Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model

Michael L. Booker, Cecilia M. Bastos, Martin L. Kramer, Robert H. Barker, Renato Skerlj, Amar Bir Sidhu, Xiaoyi Deng, Cassandra Celatka, Joseph F. Cortese, Jose E. Guerrero Bravo, Keila N. Crespo Llado, Adelfa E. Serrano, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Sara Viera, Helen Garuti, Sergio Wittlin, Petros Papastogiannidis, Jing Wen Lin, Chris J. JanseShahid M. Khan, Manoj Duraisingh, Bradley Coleman, Elizabeth J. Goldsmith, Margaret A. Phillips, Benito Munoz, Dyann F. Wirth, Jeffrey D. Klinger, Roger Wiegand, Edmund Sybertza

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl) thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED50 values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

Original languageEnglish (US)
Pages (from-to)33054-33064
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number43
DOIs
StatePublished - Oct 22 2010

Fingerprint

Antimalarials
Plasmodium falciparum
Salvaging
Thiophenes
Pyrimidines
Pharmaceutical Chemistry
Biosynthesis
Biosynthetic Pathways
Malaria
Toxicity
Parasites
Binding Sites
Throughput
X-Rays
Amino Acids
X rays
Survival
Testing
Enzymes
dihydroorotate dehydrogenase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Booker, M. L., Bastos, C. M., Kramer, M. L., Barker, R. H., Skerlj, R., Sidhu, A. B., ... Sybertza, E. (2010). Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. Journal of Biological Chemistry, 285(43), 33054-33064. https://doi.org/10.1074/jbc.M110.162081

Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. / Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara; Garuti, Helen; Wittlin, Sergio; Papastogiannidis, Petros; Lin, Jing Wen; Janse, Chris J.; Khan, Shahid M.; Duraisingh, Manoj; Coleman, Bradley; Goldsmith, Elizabeth J.; Phillips, Margaret A.; Munoz, Benito; Wirth, Dyann F.; Klinger, Jeffrey D.; Wiegand, Roger; Sybertza, Edmund.

In: Journal of Biological Chemistry, Vol. 285, No. 43, 22.10.2010, p. 33054-33064.

Research output: Contribution to journalArticle

Booker, ML, Bastos, CM, Kramer, ML, Barker, RH, Skerlj, R, Sidhu, AB, Deng, X, Celatka, C, Cortese, JF, Guerrero Bravo, JE, Crespo Llado, KN, Serrano, AE, Angulo-Barturen, I, Jiménez-Díaz, MB, Viera, S, Garuti, H, Wittlin, S, Papastogiannidis, P, Lin, JW, Janse, CJ, Khan, SM, Duraisingh, M, Coleman, B, Goldsmith, EJ, Phillips, MA, Munoz, B, Wirth, DF, Klinger, JD, Wiegand, R & Sybertza, E 2010, 'Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model', Journal of Biological Chemistry, vol. 285, no. 43, pp. 33054-33064. https://doi.org/10.1074/jbc.M110.162081
Booker, Michael L. ; Bastos, Cecilia M. ; Kramer, Martin L. ; Barker, Robert H. ; Skerlj, Renato ; Sidhu, Amar Bir ; Deng, Xiaoyi ; Celatka, Cassandra ; Cortese, Joseph F. ; Guerrero Bravo, Jose E. ; Crespo Llado, Keila N. ; Serrano, Adelfa E. ; Angulo-Barturen, Iñigo ; Jiménez-Díaz, María Belén ; Viera, Sara ; Garuti, Helen ; Wittlin, Sergio ; Papastogiannidis, Petros ; Lin, Jing Wen ; Janse, Chris J. ; Khan, Shahid M. ; Duraisingh, Manoj ; Coleman, Bradley ; Goldsmith, Elizabeth J. ; Phillips, Margaret A. ; Munoz, Benito ; Wirth, Dyann F. ; Klinger, Jeffrey D. ; Wiegand, Roger ; Sybertza, Edmund. / Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 43. pp. 33054-33064.
@article{7ea87c41843a4a519f47761b889ed595,
title = "Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model",
abstract = "Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl) thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED50 values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.",
author = "Booker, {Michael L.} and Bastos, {Cecilia M.} and Kramer, {Martin L.} and Barker, {Robert H.} and Renato Skerlj and Sidhu, {Amar Bir} and Xiaoyi Deng and Cassandra Celatka and Cortese, {Joseph F.} and {Guerrero Bravo}, {Jose E.} and {Crespo Llado}, {Keila N.} and Serrano, {Adelfa E.} and I{\~n}igo Angulo-Barturen and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a Bel{\'e}n} and Sara Viera and Helen Garuti and Sergio Wittlin and Petros Papastogiannidis and Lin, {Jing Wen} and Janse, {Chris J.} and Khan, {Shahid M.} and Manoj Duraisingh and Bradley Coleman and Goldsmith, {Elizabeth J.} and Phillips, {Margaret A.} and Benito Munoz and Wirth, {Dyann F.} and Klinger, {Jeffrey D.} and Roger Wiegand and Edmund Sybertza",
year = "2010",
month = "10",
day = "22",
doi = "10.1074/jbc.M110.162081",
language = "English (US)",
volume = "285",
pages = "33054--33064",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "43",

}

TY - JOUR

T1 - Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model

AU - Booker, Michael L.

AU - Bastos, Cecilia M.

AU - Kramer, Martin L.

AU - Barker, Robert H.

AU - Skerlj, Renato

AU - Sidhu, Amar Bir

AU - Deng, Xiaoyi

AU - Celatka, Cassandra

AU - Cortese, Joseph F.

AU - Guerrero Bravo, Jose E.

AU - Crespo Llado, Keila N.

AU - Serrano, Adelfa E.

AU - Angulo-Barturen, Iñigo

AU - Jiménez-Díaz, María Belén

AU - Viera, Sara

AU - Garuti, Helen

AU - Wittlin, Sergio

AU - Papastogiannidis, Petros

AU - Lin, Jing Wen

AU - Janse, Chris J.

AU - Khan, Shahid M.

AU - Duraisingh, Manoj

AU - Coleman, Bradley

AU - Goldsmith, Elizabeth J.

AU - Phillips, Margaret A.

AU - Munoz, Benito

AU - Wirth, Dyann F.

AU - Klinger, Jeffrey D.

AU - Wiegand, Roger

AU - Sybertza, Edmund

PY - 2010/10/22

Y1 - 2010/10/22

N2 - Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl) thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED50 values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

AB - Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl) thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED50 values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

UR - http://www.scopus.com/inward/record.url?scp=77958511348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958511348&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.162081

DO - 10.1074/jbc.M110.162081

M3 - Article

C2 - 20702404

AN - SCOPUS:77958511348

VL - 285

SP - 33054

EP - 33064

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 43

ER -