Related Experiment Video

Updated: Jan 29, 2026

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
13:38

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

Published on: January 18, 2017

12.7K

MEP Pathway: First-Synthesized IspH-Directed Prodrugs with Potent Antimycobacterial Activity

Alizée Allamand1,2, Ludovik Noël-Duchesneau1, Cédric Ettelbruck1

  • 1Laboratoire Chimie et Biochimie de Molécules Bioactives, Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.

Microorganisms
|January 28, 2026
PubMed

Insights

Researchers developed novel prodrugs targeting the IspH enzyme in the MEP pathway for treating tuberculosis. Chlorine-substituted compounds showed significant antimycobacterial activity, outperforming isoniazid.

Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Microbiology

Background:

  • The 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway is essential for bacterial survival.
  • Targeting the terminal enzyme, (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH or LytB), offers a potential strategy for antimycobacterial drug development.
  • Prodrug strategies can enhance the delivery and efficacy of phosphorylated inhibitors.

Purpose of the Study:

  • To synthesize and evaluate novel IspH-directed prodrugs.
  • To investigate the impact of substituents on prodrug permeability and antimycobacterial activity.
  • To establish the efficacy of the cycloSaligenyl (cycloSal) prodrug approach for delivering phosphorylated inhibitors.

Main Methods:

  • Synthesis of alkyne and pyridine monophosphate cycloSal prodrugs with varying substituents (electron-withdrawing and donating).
  • Evaluation of prodrugs against Mycobacterium smegmatis using agar diffusion assays.
  • Assessment of structure-activity relationships, including amino acid-functionalized and mutual prodrug analogs.

Main Results:

  • Chlorine-substituted derivatives (5c and 6c) exhibited potent antimycobacterial activity against Mycobacterium smegmatis.
  • These compounds demonstrated superior activity compared to isoniazid in agar diffusion assays.
  • Electron-withdrawing substituents were found to accelerate prodrug hydrolysis and intracellular release of the active inhibitor.

Conclusions:

  • The study presents the first experimental evidence for an IspH-targeted prodrug approach.
  • The cycloSal prodrug strategy is effective for delivering phosphorylated inhibitors.
  • This work paves the way for developing novel antimycobacterial agents targeting the MEP pathway.
Keywords:
4-hydroxy-3-methylbut-2-enyl diphosphate reductaseMycobacterium smegmatisantimycobacterialcycloSaligenyl prodrugisoniazidisoprenoid biosynthesis

More Related Videos

Facile Preparation and Photoactivation of Prodrug-Dye Nanoassemblies08:54

Facile Preparation and Photoactivation of Prodrug-Dye Nanoassemblies

Published on: February 17, 2023

1.5K
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

9.4K

Related Concept Videos

Direct Motor Pathways01:11

Direct Motor Pathways

The direct motor pathways, also known as the pyramidal tracts, are a group of neural pathways that originate in the brain and descend through the spinal cord. They control the voluntary movement of the body. There are two major direct motor pathways: the corticospinal and the corticobulbar tracts.
The corticospinal tract is responsible for the voluntary movement of the limbs and trunk. It originates in the cerebral cortex of the brain and descends through the cerebrum's internal capsule and...
4.5K
Prodrugs01:30

Prodrugs

Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
Prodrugs help overcome...
4.2K
C4 Pathway and CAM01:27

C4 Pathway and CAM

Most plants use the C3 pathway for carbon fixation. However, some plants, such as sugar cane, corn, and cacti that grow in hot conditions, use alternative pathways to fix carbon and conserve energy loss due to photorespiration. Photorespiration is the process that occurs when the oxygen concentration is high. Under such conditions, the rubisco enzyme in the Calvin cycle binds O2 instead of CO2, which halts photosynthesis and consumes energy.
C4 Pathway
The C4 pathway is used by plants such as...
49.1K
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
2.1K
Other Glycolytic Pathways01:24

Other Glycolytic Pathways

The pentose phosphate pathway (PPP) operates in parallel with glycolysis, facilitating the metabolism of both pentoses and glucose. This pathway consists of two distinct phases: the oxidative and non-oxidative phases. While it does not directly generate ATP, the intermediates formed during the process can integrate into glycolysis, contributing to cellular energy metabolism when required.Oxidative Phase: NADPH ProductionThe oxidative phase of the pentose phosphate pathway is primarily...
894
ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH301:11

ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3

All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
7.4K