Martijn D P Risseeuw | Ghent University (original) (raw)

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Papers by Martijn D P Risseeuw

Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting ... more Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Although fosmidomycin is a remarkably safe antimalarial agent, low oral absorption, short serum half-life and malaria recrudescence preclude its use in monotherapy. The development of more lipophilic Dxr inhibitors able to passively permeate into cells with improved pharmacokinetic properties could lead to more efficacious agents. Previously, we discovered that analogue 4, featuring a 3,4-dichlorophenyl substituent in -position of the phosphonate, surpasses fosmidomycin's potency in inhibiting P. falciparum growth. Here we explored the introduction of aryl or aralkyl substituents at the β-position of the known hydroxamate analogue 3.

European journal of medicinal chemistry, Sep 1, 2020

Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (Mt... more Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this enzyme constitutes a potential Achilles heel of the mycobacterium. Based on a previously reported 6-aryl-substituted pyridine MtTMPK inhibitor and guided by two co-crystal structures of MtTMPK with pyridone-and thymine-based inhibitors, in the present study, we synthesized a series of aryl-shifted cyanopyridone analogues. Much to our surprise the target compounds generally lacked good MtbTMPK inhibitory potency, but selected analogues did exhibite promising antitubercular activity. Analogue 3141 demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.

We report the synthesis of 5'-modified and 5,5'-modified thymidine analogues as TMPKmt in... more We report the synthesis of 5'-modified and 5,5'-modified thymidine analogues as TMPKmt inhibitors. 5'-Substituents involving (methylsulfonyl)methyl, (Nmethylsulfamoyl) methyl, cyanomethyl, (1H-tetrazol-5-yl)methyl were combined with a 5-methyl or a 5-hydroxymethyl group at the pyrimidine moiety. The successful synthesis of the bis-substituted analogues will be discussed as well as the capacity of the target analogues to inhibit TMPKmt.

Bioorganic & Medicinal Chemistry Letters, Dec 1, 2009

ACS Medicinal Chemistry Letters, Sep 11, 2018

Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their a... more Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. To this end, a novel efficient synthesis route was developed involving a cross metathesis reaction as a key step. Alkoxyalkyl prodrugs show decent antimalarial activities, but acyloxybenzyl prodrugs proved to be the most interesting and show enhanced antimalarial and antitubercular activity. The most active antimalarial analogues show low nanomolar IC 50 values.

European journal of medicinal chemistry, Feb 1, 2017

Antimicrobial research is increasingly being focused on the problem of resistance and biofilm for... more Antimicrobial research is increasingly being focused on the problem of resistance and biofilm formation. Hamamelitannin (HAM) was recently identified as an antimicrobial potentiator for conventional antibiotics towards Staphylococcus aureus. This paper describes the synthesis and biological evaluation of novel hamamelitannin analogues with alternative central scaffolds. Via a ligand-based approach, several interesting compounds with improved synthetic accessibility were identified as potentiators for vancomycin in the treatment of MRSA infections.

Bioorganic & Medicinal Chemistry, Oct 1, 2016

Polypeptides are important naturally occurring polymers that are second only to polysaccharides, ... more Polypeptides are important naturally occurring polymers that are second only to polysaccharides, in abundance and diversity. Most natural polypeptides consist of unbranched linear chains composed of α-amino acids. With a limited palette of twenty common amino acids polymers can be generated with an almost unlimited variety in both structure and function. Though it appears that nature has optimized amino acids as structural elements, there are a few drawbacks to the use of oligopeptides as therapeutical agents. The first and most obvious one is their stability. The interconnecting amide bond is at a first glance robust since it can only be cleaved by prolonged exposure to highly acidic conditions at elevated temperature. Nature however has found several ways to cleave this sturdy bond in a mild but effective fashion by means of proteolytic enzymes. Oligopeptides often adopt flexible structures, which might be an undesirable aspect when applied as a drug, since the tertiary structure 1 of a molecule often plays a significant role in the binding of the drug to its target and thereby its activity. Although the peptide bond itself usually adopts the s-trans configuration, the flexibility of peptides stems from the rotational freedom of the remaining linkages. The rotational angles of a simple dipeptide are depicted in Figure 1.

Methods that allow high throughput identification of cellular targets of small molecules are valu... more Methods that allow high throughput identification of cellular targets of small molecules are valuable assets in pharmaceutical research. They are useful in mechanism of action studies of hits identified via phenotypic screening. Alternatively, they may uncover "off-target" proteins of established drugs, which may contribute to their therapeutic efficacy. Finally, such methods also allow profiling small molecules against a series of related intracellular targets (e.g. kinases).

Molecules, Mar 27, 2020

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerg... more In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter' systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu 5 R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu 5 Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu 5 R allosteric modulators.

Bioorganic & Medicinal Chemistry Letters, May 1, 2019

A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and in... more A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N-benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC 50 value of 0.64 µM. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.

Forensic Science International, Jul 1, 2018

Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy-a risk t... more Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy-a risk to public health

Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting ... more Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Although fosmidomycin is a remarkably safe antimalarial agent, low oral absorption, short serum half-life and malaria recrudescence preclude its use in monotherapy. The development of more lipophilic Dxr inhibitors able to passively permeate into cells with improved pharmacokinetic properties could lead to more efficacious agents. Previously, we discovered that analogue 4, featuring a 3,4-dichlorophenyl substituent in -position of the phosphonate, surpasses fosmidomycin's potency in inhibiting P. falciparum growth. Here we explored the introduction of aryl or aralkyl substituents at the β-position of the known hydroxamate analogue 3.

European journal of medicinal chemistry, Sep 1, 2020

Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (Mt... more Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this enzyme constitutes a potential Achilles heel of the mycobacterium. Based on a previously reported 6-aryl-substituted pyridine MtTMPK inhibitor and guided by two co-crystal structures of MtTMPK with pyridone-and thymine-based inhibitors, in the present study, we synthesized a series of aryl-shifted cyanopyridone analogues. Much to our surprise the target compounds generally lacked good MtbTMPK inhibitory potency, but selected analogues did exhibite promising antitubercular activity. Analogue 3141 demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.

We report the synthesis of 5'-modified and 5,5'-modified thymidine analogues as TMPKmt in... more We report the synthesis of 5'-modified and 5,5'-modified thymidine analogues as TMPKmt inhibitors. 5'-Substituents involving (methylsulfonyl)methyl, (Nmethylsulfamoyl) methyl, cyanomethyl, (1H-tetrazol-5-yl)methyl were combined with a 5-methyl or a 5-hydroxymethyl group at the pyrimidine moiety. The successful synthesis of the bis-substituted analogues will be discussed as well as the capacity of the target analogues to inhibit TMPKmt.

Bioorganic & Medicinal Chemistry Letters, Dec 1, 2009

ACS Medicinal Chemistry Letters, Sep 11, 2018

Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their a... more Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. To this end, a novel efficient synthesis route was developed involving a cross metathesis reaction as a key step. Alkoxyalkyl prodrugs show decent antimalarial activities, but acyloxybenzyl prodrugs proved to be the most interesting and show enhanced antimalarial and antitubercular activity. The most active antimalarial analogues show low nanomolar IC 50 values.

European journal of medicinal chemistry, Feb 1, 2017

Antimicrobial research is increasingly being focused on the problem of resistance and biofilm for... more Antimicrobial research is increasingly being focused on the problem of resistance and biofilm formation. Hamamelitannin (HAM) was recently identified as an antimicrobial potentiator for conventional antibiotics towards Staphylococcus aureus. This paper describes the synthesis and biological evaluation of novel hamamelitannin analogues with alternative central scaffolds. Via a ligand-based approach, several interesting compounds with improved synthetic accessibility were identified as potentiators for vancomycin in the treatment of MRSA infections.

Bioorganic & Medicinal Chemistry, Oct 1, 2016

Polypeptides are important naturally occurring polymers that are second only to polysaccharides, ... more Polypeptides are important naturally occurring polymers that are second only to polysaccharides, in abundance and diversity. Most natural polypeptides consist of unbranched linear chains composed of α-amino acids. With a limited palette of twenty common amino acids polymers can be generated with an almost unlimited variety in both structure and function. Though it appears that nature has optimized amino acids as structural elements, there are a few drawbacks to the use of oligopeptides as therapeutical agents. The first and most obvious one is their stability. The interconnecting amide bond is at a first glance robust since it can only be cleaved by prolonged exposure to highly acidic conditions at elevated temperature. Nature however has found several ways to cleave this sturdy bond in a mild but effective fashion by means of proteolytic enzymes. Oligopeptides often adopt flexible structures, which might be an undesirable aspect when applied as a drug, since the tertiary structure 1 of a molecule often plays a significant role in the binding of the drug to its target and thereby its activity. Although the peptide bond itself usually adopts the s-trans configuration, the flexibility of peptides stems from the rotational freedom of the remaining linkages. The rotational angles of a simple dipeptide are depicted in Figure 1.

Methods that allow high throughput identification of cellular targets of small molecules are valu... more Methods that allow high throughput identification of cellular targets of small molecules are valuable assets in pharmaceutical research. They are useful in mechanism of action studies of hits identified via phenotypic screening. Alternatively, they may uncover "off-target" proteins of established drugs, which may contribute to their therapeutic efficacy. Finally, such methods also allow profiling small molecules against a series of related intracellular targets (e.g. kinases).

Molecules, Mar 27, 2020

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerg... more In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter' systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu 5 R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu 5 Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu 5 R allosteric modulators.

Bioorganic & Medicinal Chemistry Letters, May 1, 2019

A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and in... more A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N-benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC 50 value of 0.64 µM. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.

Forensic Science International, Jul 1, 2018

Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy-a risk t... more Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy-a risk to public health