Synthesis and anti-parasitic activity of achiral N-benzylated phosphoramidic acid derivatives

Christiana M Adeyemi; Anne C Conibear; Marius K Mutorwa; Iviwe C Nokalipa; Michelle Isaacs; Dumisani Mnkandhla; Heinrich C Hoppe; Kevin A Lobb; Rosalyn Klein; Perry T Kaye

doi:10.1016/j.bioorg.2020.103947

Synthesis and anti-parasitic activity of achiral N-benzylated phosphoramidic acid derivatives

Bioorg Chem. 2020 Aug:101:103947. doi: 10.1016/j.bioorg.2020.103947. Epub 2020 May 16.

Affiliations

¹ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa.
² Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
³ 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; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
⁵ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa. Electronic address: [email protected].

PMID: 32559578
DOI: 10.1016/j.bioorg.2020.103947

Abstract

Synthetic pathways have been developed to access a series of N-benzylated phosphoramidic acid derivatives as novel, achiral analogues of the established Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductase (PfDXR) enzyme inhibitor, FR900098. Bioassays of the targeted compounds and their synthetic precursors have revealed minimal antimalarial activity but encouraging anti-trypanosomal activity - in one case with an IC₅₀ value of 5.4 µM against Trypanosoma brucei, the parasite responsible for Nagana (African cattle sleeping sickness). The results of relevant in silico modelling and docking studies undertaken in the design and evaluation of these compounds are discussed.

Keywords: Anti-malarial; Anti-parasitic; Anti-trypanosomal; N-benzylated phosphoramidate; Nagana Trypanosoma brucei.

Publication types

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

MeSH terms

Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology*
Animals
Antimalarials / chemical synthesis*
Antimalarials / chemistry
Antimalarials / pharmacology*
Cattle
Phosphoric Acids / chemical synthesis*
Phosphoric Acids / chemistry
Phosphoric Acids / pharmacology*
Plasmodium falciparum / drug effects
Structure-Activity Relationship
Trypanocidal Agents / chemical synthesis*
Trypanocidal Agents / pharmacology*

Substances

Amides
Antimalarials
Phosphoric Acids
Trypanocidal Agents
phosphoramidic acid