to yield potent and highly efficacious compounds that are now poised to enter clinical trials. More recently, GNF/Novartis, GSK, and others have employed the same approach in high-throughput screening (HTS) of large compound libraries to find novel scaffolds that have also been optimized to clinical candidates by GNF/Novartis. This perspective outlines some of the inherent challenges in cell-based medicinal chemistry optimization, including optimization of oral exposure and hERG activity.
|
Antiplasmodial activity against Plasmodium falciparum assessed as [3H]-hypoxanthine incorporation after 48 hrs by liquid scintillation counting analysis
|
Plasmodium falciparum
|
0.9
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Pharmacokinetics, metabolism, and in vivo efficacy of the antimalarial natural product bromophycolide A.
Year : 2013
Volume : 4
Issue : 10
First Page : 989
Last Page : 993
Authors : Teasdale ME, Prudhomme J, Torres M, Braley M, Cervantes S, Bhatia SC, La Clair JJ, Le Roch K, Kubanek J.
Abstract : A suite of pharmacokinetic and pharmacological studies show that bromophycolide A (1), an inhibitor of drug-sensitive and drug-resistant Plasmodium falciparum, displays a typical small molecule profile with low toxicity and good bioavailability. Despite susceptibility to liver metabolism and a short in vivo half-life, 1 significantly decreased parasitemia in a malaria mouse model. Combining these data with prior SAR analyses, we demonstrate the potential for future development of 1 and its bioactive ester analogs.
|
Antiplasmodial activity against ring stage synchronized Plasmodium falciparum 3D7 infected in erythrocytes assessed as parasitemia level after 48 hrs by flow cytometry relative to control
|
Plasmodium falciparum 3D7
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum.
Year : 2014
Volume : 78
First Page : 375
Last Page : 382
Authors : Schuck DC, Jordão AK, Nakabashi M, Cunha AC, Ferreira VF, Garcia CR.
Abstract : Discovering the mechanisms by which cell signaling controls the cell cycle of the human malaria parasite Plasmodium falciparum is fundamental to designing more effective antimalarials. To better understand the impacts of melatonin structure and function on the cell cycle of P. falciparum, we have synthesized two families of structurally-related melatonin compounds (7-11 and 12-16). All synthesized melatonin analogs were assayed in P. falciparum culture and their antimalarial activities were measured by flow cytometry. We have found that the chemical modification of the carboxamide group attached at C-3 position of the indole ring of melatonin (6) was crucial for the action of the indole-related compounds on the P. falciparum cell cycle. Among the melatonin derivatives, only the compounds 12, 13 and 14 were capable of inhibiting the P. falciparum growth in low micromolar IC50. These results open good perspectives for the development of new drugs with novel mechanisms of action.
|
Antimalarial activity against drug-resistant Plasmodium falciparum Dd2 harboring ATP4 P990R/D124Y double mutant
|
Plasmodium falciparum Dd2
|
4.5
nM
|
|
Journal : J Med Chem
Title : Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ null Mouse Model of Malaria.
Year : 2018
Volume : 61
Issue : 9
First Page : 4213
Last Page : 4227
Authors : Nchinda AT, Le Manach C, Paquet T, Gonzàlez Cabrera D, Wicht KJ, Brunschwig C, Njoroge M, Abay E, Taylor D, Lawrence N, Wittlin S, Jiménez-Díaz MB, Santos Martínez M, Ferrer S, Angulo-Barturen I, Lafuente-Monasterio MJ, Duffy J, Burrows J, Street LJ, Chibale K.
Abstract : Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.
|
Antimalarial activity against wild type Plasmodium falciparum Dd2
|
Plasmodium falciparum Dd2
|
0.6
nM
|
|
Journal : J Med Chem
Title : Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ null Mouse Model of Malaria.
Year : 2018
Volume : 61
Issue : 9
First Page : 4213
Last Page : 4227
Authors : Nchinda AT, Le Manach C, Paquet T, Gonzàlez Cabrera D, Wicht KJ, Brunschwig C, Njoroge M, Abay E, Taylor D, Lawrence N, Wittlin S, Jiménez-Díaz MB, Santos Martínez M, Ferrer S, Angulo-Barturen I, Lafuente-Monasterio MJ, Duffy J, Burrows J, Street LJ, Chibale K.
Abstract : Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.
|
Antimalarial activity against Plasmodium falciparum 3D7 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum NF54 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum K1 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum W2 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum 7G8 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum TM90C2A infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum TM91C235 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum D6 infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
Antimalarial activity against Plasmodium falciparum V1/S infected in human erythrocytes assessed as reduction in [3H]-hypoxanthine incorporation incubated for 48 hrs followed by addition of [3H]-hypoxanthine and measured after 24 hrs by liquid scintillation counting method
|
Plasmodium falciparum
|
0.5
nM
|
|
Journal : J Med Chem
Title : The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.
Year : 2019
Volume : 62
Issue : 23
First Page : 10526
Last Page : 10562
Authors : Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE.
Abstract : Malaria is a devastating disease caused by <i>Plasmodium</i> parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the <i>Plasmodium</i> parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
7.31
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
12.37
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
12.37
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
