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Area of Science:

  • Medicinal Chemistry
  • Parasitology
  • Enzymology

Background:

  • The 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) enzyme is a validated target for antiplasmodial drug development due to its essentiality in Plasmodium parasites and absence in humans.
  • Fosmidomycin, a DXR inhibitor, demonstrated clinical potential but faced limitations due to recrudescence associated with its polar phosphonic acid group.

Purpose of the Study:

  • To develop novel lipophilic fosmidomycin derivatives with improved antiplasmodial activity and reduced recrudescence.
  • To investigate the mechanism of inhibition and binding interactions of these new derivatives with Plasmodium falciparum DXR (PfDXR).

Main Methods:

  • Synthesis of reverse α-phenyl fosmidomycin derivatives incorporating lipophilic N-benzamidoalkyl and N-phthalimidoalkyl substituents.
  • Enzymatic inhibition assays to determine IC50 values against PfDXR.
  • Antiplasmodial activity assays against Plasmodium falciparum strains.
  • Mode of inhibition studies and co-crystallization with PfDXR.

Main Results:

  • Lipophilic modifications, particularly with elongated alkyl linkers, significantly enhanced PfDXR inhibition (e.g., compound 15e, IC50 = 4.3 nM).
  • The optimized derivatives exhibited potent antiplasmodial activity (e.g., compound 16e, IC50 = 0.28 μM).
  • Inhibition studies confirmed competitive binding with both DXR substrate and NADPH cofactor (16e Ki = 0.068 μM), and co-crystallization revealed binding within the NADPH site.

Conclusions:

  • Lipophilic N-benzamidoalkyl and N-phthalimidoalkyl modifications of reverse α-phenyl fosmidomycin derivatives effectively enhance antiplasmodial activity.
  • These compounds represent promising leads for malaria treatment by targeting the essential PfDXR enzyme and potentially overcoming limitations of earlier inhibitors.