Exploring the Anti‐Tubercular Potential of 2‐(1<i>H</i>‐Pyrazol‐1‐yl) Pyrimidine: Design, Synthesis, Biological Evaluation and Molecular Docking Studies

ABSTRACT We designed and synthesised pyrazolyl pyrimidine‐containing derivatives and screened for anti‐mycobacterial activity. Key intermediate 4‐chloro‐2‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐6‐methyl pyrimidine is prepared via the literature‐reported protocol. From this intermediate, the two sets of final compounds were prepared. Different spectral techniques like HRMS, 1 H, and 13 C NMR are deployed for the structural confirmation of final derivatives. Final compounds were screened against the Mycobacterium tuberculosis H37Rv strain. Using microplate alamar blue assay, the concentration of compound required to inhibit bacterial growth was assessed. Rifampicin was used as a standard, whose minimum inhibitory concentration (MIC) is 3.12 µg/mL. MIC values of the synthesised compounds varied from 6.25 to 25 µg/mL. Three derivatives, F‐2 , F‐5 and F‐9 among the synthesised, are most active with MIC values of 6.25 µg/mL. F‐2 , F‐5 and F‐9 compounds were also screened for their cytotoxicity against normal cells, where F‐9 has shown selectivity over normal human embryonic kidney cell lines (HEK293T). In silico ADME was evaluated using the SWISS ADME tool. Docking studies were carried out for F‐2 , F‐5 and F‐9 at the active site of InhA (PDB ID: 4TZK), the enoyl acyl carrier protein reductase. MD simulations were carried out for F‐9 to assess the stability of the protein–ligand complex.