New Tetrazole-Annulated Pyrazolyl–Pyrimidine Derivatives as Antimycobacterial Targets: Design, Synthesis, Molecular Docking, and ADME Profiling

Herein, the constructing synthon pyrazolyl-pyrimidine derivatives were synthesized and utilized for building a wide variety of 1,2,3-triazole and tetrazole compounds that can be used as antimicrobial and antitubercular medications. The structures of all synthesized compounds were characterized using different spectroscopic techniques (¹H, ¹³C NMR, IR and MS). The novel o,p-dihydroxyphenyl and isopropyl substituted tetrazoles have a remarkable antimicrobial activity against K. pneumoniae (MICs = 4.93±0.02, 4.13±0.01 µg/mL) and S. aureus (MICs = 7.72±0.02, 17.34±0.01 µg/mL). Antifungal activity of pyrazolyl-pyrimidine containing with p-hydroxybenzyl, o-hydroxy, and m-nitrophenyltriazoles displayed potent antifungal activity against A. niger, and its MIC was found to be, 5.45±0.02, 4.12±0.03, and 6.31±0.01 µg/mL. All the prepared tetrazoles exposed excellent antitubercular activity comparison with the standard drug against H₃₇RV strain. From docking investigations, the p-hydroxybenzyl-linked triazole revealed the strongest H-bonds among the residues Ile¹⁴(A), Arg⁴⁵(A), Gln⁶⁸(A), Gln⁹⁸(A) × 2, Thr⁴⁶(A), and Gly⁹⁶(A) against 1DF7 protein. Finally, the in silico pharmacokinetic profile of all the derivatives was estimated using SwissADME and some of the compounds have Lipinski rule of five without deviation.