The present study involves the synthesis of a new series of α-aminophosphonate derivatives in good yields with a simple workup via the Kabachnik-Fields reaction using lithium perchlorate (LiClO₄) as a catalyst to facilitate the reaction. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data, and the obtained results correlated with the proposed molecular structure. The in vitro antimicrobial activities of each compound were evaluated against different clinical isolates. The results indicated that among these derivatives, two compounds (5a and 5b) were the most active and displayed potent activity with MICs in the range from 0.06 to 0.25 μg mL^-1 compared with fosfomycin and fluconazole as standard antibiotics. Moreover, the synthesized phosphonates displayed a broad spectrum of bactericidal and fungicidal activities depending on MICs, MBCs/MFCs, and the time-kill kinetics. In addition, the checkerboard assay showed synergistic and partial synergistic activities between the active compounds combined with fosfomycin and fluconazole. Furthermore, the SEM images showed distinct ruptures of the OM integrity of the FOS-R E. coli at their MICs, which was further indicated by the increased EtBr accumulation within the bacterial cells. Moreover, active derivatives revealed MurA inhibitory activity with IC₅₀ values of 3.8 ± 0.39 and 4.5 ± 0.23 μM compared with fosfomycin (IC₅₀ = 12.7 ± 0.27 μM). To our surprise, exposing 5a and 5b compounds to different gamma radiation doses revealed that 7.0 kGy eradicated the microbial load completely. Finally, the results of quantum chemical study supported the binding mode obtained from the docking study performed inside the active site of MurA (PDB: 1UAE), suggesting that these phosphonates may be promising safe candidates for MDR infection therapy clinical trials with no toxic effects on the normal human cells.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	30
2	Natural Sciences	1	1	30
3	Biochemistry	1	1	30
4	Pharmacology	1	1	30
5	Bioorganic Chemistry	1	1	30

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