Synthesis, Antimicrobial Activity and Molecular Docking Study of Novel α‐(Diphenylphosphoryl)‐ and α‐(Diphenylphosphorothioyl)cycloalkanone Oximes

Abstract

A series of novel α-(diphenylphosphoryl)and α-(diphenylphosphorothioyl)cycloalkanone oximes have been synthesized in search for novel bioactive molecules. Their structures were characterized by various spectroscopic methods including IR, NMR ( 1 H, 31 P, 13 C), mass spectrometry and single crystal X-ray diffraction. The newly synthesized phosphorus-containing oximes were screened for their in vitro antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gramnegative bacteria (Escherichia coli and Salmonella typhimurium) and fungal strains (Candida albicans and Candida glabrata).The biological assays showed that all the studied compounds (2a-f) exhibited high antibacterial and antifungal activities at only 0.1-2.1 μg/mL. In silico molecular docking studies in FabH enzyme active site were performed in order to predict the possible interaction modes and binding energies of the drug candidates at the molecular level.

Experimental and computational investigation of Z/E isomerism, X-ray crystal structure and molecular docking study of (2-(hydroxyimino)cyclohexyl)diphenylphosphine sulfide, a potential antibacterial agent

“…S3 in Supplementary Information), revealed that the Z -( 2 ) isomer has the smaller LUMO-HOMO energy gap, indicating a predicted better antibacterial activity than E -( 2 ) isomer. Such results could explain the general tendency observed in our previous study on similar compounds [12] , showing that oximes more rich in Z isomer exhibited a better antibacterial activity.…”

“…The studied compound C 18 H 20 NOPS ( 2 ) was prepared by using a two-step synthetic pathway from a cyclic enamine, via the oximation of 2-(diphenylphosphorothioyl)cyclohexanone intermediate ( 1 ), according to the recently reported procedure developed by our group [12] .…”

“…We have recently reported that compound ( 2 ), as a mixture of Z and E isomers, exhibited very promising antibacterial activity against both Gram-positive and Gram-negative bacteria [12] . Here, we attempted to compare the antibacterial activities of both Z and E isomers of ( 2 ) in correlation with their LUMO-HOMO energy gap.…”

“…In the frame of our research program on the synthesis and evaluation of novel phosphorus-containing compounds with possible biological properties [11] , we recently described an efficient approach to unprecedented α-(diphenylphosphoryl)and α-(diphenylphosphorothioyl)cycloalkanone oximes, by using a twostep synthetic pathway from cyclic enamines, via the oximation of the α-(diphenylphosphoryl)and α-(diphenylphosphorothioyl) cycloalkanones intermediates [12] . The obtained phosphoruscontaining oximes have shown promising antibacterial activities, what prompted us for further investigations to gain a deeper understanding of their structural and biological properties.…”

“…To reach this goal, we select the α-(diphenylphosphorothioyl) cycloalkanone oxime derivative ( 2 ) [(2-(hydroxyimino)cyclohexyl) diphenylphosphine sulfide, C 18 H 20 NOPS] which was obtained as a mixture of Z and E isomers in 42:58 ratio, and was found to display high antibacterial activities against Gram-positive ( i.e ., Staphylococus aureus and Bacillus subtilis ) and Gram-negative ( i.e., Escherichia coli and Salmonella typhimurium ) bacteria with minimal inhibitory concentrations, MIC, in the range 0.9-1.8 μg/mL and minimal bactericidal concentrations, MBC, around 2.0 μg/mL (see compound 2d in reference [12] ). Herein, we report the spectroscopic characterization and structural study by X-ray diffraction of this phosphorus-containing oxime ( 2 ).…”