Sonochemical Synthesis and In Silico Studies of Phthalazine Scaffolds Bearing 1,3,4-Oxadiazolyl-1,2,3-triazoles as Potent Antitubercular Agents

The sonochemical synthesis and biological properties of compounds simultaneously containing several heterocycles, namely phthalazine, 1,3,4-oxadiazole, and 1,2,3-triazole rings, have been studied as part of our ongoing research in the field of organic and medicinal chemistry. In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for substituted 1,2,3-triazole–1,3,4-oxadiazole–phthalazin-1(2H)-one hybrids from 2-[4-ethyl-1-oxophthalazin-2(1H)-yl]acetohydrazide as key intermediate product. The prepared compounds were characterized by ¹H and ¹³C NMR, IR, and mass spectra and elemental analyses. The synthesized scaffolds were screened for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain by the agar microdilution method. The compounds were further evaluated for their ADMET properties by using ADEMTlab 2.0 and SwissADME. Molecular docking study was also performed against M. tuberculosis DNA gyrase using AutoDock 4.2. The o-fluorophenyl 1,3,4-oxadiazolyl–1,2,3-triazole derivative, which showed excellent antitubercular activity against H₃₇Rv strain with MIC = 3.24 μg/mL (compared to streptomycin, MIC = 3.12 μg/mL), was found to exhibit the strongest bondings with the amino acid residues Asp94(A), Tyr93(A), Pro123(A), Lys72(A), Ala124(A), Arg128(A), Ala126(A), Pro124(A), Ala74(A), and Met127(A) with a docking score of –6.992 kcal/mol.