Design, Synthesis, Antioxidant, Antitubercular Activity, and In Silico Studies of Novel α-Amino Phosphonates of Vanillin, a Potent Bioactive Molecule

Abstract

Objective: This research article presents a streamlined method for the synthesis of α-amino phosphonates derived from vanillin, aimed at exploring their potential antioxidant and antitubercular activities, along with in silico studies. Methods: We prepared vanillin analogs through oxidative deamination followed by the Kabachnik–Fields reaction. The procedure involves a one-pot synthesis in which various anilines are reacted with vanillin in the presence of trimethyl phosphite and dichloromethane. This methodology demonstrates a broad substrate scope and yields α-amino phosphonates in satisfactory amounts. Comprehensive characterization using ¹H, ¹³C NMR, and HRMS analysis confirms the structures of the synthesized compounds. Results and Discussion: Biological evaluation of the compounds’ potential antitubercular activity against the Mycobacterium tuberculosis H37Rv strain (ATCC no. 27294) revealed promising results, with all compounds exhibiting MICs in the range of 12–100 µg/mL. Additionally, the synthesized compounds were assessed for antioxidant activity. The lead compounds were also evaluated for binding interactions with target proteins. Compounds (IIIa) and (IIIh) showed significant docking scores of –7.2, –7.3, –7.4, and –7.6 kcal/mol, respectively, indicating their potential to interact with tuberculosis-related proteins DprE1 and Polyketide synthase. Conclusions: The observed significant antimycobacterial efficacy suggests the potential utility of these compounds as lead candidates for developing antitubercular agents, underscoring their importance in combating tuberculosis infections.