Strategies Towards the Development of Guanidinophenyl Piperazine Derivatives as Potential Anti-Tubercular Agents

Abstract

This thesis presents the development and evaluation of guanidinophenyl piperazine derivatives as novel anti-tubercular agents targeting enoyl-acyl carrier reductase (InhA), a key enzyme in mycolic acid synthesis of Mycobacterium tuberculosis. In 2023, according to the World Health Organisation (WHO) Global Tuberculosis Report, an estimated 10.8 million people fell ill with TB while a further 1.25 million people died as a result of the disease. With complicated treatment regimes and anti-biotic resistance on the rise there is an urgent need for new tuberculosis therapies. Hence, this project deals with the further development of 1, a trifluoromethyl substituted guanidinophenyl piperazine which has shown to be active in Mycobacterium smegmatis. Beginning with computational studies, bioisosteres were identified for the trifluoromethyl functional group due to recent concerns over its negative environmental effects. Potential bioisosteres were considered through the systematic comparison of size, electronic properties, and lipophilicity. Molecular docking investigations, including a flexible side-chain approach, revealed novel binding modes for these guanidino piperazine derivatives in the InhA active site, incorporating hydrogen bond and �-cation interactions with the NADH cofactor and InhA which could be explain the activity of these compounds. New derivatives were synthesised and thus evaluated as potential anti-tubercular agents. Biological evaluation against M. tuberculosis strain mc2 6230 identified derivative 7 (-SF5) and derivative 21 (alkylguanidine) as the most promising candidates with MIC values of 4-8 �g mL-1 and 8 �g/mL-1, respectively. However, preliminary ADMET studies revealed hepatotoxicity concerns for these compounds, with selectivity indices below acceptable thresholds. Thusly it is proposed parent compound 1 (-CF�) should be the focus of further development as it demonstrated a balance between moderate antitubercular activity (32 �g mL-1) and an excellent safety profile. Given the molecular modelling results, new avenues of further development have also been identified.