In Vitro Toxicity and Bioactivity of some Pyrimethamine Derivatives as Anti-Tuberculosis Agents

Abstract

Tuberculosis has become such a public health threat that the WHO has declared TB a global public health emergency. However, no single anti-mycobacterial agent has been introduced into widespread use since rifampicin in the 1960s. This project is aimed at synthesising and testing of novel potential DHFR inhibitors. The testing involved the toxicity evaluation of some potential DHFR inhibitors synthesised by a previous worker and study of efficacy and toxicity of newly synthesised compounds. The in vitro toxicity of two potential inhibitors was determined using human mononuclear leucocytes (MNLs) as target cells. Due to the high toxicity encountered, their structures were modified to reduce the toxicity and a series of related new compounds were synthesised. The minimum inhibitory concentration against Mycobacterium fortuitum and in vitro toxicity for the newly synthesised compounds were also studied. Although all the compounds showed low potency, the toxicity and bioactivity data can be used as a basis in further research to yield useful information about structuretoxicity and structure-efficacy relationship.