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Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Siegl P, Marfurt J, Wirjanata G, Sebayang BF, Price RN, Chatterjee A, Nagle A, Stasiak M, Charman SA, Angulo-Barturen I, Ferrer S, Belén Jiménez-Díaz M, Martínez MS, Gamo FJ, Avery VM, Ruecker A, Delves M, Kirk K, Berriman M, Kortagere S, Burrows J, Fan E, Bergman LW - Nat Commun (2014)

Bottom Line: Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds.A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites.Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.

ABSTRACT
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

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Synthetic schemes and reaction conditions for pyrazoleamides.(a) For PA21A050 and PA21A092: 2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetic acid, Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide), triethylamine, in dichloromethane/tetrahydrofuran, microwave, 75 °C, 30 min. (b) For PA21A102: (i) Fmoc-(R)-3-amino-4-(4-fluorophenyl)butanoyl chloride in dichloromethane, (ii) DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in ethyl acetate.
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f6: Synthetic schemes and reaction conditions for pyrazoleamides.(a) For PA21A050 and PA21A092: 2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetic acid, Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide), triethylamine, in dichloromethane/tetrahydrofuran, microwave, 75 °C, 30 min. (b) For PA21A102: (i) Fmoc-(R)-3-amino-4-(4-fluorophenyl)butanoyl chloride in dichloromethane, (ii) DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in ethyl acetate.

Mentions: All reagents and starting materials described in the procedures are commercially available and were used without further purification. Synthetic route for N-(4-(4-chloro-2-fluorophenyl)-3-(trifluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetamide (Compound PA21A050) is illustrated in Fig. 6. To a mixture of 2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetic acid (0.16 mmol) and Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide, 0.38 mmol) in 1.5 ml anhydrous dichloromethane (DCM), 4-(4-chloro-2-fluorophenyl)-3-(trifluoromethyl)-1-methyl-1H-pyrazol-5-amine (0.12 mmol), triethylamine (0.40 mmol) and 0.5 ml of anhydrous tetrahydrofuran were added. The mixture was vortexed and subjected to microwave irradiation for 30 min at 75 °C to give a deep-green clear solution. Then 80 ml of ethyl acetate was added and the solution was washed with 80 ml of saturated NaHCO3 twice, and with brine, and then dried over MgSO4. After solvent removal and purification on a flash silica gel column using ethyl acetate and hexane as eluent, a slightly brown-coloured solid was obtained. After recrystallization in ethyl acetate/hexane, 45 mg of Compound PA21A050 was obtained as a white powder. Yield: 76%. Purity: >95% by HPLC (UV at 220 nm). 1H NMR (500 MHz, MeOD) δ 7.81–7.83 (m, 1H), 7.60–7.70 (m, 3H), 7.26–7.36 (m, 3H), 5.54 (s, 2H), 3.92 (s, 3H), 3.50–3.55 (m, 1H), 1.50 (d, J=6.9 Hz, 6H). 13C-NMR (126 MHz, MeOD) δ 169.30, 162.35, 162.02, 160.36, 142.93, 136.64, 136.55, 136.24, 134.19, 125.84, 123.87, 123.59, 119.31, 117.68, 117.60, 117.56, 117.39, 110.42, 46.39, 37.06, 27.47, 21.81. high-resolution mass spectrometry, electrospray ionisation (HRMS(ESI)): M/Z calculated for C23H20ClF4N5O+H+ [M+H+]: 494.1365. Found: 494.1358. Traces of liquid chromatography/mass spectrometry (LC/MS), 1H NMR and 13C-NMR of PA21A050 are shown in Supplementary Figs 7 and 8.


Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Siegl P, Marfurt J, Wirjanata G, Sebayang BF, Price RN, Chatterjee A, Nagle A, Stasiak M, Charman SA, Angulo-Barturen I, Ferrer S, Belén Jiménez-Díaz M, Martínez MS, Gamo FJ, Avery VM, Ruecker A, Delves M, Kirk K, Berriman M, Kortagere S, Burrows J, Fan E, Bergman LW - Nat Commun (2014)

Synthetic schemes and reaction conditions for pyrazoleamides.(a) For PA21A050 and PA21A092: 2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetic acid, Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide), triethylamine, in dichloromethane/tetrahydrofuran, microwave, 75 °C, 30 min. (b) For PA21A102: (i) Fmoc-(R)-3-amino-4-(4-fluorophenyl)butanoyl chloride in dichloromethane, (ii) DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in ethyl acetate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263321&req=5

f6: Synthetic schemes and reaction conditions for pyrazoleamides.(a) For PA21A050 and PA21A092: 2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetic acid, Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide), triethylamine, in dichloromethane/tetrahydrofuran, microwave, 75 °C, 30 min. (b) For PA21A102: (i) Fmoc-(R)-3-amino-4-(4-fluorophenyl)butanoyl chloride in dichloromethane, (ii) DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in ethyl acetate.
Mentions: All reagents and starting materials described in the procedures are commercially available and were used without further purification. Synthetic route for N-(4-(4-chloro-2-fluorophenyl)-3-(trifluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetamide (Compound PA21A050) is illustrated in Fig. 6. To a mixture of 2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)acetic acid (0.16 mmol) and Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide, 0.38 mmol) in 1.5 ml anhydrous dichloromethane (DCM), 4-(4-chloro-2-fluorophenyl)-3-(trifluoromethyl)-1-methyl-1H-pyrazol-5-amine (0.12 mmol), triethylamine (0.40 mmol) and 0.5 ml of anhydrous tetrahydrofuran were added. The mixture was vortexed and subjected to microwave irradiation for 30 min at 75 °C to give a deep-green clear solution. Then 80 ml of ethyl acetate was added and the solution was washed with 80 ml of saturated NaHCO3 twice, and with brine, and then dried over MgSO4. After solvent removal and purification on a flash silica gel column using ethyl acetate and hexane as eluent, a slightly brown-coloured solid was obtained. After recrystallization in ethyl acetate/hexane, 45 mg of Compound PA21A050 was obtained as a white powder. Yield: 76%. Purity: >95% by HPLC (UV at 220 nm). 1H NMR (500 MHz, MeOD) δ 7.81–7.83 (m, 1H), 7.60–7.70 (m, 3H), 7.26–7.36 (m, 3H), 5.54 (s, 2H), 3.92 (s, 3H), 3.50–3.55 (m, 1H), 1.50 (d, J=6.9 Hz, 6H). 13C-NMR (126 MHz, MeOD) δ 169.30, 162.35, 162.02, 160.36, 142.93, 136.64, 136.55, 136.24, 134.19, 125.84, 123.87, 123.59, 119.31, 117.68, 117.60, 117.56, 117.39, 110.42, 46.39, 37.06, 27.47, 21.81. high-resolution mass spectrometry, electrospray ionisation (HRMS(ESI)): M/Z calculated for C23H20ClF4N5O+H+ [M+H+]: 494.1365. Found: 494.1358. Traces of liquid chromatography/mass spectrometry (LC/MS), 1H NMR and 13C-NMR of PA21A050 are shown in Supplementary Figs 7 and 8.

Bottom Line: Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds.A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites.Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.

ABSTRACT
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

Show MeSH
Related in: MedlinePlus