Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities.

Tuberculosis (TB) is a chronic, potentially fatal disease caused by (). The dihyrofolate reductase in (-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of to function at the whole cell level. In the current study, we designed and synthesized a series of -DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against H37Ra. Among them, compound showed a good anti-TB activity (MIC = 6.25 μg/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on -DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure -DHFR binding assays.