Synthesis, anti-microbial, toxicity and molecular docking studies of N-nitroso-N-phenylhydroxylamine (cupferron) and its derivatives

Ibrahim Waziri; Mustafa A Isa; Molahlehi Sonopo; D Bradley G Williams; Alfred Muller

doi:10.1016/j.bmcl.2021.128381

Synthesis, anti-microbial, toxicity and molecular docking studies of N-nitroso-N-phenylhydroxylamine (cupferron) and its derivatives

Bioorg Med Chem Lett. 2021 Nov 15:52:128381. doi: 10.1016/j.bmcl.2021.128381. Epub 2021 Sep 24.

Authors

Ibrahim Waziri¹, Mustafa A Isa², Molahlehi Sonopo³, D Bradley G Williams⁴, Alfred Muller⁵

Affiliations

¹ Department of Chemical Sciences, University of Johannesburg, P.O. Box 524, Auckland Park 2006, South Africa.
² Department of Microbiology, University of Maiduguri, P.M.B. 1069, Maiduguri, Nigeria.
³ Radiochemistry, Department of Applied Chemistry, Necsa (South African Nuclear Energy Corporation Ltd.), P.O. Box 582, Pretoria 0001, South Africa.
⁴ University of Technology Sydney, School of Mathematical and Physical Sciences, P.O. Box 123, Broadway, Sydney, NSW 2007, Australia. Electronic address: bradley.williams@uts.edu.au.
⁵ Department of Chemical Sciences, University of Johannesburg, P.O. Box 524, Auckland Park 2006, South Africa. Electronic address: mullera@uj.ac.za.

PMID: 34571137
DOI: 10.1016/j.bmcl.2021.128381

Abstract

Bacterial resistance to antimicrobial agents is increasing at an alarming rate globally and requires new lead compounds for antibiotics. In this study, N-phenyl-N-nitroso hydroxylamine (cupferron) and its derivatives have been synthesised using readily available starting materials. The compounds were obtained in high yield and purity. They show activity towards a range of Gram-positive and Gram-negative pathogenic bacteria, with minimum inhibitory concentration (MIC) values as low as 2 μg.mL^-1 against the tested organisms, especially for Gram-positive species. Toxicity studies on the lead compound 3b indicate insignificant effects on healthy cell lines. Molecular docking studies on the lead compound identify possible binding modes of the compound, and the results obtained correlate with those of in vitro and MIC studies. The lead compound shows excellent drug-likeness properties.

Keywords: Antibiotics; Antimicrobial resistance; Bacteria; Cupferron.

Publication types

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Gram-Negative Bacteria / drug effects*
Gram-Positive Bacteria / drug effects*
Microbial Sensitivity Tests
Molecular Docking Simulation*
Molecular Structure
Nitrosamines / chemical synthesis
Nitrosamines / chemistry
Nitrosamines / pharmacology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Nitrosamines
cupferron