Synthesis and Biological Evaluation of P, N-Type Schiff Bases, Secondary Amines, and Thioamide Derivatives with...

In this study, P, N-type Schiff bases (iminophosphine) with their secondary amine (aminophosphine) and thioamide derivatives were synthesized. Structural identification of the synthesized compounds was performed by ¹H─NMR, ¹³C─NMR, GC-MS, FTIR, and elemental analysis. After the successful synthesis of all the target molecules, the antioxidant activities were examined by the DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) methods, and IC₅₀ values were calculated. Secondary amines (amino-phosphine derivatives 6 and 7) obtained by reduction of Schiff bases (imino-phosphine derivatives 3 and 5) were found to exhibit high DPPH free radical scavenging activity, whereas all synthesized molecules demonstrated very high ABTS cationic radical scavenging activity. Compound 6 exhibited strong DPPH scavenging activity (IC₅₀ = 51.3 µg/mL), comparable to the standard antioxidant butylated hydroxytoluene (BHT) (IC₅₀ = 40.9 µg/mL). Compound 7 displayed lower activity (IC₅₀ = 262.6 µg/mL), indicating that positional isomerism significantly influences activity. In ABTS assays, Schiff bases 3 and 5 showed the best performance, with IC₅₀ values of 1.12 and 1.34 µg/mL, respectively, surpassing BHT (4.10 µg/mL) and butylated hydroxyanisole (BHA) (4.41 µg/mL). Furthermore, the antibacterial and antifungal activities of all synthesized molecules were investigated. The thioamide derivatives (compounds 8 and 9) demonstrated potent and selective antibacterial effects against Escherichia coli and Bacillus spizizenii, with inhibition zones exceeding 22 mm. They also exhibited notable antifungal activity against Candida tropicalis. In antibiofilm assays, compound 8 displayed strong inhibitory activity with a low BIC90 value, highlighting its potential as an antibiofilm agent. In the last step, molecular docking studies of all synthesized molecules were performed. Molecular docking studies revealed that compound 6 bound most strongly to the 6QXS protein (-6.895 kcal/mol) through pi-stacking with TRP84. Compounds 8 and 9 showed the most favorable interactions with 2J9P (-4.845 and -4.586 kcal/mol, respectively), and compound 9 showed the most favorable interaction with 2MTZ (-3.841 kcal/mol). These results demonstrate that minor structural modifications to P, N-type Schiff bases and their derivatives significantly impact antioxidant, antimicrobial, and antibiofilm properties, as supported by docking studies.