The Experts below are selected from a list of 450 Experts worldwide ranked by ideXlab platform
Farah El Mazouni - One of the best experts on this subject based on the ideXlab platform.
-
isoxazolopyrimidine based inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity
ACS omega, 2018Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Karen L White, John H White, David M Shackleford, Maria Jose Lafuentemonasterio, Paul Rowland, Krishne Manjalanagara, Jayan T Joseph, Adolfo GarciaperezAbstract:Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a Triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their Triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.
-
Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity
2018Co-Authors: Sreekanth Kokkonda, John White, Farah El Mazouni, Karen L White, David M Shackleford, Paul Rowland, Krishne Manjalanagara, Jayan T Joseph, Maria Jose Lafuente-monasterio, Adolfo Garcia-pérezAbstract:Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a Triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their Triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria
-
tetrahydro 2 naphthyl and 2 indanyl Triazolopyrimidines targeting plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity
Journal of Medicinal Chemistry, 2016Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Jose M Coteron, Xiaoyi Deng, Karen L White, John H White, Maria L Marco, Laura Fernandez De Las Heras, Diana R Tomchick, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher m...
-
Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
2016Co-Authors: Sreekanth Kokkonda, John White, Farah El Mazouni, Jose M Coteron, Maria Di Marco, Xiaoyi Deng, Laura Fernandez De Las Heras, Diana R Tomchick, Karen L. White, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen
-
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors
2015Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, John White, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, Werner Kaminsky, Jeremy N. Burrows, David Matthews, Margaret A PhillipsAbstract: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
Xiaoyi Deng - One of the best experts on this subject based on the ideXlab platform.
-
tetrahydro 2 naphthyl and 2 indanyl Triazolopyrimidines targeting plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity
Journal of Medicinal Chemistry, 2016Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Jose M Coteron, Xiaoyi Deng, Karen L White, John H White, Maria L Marco, Laura Fernandez De Las Heras, Diana R Tomchick, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher m...
-
Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
2016Co-Authors: Sreekanth Kokkonda, John White, Farah El Mazouni, Jose M Coteron, Maria Di Marco, Xiaoyi Deng, Laura Fernandez De Las Heras, Diana R Tomchick, Karen L. White, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen
-
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors
2015Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, John White, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, Werner Kaminsky, Jeremy N. Burrows, David Matthews, Margaret A PhillipsAbstract: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
-
fluorine modulates species selectivity in the Triazolopyrimidine class of plasmodium falciparum dihydroorotate dehydrogenase inhibitors
Journal of Medicinal Chemistry, 2014Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, John H White, Jeremy Burrows, Werner Kaminsky, David Matthews, Margaret A PhillipsAbstract: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 in...
-
structure guided lead optimization of Triazolopyrimidine ring substituents identifies potent plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential
Journal of Medicinal Chemistry, 2011Co-Authors: Jose M Coteron, John White, Farah El Mazouni, Sreekanth Kokkonda, Maria Di Marco, Jorge Esquivias, Xiaoyi Deng, Karen L White, Maria Koltun, Kasiram KatneniAbstract:Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified Triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the Triazolopyrimidine series to meet previously established progression criteria for ef...
John H White - One of the best experts on this subject based on the ideXlab platform.
-
isoxazolopyrimidine based inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity
ACS omega, 2018Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Karen L White, John H White, David M Shackleford, Maria Jose Lafuentemonasterio, Paul Rowland, Krishne Manjalanagara, Jayan T Joseph, Adolfo GarciaperezAbstract:Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a Triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their Triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.
-
tetrahydro 2 naphthyl and 2 indanyl Triazolopyrimidines targeting plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity
Journal of Medicinal Chemistry, 2016Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Jose M Coteron, Xiaoyi Deng, Karen L White, John H White, Maria L Marco, Laura Fernandez De Las Heras, Diana R Tomchick, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher m...
-
fluorine modulates species selectivity in the Triazolopyrimidine class of plasmodium falciparum dihydroorotate dehydrogenase inhibitors
Journal of Medicinal Chemistry, 2014Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, John H White, Jeremy Burrows, Werner Kaminsky, David Matthews, Margaret A PhillipsAbstract: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 in...
-
structure guided lead optimization of Triazolopyrimidine ring substituents identifies potent plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential
Journal of Medicinal Chemistry, 2011Co-Authors: Jose M Coteron, Farah El Mazouni, Sreekanth Kokkonda, Jorge Esquivias, Xiaoyi Deng, Karen L White, Maria Koltun, John H White, Maria L Marco, Kasiram KatneniAbstract:Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified Triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the Triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.
-
lead optimization of aryl and aralkyl amine based Triazolopyrimidine inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice
Journal of Medicinal Chemistry, 2011Co-Authors: Ramesh Gujjar, Farah El Mazouni, Sharon A Creason, Xiaoyi Deng, Karen L White, John H White, David M Shackleford, William N Charman, Ian Bathurst, Jeremy BurrowsAbstract:Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of Triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a Triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4-CF3-Ph), which, when coupled to the Triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse ...
Pradipsinh K Rathod - One of the best experts on this subject based on the ideXlab platform.
-
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors
2015Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, John White, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, Werner Kaminsky, Jeremy N. Burrows, David Matthews, Margaret A PhillipsAbstract: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
-
fluorine modulates species selectivity in the Triazolopyrimidine class of plasmodium falciparum dihydroorotate dehydrogenase inhibitors
Journal of Medicinal Chemistry, 2014Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, John H White, Jeremy Burrows, Werner Kaminsky, David Matthews, Margaret A PhillipsAbstract: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 in...
-
bioisosteric transformations and permutations in the Triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against plasmodium falciparum dihydroorotate dehydrogenase
Journal of Medicinal Chemistry, 2012Co-Authors: Alka Marwaha, Margaret A Phillips, John White, Farah El Mazouni, Sharon A Creason, Sreekanth Kokkonda, Frederick S Buckner, Susan A Charman, Pradipsinh K RathodAbstract:Plasmodium falciparum causes approximately 1 million deaths annually. However, increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective Triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the Triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-a]pyrimidines were shown to bind somewhat more potently than the Triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC50 = 0.077 μM) than the equivalent triazo...
-
structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds
Journal of Biological Chemistry, 2009Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, Farah El Mazouni, Ramesh Gujjar, Nicholas A Malmquist, Werner Kaminsky, Elizabeth J Goldsmith, Margaret A PhillipsAbstract:Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective Triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small molecule crystallography, is that the Triazolopyrimidines populate a resonance form that promotes charge separation. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that Triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-Triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.
-
Triazolopyrimidine based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite plasmodium falciparum
Journal of Medicinal Chemistry, 2008Co-Authors: Margaret A Phillips, Farah El Mazouni, Ramesh Gujjar, Nicholas A Malmquist, John H White, Jeffrey Baldwin, Pradipsinh K RathodAbstract:A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted Triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).
Sreekanth Kokkonda - One of the best experts on this subject based on the ideXlab platform.
-
isoxazolopyrimidine based inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity
ACS omega, 2018Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Karen L White, John H White, David M Shackleford, Maria Jose Lafuentemonasterio, Paul Rowland, Krishne Manjalanagara, Jayan T Joseph, Adolfo GarciaperezAbstract:Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a Triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their Triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.
-
Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity
2018Co-Authors: Sreekanth Kokkonda, John White, Farah El Mazouni, Karen L White, David M Shackleford, Paul Rowland, Krishne Manjalanagara, Jayan T Joseph, Maria Jose Lafuente-monasterio, Adolfo Garcia-pérezAbstract:Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a Triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their Triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria
-
tetrahydro 2 naphthyl and 2 indanyl Triazolopyrimidines targeting plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity
Journal of Medicinal Chemistry, 2016Co-Authors: Sreekanth Kokkonda, Farah El Mazouni, Jose M Coteron, Xiaoyi Deng, Karen L White, John H White, Maria L Marco, Laura Fernandez De Las Heras, Diana R Tomchick, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher m...
-
Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
2016Co-Authors: Sreekanth Kokkonda, John White, Farah El Mazouni, Jose M Coteron, Maria Di Marco, Xiaoyi Deng, Laura Fernandez De Las Heras, Diana R Tomchick, Karen L. White, Krishne ManjalanagaraAbstract:Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a Triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel Triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen
-
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors
2015Co-Authors: Xiaoyi Deng, Pradipsinh K Rathod, John White, Farah El Mazouni, Sreekanth Kokkonda, Susan A Charman, Werner Kaminsky, Jeremy N. Burrows, David Matthews, Margaret A PhillipsAbstract: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
