Successive paired electrochemical late-stage modification of niclosamide a common anthelmintic drug. A green protocol for the synthesis of new drug-like molecules

Abstract

Drugs based on salicylanilides such as niclosamide are of particular interest to medicinal chemistry researchers. They exhibit a wide range of biological activities, including anticancer and antiviral activities. Niclosamide is a common oral anthelmintic that has the potential to be an antiviral and anticancer drug. However, two characteristics of it, including poor oral bioavailability and high cytotoxicity, have limited its use. The synthesis of new niclosamide analogs is an attempt to overcome these limitations. The electrochemical behavior of niclosamide shows that the drug can be reduced and then oxidized at the cathode and anode, respectively. This property, along with the special capabilities of electrosynthesis methods, makes it possible to obtain unique niclosamide analogs. In this study, novel niclosamide analogs were synthesized via successive paired electrolysis of niclosamide in the presence of arylsulfinic acids as nucleophiles. The results show that niclosamide is converted to the desired product (5-chloro-N-(2-chloro-4-(phenylsulfonamido)phenyl)-2-hydroxy benzamide) after reduction and oxidation steps and reaction with the nucleophile. In the synthesized niclosamide analogs, a sulfonamide moiety is attached to the drug molecule. This work presents a green method for the synthesis of new niclosamide analogs without the need for catalysts, reductants or oxidants under mild conditions in a one-pot process.