Synthesis, antitubercular activity and computational studies of click-tethered phosphonium salts

This study reports the synthesis of a library comprising three series of 21 phosphonium salt hybrids (1a-1 g, 2a-2 g, 3a-3 g) generated via a click reaction yielding 1, 2, 3-triazoles with potential antitubercular activity. The phosphonium salts were synthesized through a 1, 3-dipolar cycloaddition (click) reaction. The structures of all synthesized compounds were elucidated using ¹H NMR, ¹³C NMR, AT-FTIR, and HR-LCMS spectroscopy. The compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv and multidrug-resistant TB (MDR-TB) with Rifampicin and Isoniazid, Notably, derivatives 1d and 1e demonstrated the most potent activity, achieving 100 % inhibition of MDR-TB at a minimum inhibitory concentration (MIC) of 6.25 μg/mL. At 100 μg/mL, these compounds reduced the colony-forming units (CFU) of MDR-TB by 96 % and 64 %, respectively. Compounds 2e, 3e, and 3f also displayed inhibitory activity against H37Rv, with 2e showing moderate efficacy (68 % inhibition, 6.25 μg/mL) towards MDR-TB and the highest selectivity index against murine macrophages. Molecular docking studies against seventeen (17) M. tuberculosis target proteins revealed that compounds 1d, 1e, and 2e displayed the strongest binding affinity for InhA (PDB ID: 5MTP), a key enzyme in mycolic acid biosynthesis, interacting critically with residues TYR158, PHE149, MET199, ILE194, and SER94. MM/GBSA calculations further confirmed the favorable binding free energies of these complexes. All compounds exhibited favorable predicted oral bioavailability and drug-like properties. These findings highlight the click-tethered phosphonium salts, particularly 1d, as promising lead candidates for the development of novel antitubercular agents targeting InhA through a mechanism of dynamic stabilization.

Antitubercular; H37Rv; InhA inhibition; MDR-TB; Molecular dynamics; Phosphonium salts; Triazoles.