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

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: P.Kaye@ru.ac.za.

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

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

Christiana M Adeyemi et al. Bioorg Chem. 2020 Dec.

. 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: P.Kaye@ru.ac.za.

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.

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

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

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