Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors: State of Art Past 20 Years

Abstract

Tuberculosis is a disease with a high level of incidence and mortality. Due to the problems associated with current therapy, it is necessary and urgent to develop new drugs for treatment. Dihydrofolate reductase (DHFR) is a recognized target for the action of several drugs. The 3D structure of the Mycobacterium tuberculosis DHFR (MtDHFR) elucidates the key amino acid residues responsible for the active site architecture formation and structural basis for ligand specificity compared to the human DHFR (hDHFR). This article aims to offer a view on state of the art about new MtDHFR inhibitors developed in the last twenty years. This study demonstrates a correlation between efficacy and the presence of specific groups, such as the diaminopyridimidine ring that binds to the enzyme active site and the similarity of the structures with classic DHFR inhibitors methotrexate. Herein, it is also reported the recent efforts to develop molecules non-traditional cores, which could be more selective and effective against tuberculosis.