Synthesis, In Silico and In Vitro Antimicrobial Evaluation of Cyanoketene S,N-Acetals and Their Pyrazoles Against Staphylococcus Aureus DNA Gyrase Enzyme

Abstract

Objectives: The continuous reporting of bacterial resistance to antibiotics is an ongoing challenge that can be life-threatening. Actions to develop new chemicals to overcome the bacterial resistance has gained a significant importance. Methods: A series of ketene S,N-acetals 4a-k and their pyrazoles 6a-k were synthesized and their structures were established by spectral data. Membrane permeability predictions and in vitro antimicrobial activity against multi-drug resistant (MDR) Gram-positive bacteria and other microorganisms was determined. The binding affinity with DNA gyrase was assessed using in silico studies in comparison to ciprofloxacin then tthe gyrase inhibition assay was conducted to detect the mode of action. Results: All the synthesized compounds have a good affinity to pass through the phospholipid membrane of Staphylococcus aureus (S. aureus). Compound 6g exhibited the most potent antibacterial activity with MIC values ranged between 16 and 32 µg/mL. The compound also showed a higher binding affinity than ciprofloxacin with DNA gyrase in the in silico studies and this effect was clearly shown by a very good IC50 value of the gyrase inhibition assay. Conclusions: According to our data, compound 6g is a possible candidate to act against MDR bacteria and its main mode of action is through inhibition of the gyrase enzyme, further modifications are still required to enhance its activity.