Synthesis and anti-parasitic activity of N-benzylated phosphoramidate Mg2+-chelating ligands

Christiana M Adeyemi; Heinrich C Hoppe; Michelle Isaacs; Dumisani Mnkandhla; Kevin A Lobb; Rosalyn Klein; Perry T Kaye

doi:10.1016/j.bioorg.2020.104280

Synthesis and anti-parasitic activity of N-benzylated phosphoramidate Mg²⁺-chelating ligands

Bioorg Chem. 2020 Dec:105:104280. doi: 10.1016/j.bioorg.2020.104280. Epub 2020 Sep 17.

Authors

Christiana M Adeyemi¹, Heinrich C Hoppe², Michelle Isaacs², Dumisani Mnkandhla², Kevin A Lobb³, Rosalyn Klein³, Perry T Kaye⁴

Affiliations

¹ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa; Department of Biochemistry and Microbiolgy, Rhodes University, Grahamstown 6140, South Africa.
² Department of Biochemistry and Microbiolgy, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
³ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa; Department of Biochemistry and Microbiolgy, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
⁴ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa; Department of Biochemistry and Microbiolgy, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa. Electronic address: [email protected].

PMID: 33152647
DOI: 10.1016/j.bioorg.2020.104280

Abstract

A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg²⁺-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-d-xylulose-5-phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg²⁺-chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC₅₀ values of 5.6-16.4 µM against Plasmodium falciparum parasites and IC₅₀ values of 5.2 - 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)⁵ support their potential as PfDXR inhibitors.

Keywords: Anti-trypanosmal; Antimalarial; Fosmidomycin analogues; N-benzylated phosphoramidate esters.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis*
Antimalarials / chemical synthesis*
Antimalarials / pharmacology
Coordination Complexes / chemical synthesis*
Coordination Complexes / pharmacology
Dose-Response Relationship, Drug
Drug Design
Fosfomycin / analogs & derivatives
Fosfomycin / pharmacology
HeLa Cells
Humans
Ligands
Magnesium / chemistry*
Molecular Docking Simulation
Phosphoric Acids / chemical synthesis*
Plasmodium falciparum / drug effects*
Trypanosoma brucei brucei / drug effects

Substances

Amides
Antimalarials
Coordination Complexes
Ligands
Phosphoric Acids
Fosfomycin
fosmidomycin
phosphoramidic acid
Magnesium