|
Inhibitory concentration tested on enzyme dihydroorotate dehydrogenase in mouse
|
None
|
69.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds.
Year : 1996
Volume : 39
Issue : 23
First Page : 4608
Last Page : 4621
Authors : Kuo EA, Hambleton PT, Kay DP, Evans PL, Matharu SS, Little E, McDowall N, Jones CB, Hedgecock CJ, Yea CM, Chan AW, Hairsine PW, Ager IR, Tully WR, Williamson RA, Westwood R.
Abstract : The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
|
Inhibitory concentration tested against enzyme dihydroorotate dehydrogenase in rat
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds.
Year : 1996
Volume : 39
Issue : 23
First Page : 4608
Last Page : 4621
Authors : Kuo EA, Hambleton PT, Kay DP, Evans PL, Matharu SS, Little E, McDowall N, Jones CB, Hedgecock CJ, Yea CM, Chan AW, Hairsine PW, Ager IR, Tully WR, Williamson RA, Westwood R.
Abstract : The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
|
Inhibitory activity against rat dihydroorotate dehydrogenase
|
Rattus norvegicus
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors.
Year : 2005
Volume : 15
Issue : 21
First Page : 4854
Last Page : 4857
Authors : Leban J, Kralik M, Mies J, Gassen M, Tentschert K, Baumgartner R.
Abstract : Novel DHODH inhibitors were developed based on a previously described series by introduction of heteroatoms into the cyclopentene ring and hydroxyl groups attached to it. Also, the hydrophobic biphenyl side chain was replaced with benzyloxy phenyl groups. Activities on human, rat, and mouse enzymes indicate a species specificity of these inhibitors.
|
Inhibitory activity against mouse dihydroorotate dehydrogenase
|
Mus musculus
|
156.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors.
Year : 2005
Volume : 15
Issue : 21
First Page : 4854
Last Page : 4857
Authors : Leban J, Kralik M, Mies J, Gassen M, Tentschert K, Baumgartner R.
Abstract : Novel DHODH inhibitors were developed based on a previously described series by introduction of heteroatoms into the cyclopentene ring and hydroxyl groups attached to it. Also, the hydrophobic biphenyl side chain was replaced with benzyloxy phenyl groups. Activities on human, rat, and mouse enzymes indicate a species specificity of these inhibitors.
|
Inhibition of N-terminally truncated recombinant human dihydroorotate dehydrogenase using in vitro enzyme assay
|
Homo sapiens
|
420.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors.
Year : 2005
Volume : 15
Issue : 21
First Page : 4854
Last Page : 4857
Authors : Leban J, Kralik M, Mies J, Gassen M, Tentschert K, Baumgartner R.
Abstract : Novel DHODH inhibitors were developed based on a previously described series by introduction of heteroatoms into the cyclopentene ring and hydroxyl groups attached to it. Also, the hydrophobic biphenyl side chain was replaced with benzyloxy phenyl groups. Activities on human, rat, and mouse enzymes indicate a species specificity of these inhibitors.
|
Inhibition of human recombinant DHODH
|
Homo sapiens
|
260.0
nM
|
|
Inhibition of human recombinant DHODH
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.
Year : 2007
Volume : 50
Issue : 2
First Page : 186
Last Page : 191
Authors : Heikkilä T, Ramsey C, Davies M, Galtier C, Stead AM, Johnson AP, Fishwick CW, Boa AN, McConkey GA.
Abstract : Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.
|
Inhibition of ubiquinone binding site of human dihydroorotate dehydrogenase
|
Homo sapiens
|
32.0
nM
|
|
Inhibition of ubiquinone binding site of human dihydroorotate dehydrogenase
|
Homo sapiens
|
261.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases.
Year : 2009
Volume : 52
Issue : 9
First Page : 2683
Last Page : 2693
Authors : Davies M, Heikkilä T, McConkey GA, Fishwick CW, Parsons MR, Johnson AP.
Abstract : Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.
|
Inhibition of Escherichia coli D-alanine-D-alanine ligase B assessed as residual activity at 2 mM preincubated for 30 mins by malachite green assay
|
Escherichia coli
|
114.52
%
|
|
Journal : Bioorg. Med. Chem.
Title : ATP competitive inhibitors of D-alanine-D-alanine ligase based on protein kinase inhibitor scaffolds.
Year : 2009
Volume : 17
Issue : 3
First Page : 1079
Last Page : 1087
Authors : Triola G, Wetzel S, Ellinger B, Koch MA, Hübel K, Rauh D, Waldmann H.
Abstract : D-Alanine-D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons's tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a K(i) of 185 microM. A series of malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl.
|
Antimalarial activity against Plasmodium falciparum W2mef at 10 uM after 48 hrs by hoechst 33342-thiazole orange stain based flow cytometry assay
|
Plasmodium falciparum
|
4.96
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Addressing the malaria drug resistance challenge using flow cytometry to discover new antimalarials.
Year : 2009
Volume : 19
Issue : 18
First Page : 5452
Last Page : 5457
Authors : Grimberg BT, Jaworska MM, Hough LB, Zimmerman PA, Phillips JG.
Abstract : A new flow cytometry method that uses an optimized DNA and RNA staining strategy to monitor the growth and development of the Plasmodium falciparum strain W2mef has been used in a pilot study and has identified Bay 43-9006 1, SU 11274 2, and TMC 125 5 as compounds that exhibit potent (<1 microM) overall and ring stage in vitro antimalarial activity.
|
Inhibition of DHODH in Wistar rat liver homogenates by DCIP reduction assay
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 1,2,5-Oxadiazole analogues of leflunomide and related compounds.
Year : 2011
Volume : 46
Issue : 1
First Page : 383
Last Page : 392
Authors : Giorgis M, Lolli ML, Rolando B, Rao A, Tosco P, Chaurasia S, Marabello D, Fruttero R, Gasco A.
Abstract : A new series of compounds, structurally related to leflunomide, based on the 1,2,5-oxadiazole ring system (furazan) has been synthesised, and their ability to undergo ring scission at physiological pH to afford the corresponding cyano-oximes has been analyzed. The latter, together with the respective nitro derivatives obtained by oxidation, have been characterised as weak inhibitors of rat dihydroorotate dehydrogenase (DHODH).
|
Inhibition of rat dihydroorotate dehydrogenase
|
Rattus norvegicus
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biaryl analogues of teriflunomide as potent DHODH inhibitors.
Year : 2011
Volume : 21
Issue : 24
First Page : 7268
Last Page : 7272
Authors : Erra M, Moreno I, Sanahuja J, Andrés M, Reinoso RF, Lozoya E, Pizcueta P, Godessart N, Castro-Palomino JC.
Abstract : The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.
|
Inhibition of dihydroorotate dehydrogenase in Wistar rat liver mitochondrial/microsomal membranes measured for 5 mins by 2,6-dichlorophenolindophenol reduction-based spectrophotometry
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold.
Year : 2012
Volume : 49
First Page : 102
Last Page : 109
Authors : Lolli ML, Giorgis M, Tosco P, Foti A, Fruttero R, Gasco A.
Abstract : Based on some structural analogies with leflunomide and brequinar, two well-known inhibitors of dihydroorotate dehydrogenase (DHODH), a new series of products was designed, by joining the substituted biphenyl moiety to the 4-hydroxy-1,2,5-oxadiazol-3-yl scaffold through an amide bridge. The compounds were studied for their DHODH inhibitory activity on rat liver mitochondrial/microsomal membranes. The activity was found to be closely dependent on the substitution pattern at the biphenyl system; the most potent products were those bearing two or four fluorine atoms at the phenyl adjacent to the oxadiazole ring. A molecular modeling study suggested that these structures might have a brequinar-like binding mode. The greater potency of fluorinated analogs may depend partly on enhanced interactions with the hydrophobic ubiquinone channel, and partly on the role of fluorine in stabilizing the putative bioactive conformation.
|
Inhibition of human DHODH expressed in Escherichia coli BL21(DE3) using L-dihydroorotate as substrate after 10 mins by DCIP dye reduction assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of diverse human dihydroorotate dehydrogenase inhibitors as immunosuppressive agents by structure-based virtual screening.
Year : 2012
Volume : 55
Issue : 19
First Page : 8341
Last Page : 8349
Authors : Diao Y, Lu W, Jin H, Zhu J, Han L, Xu M, Gao R, Shen X, Zhao Z, Liu X, Xu Y, Huang J, Li H.
Abstract : This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (hDHODH) inhibitors. Eighteen compounds with IC(50) values ranging from 0.11 to 18.8 μM were identified as novel hDHODH inhibitors that exhibited overall species-selectivity over Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH). Compound 8, the most potent one, showed low micromolar inhibitory activity against hDHODH with an IC(50) value of 0.11 μM. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound 18 exhibited potent B-cell inhibitory activity (IC(50) = 1.78 μM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.
|
Inhibition of N-terminal His10-tagged human DHODH (Met30 to Arg396) expressed in Escherichia coli BL21 (DE3) using dihydroorotate as substrate measured every 30 secs for 6 mins by DCIP dye-based assay
|
Homo sapiens
|
137.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives.
Year : 2013
Volume : 56
Issue : 20
First Page : 7911
Last Page : 7924
Authors : Xu M, Zhu J, Diao Y, Zhou H, Ren X, Sun D, Huang J, Han D, Zhao Z, Zhu L, Xu Y, Li H.
Abstract : Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14,000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.
|
Inhibition of mouse DHODH (amino acid residues 30 to 396) expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by DCIP dye-based assay
|
Mus musculus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of C-terminal His6-tagged human DHODH (amino acid residues 30 to 396) expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by DCIP dye-based assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of rat DHODH (amino acid residues 30 to 396) expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by DCIP dye-based assay
|
Rattus norvegicus
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of dog DHODH (amino acid residues 48 to 414) expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by DCIP dye-based assay
|
Canis lupus familiaris
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of C-terminal His6-tagged human DHODH (amino acid residues 30 to 396) expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by direct assay in presence of oxygen depleting system
|
Homo sapiens
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of C-terminal His6-tagged human DHODH (amino acid residues 30 to 396) L46A mutant expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by direct assay in presence of oxygen depleting system
|
Homo sapiens
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of C-terminal His6-tagged human DHODH (amino acid residues 30 to 396) L359A mutant expressed in Escherichia coli BL21 cells assessed as orotic acid production using dihydroorotate as substrate by direct assay in presence of oxygen depleting system
|
Homo sapiens
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Year : 2014
Volume : 57
Issue : 12
First Page : 5381
Last Page : 5394
Authors : Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA.
Abstract : Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
|
Inhibition of human DHODH using dihydroorotate substrate by DCIP assay
|
Homo sapiens
|
163.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase.
Year : 2015
Volume : 58
Issue : 3
First Page : 1123
Last Page : 1139
Authors : Zhu J, Han L, Diao Y, Ren X, Xu M, Xu L, Li S, Li Q, Dong D, Huang J, Liu X, Zhao Z, Wang R, Zhu L, Xu Y, Qian X, Li H.
Abstract : Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound 4, which was previously identified as potential HsDHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues 12 and 33 confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds 44, 46, and 47 which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, 44 presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of HsDHODH.
|
Inhibition of human DHODH assessed as decrease in DCIP at 10 uM using dihydroorotate as substrate measured every 30 seconds for 6 mins
|
Homo sapiens
|
64.03
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and inhibitory activity against human dihydroorotate dehydrogenase (hDHODH) of 1,3-benzoazole derivatives bearing amide units.
Year : 2016
Volume : 26
Issue : 13
First Page : 3064
Last Page : 3066
Authors : Li J, Wu D, Xu X, Huang J, Shao X, Li Z.
Abstract : A series of 1,3-benzoazole derivatives possessing amide moieties were designed, synthesized and evaluated as inhibitors against human dihydroorotate dehydrogenase (hDHODH). Compounds A11, A14 and A26 exhibited good to excellent activities against hDHODH at the concentration of 10μM. In particular, compound A14 displayed an IC50 value of 0.178μM with 2-fold preference over A771726. The result implied that a proper degree of steric size and electron density of the C-6 amide moiety was necessary to retain the inhibitory activity of the synthesized compounds.
|
Inhibition of human DHODH assessed as decrease in DCIP using dihydroorotate as substrate measured every 30 seconds for 6 mins
|
Homo sapiens
|
356.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and inhibitory activity against human dihydroorotate dehydrogenase (hDHODH) of 1,3-benzoazole derivatives bearing amide units.
Year : 2016
Volume : 26
Issue : 13
First Page : 3064
Last Page : 3066
Authors : Li J, Wu D, Xu X, Huang J, Shao X, Li Z.
Abstract : A series of 1,3-benzoazole derivatives possessing amide moieties were designed, synthesized and evaluated as inhibitors against human dihydroorotate dehydrogenase (hDHODH). Compounds A11, A14 and A26 exhibited good to excellent activities against hDHODH at the concentration of 10μM. In particular, compound A14 displayed an IC50 value of 0.178μM with 2-fold preference over A771726. The result implied that a proper degree of steric size and electron density of the C-6 amide moiety was necessary to retain the inhibitory activity of the synthesized compounds.
|
Inhibition of recombinant human N-terminal truncated GST-tagged DHFR (31 to 395 residues) expressed in Escherichia coli BL21(DE3) pyrD using DHO as substrate preincubated for 5 mins followed by substrate addition measured for 5 mins by DCIP oxidation based CoQ10 enzyme coupled assay
|
Homo sapiens
|
388.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.
Year : 2017
Volume : 129
First Page : 287
Last Page : 302
Authors : Sainas S, Pippione AC, Giorgis M, Lupino E, Goyal P, Ramondetti C, Buccinnà B, Piccinini M, Braga RC, Andrade CH, Andersson M, Moritzer AC, Friemann R, Mensa S, Al-Kadaraghi S, Boschi D, Lolli ML.
Abstract : A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.
|
Inhibition of recombinant N-terminal GST-tagged human DHODH (31 to 395 residues) expressed in Escherichia coli BL21(DE3) assessed as inhibition of DCIP reduction using dihydroorotate as substrate preincubated for 5 mins followed by substrate addition measured after 5 mins
|
Homo sapiens
|
388.0
nM
|
|
Journal : J Med Chem
Title : Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors.
Year : 2018
Volume : 61
Issue : 14
First Page : 6034
Last Page : 6055
Authors : Sainas S, Pippione AC, Lupino E, Giorgis M, Circosta P, Gaidano V, Goyal P, Bonanni D, Rolando B, Cignetti A, Ducime A, Andersson M, Järvå M, Friemann R, Piccinini M, Ramondetti C, Buccinnà B, Al-Karadaghi S, Boschi D, Saglio G, Lolli ML.
Abstract : Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
1.28
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of C-terminal 6-His tagged recombinant human DHODH N-terminal domain delta29 mutant expressed in Escherichia coli BL21(DE3) using dihydroorotate as substrate measured every 30 secs for 6 mins by DCIP dye based assay
|
Homo sapiens
|
280.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors.
Year : 2019
Volume : 62
Issue : 8
First Page : 4056
Last Page : 4073
Authors : Yang Y, Cao L, Gao H, Wu Y, Wang Y, Fang F, Lan T, Lou Z, Rao Y.
Abstract : Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.
|
Inhibition of human DHODH using DHO as substrate measured at 4 secs interval for 60 secs by DCIP reduction based indirect assay
|
Homo sapiens
|
312.0
nM
|
|
Journal : Eur J Med Chem
Title : Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase.
Year : 2019
Volume : 167
First Page : 357
Last Page : 366
Authors : Calil FA, David JS, Chiappetta ERC, Fumagalli F, Mello RB, Leite FHA, Castilho MS, Emery FS, Nonato MC.
Abstract : Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH. The best compound identified is 17 (2-hydroxy-3-isopentylnaphthalene-1,4-dione) with IC<sub>50</sub> = 23 ± 4 nM and selectivity index of 30.83. Some of the new compounds are useful pharmacological tools and represent new lead structures for further optimization.
|
Inhibition of human DHODH
|
Homo sapiens
|
320.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
35.02
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.27
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.14
%
|
|
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
|
-0.13
%
|
|
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
|
0.08
%
|
|
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
|
-0.15
%
|
|
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
|
0.08
%
|
|
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
|
-0.15
%
|
|
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
|
-0.13
%
|
|
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.
|
Inhibition of C-terminal His6-tagged human DHODH expressed in Escherichia coli BL21(DE3) cells using L-DHO as substrate by DCIP dye based assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.
Year : 2020
Volume : 63
Issue : 9
First Page : 4929
Last Page : 4956
Authors : Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, Phillips MA.
Abstract : Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (<b>1</b>) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus <i>Plasmodium</i> DHODH and <i>Plasmodium</i> parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from <b>1</b> leading to improved species selectivity versus mammalian enzymes and equivalent activity on <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> DHODH. The best lead DSM502 (<b>37</b>) showed <i>in vivo</i> efficacy at similar levels of blood exposure to <b>1</b>, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
|
Inhibition of C-terminal His6-tagged mouse DHODH expressed in Escherichia coli BL21(DE3) cells using L-DHO as substrate by DCIP dye based assay
|
Mus musculus
|
110.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.
Year : 2020
Volume : 63
Issue : 9
First Page : 4929
Last Page : 4956
Authors : Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, Phillips MA.
Abstract : Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (<b>1</b>) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus <i>Plasmodium</i> DHODH and <i>Plasmodium</i> parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from <b>1</b> leading to improved species selectivity versus mammalian enzymes and equivalent activity on <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> DHODH. The best lead DSM502 (<b>37</b>) showed <i>in vivo</i> efficacy at similar levels of blood exposure to <b>1</b>, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
|
Inhibition of C-terminal His6-tagged rat DHODH expressed in Escherichia coli BL21(DE3) cells using L-DHO as substrate by DCIP dye based assay
|
Rattus norvegicus
|
17.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.
Year : 2020
Volume : 63
Issue : 9
First Page : 4929
Last Page : 4956
Authors : Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, Phillips MA.
Abstract : Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (<b>1</b>) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus <i>Plasmodium</i> DHODH and <i>Plasmodium</i> parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from <b>1</b> leading to improved species selectivity versus mammalian enzymes and equivalent activity on <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> DHODH. The best lead DSM502 (<b>37</b>) showed <i>in vivo</i> efficacy at similar levels of blood exposure to <b>1</b>, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
|
Inhibition of C-terminal His6-tagged dog DHODH expressed in Escherichia coli BL21(DE3) cells using L-DHO as substrate by DCIP dye based assay
|
Canis lupus familiaris
|
200.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.
Year : 2020
Volume : 63
Issue : 9
First Page : 4929
Last Page : 4956
Authors : Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, Phillips MA.
Abstract : Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (<b>1</b>) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus <i>Plasmodium</i> DHODH and <i>Plasmodium</i> parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from <b>1</b> leading to improved species selectivity versus mammalian enzymes and equivalent activity on <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> DHODH. The best lead DSM502 (<b>37</b>) showed <i>in vivo</i> efficacy at similar levels of blood exposure to <b>1</b>, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
|
Inhibition of human recombinant DHODH expressed in Escherichia coli BL21 (DE3) using dihydroorotate as substrate and CoQ6 as co-substrate incubated for 10 mins by DCIP based multimode microplate reader analysis
|
Homo sapiens
|
227.0
nM
|
|
