Design, Synthesis, And Antibacterial Study Of New Gatifloxacin Conjugated With Guaiacol And Paracetamol Analogues As Mutual Prodrug

Abstract

Objective: The objective of  the work  to  design, and synthesize new mutual prodrugs of gatifloxacin to improve the therapeutic action as anti-microbial mainly as anti-bacterial to overcome the emergent anti-bacterial  resistance of the gatifloxacin in first approach and to broaden the anti-bacterial spectrum secondly .In our study we choose the ligand (quaiacol and paracrtamol) to link via an ester bond with gatifloxacin by spacer arm chloroacetyl chloride. The quaiacol is a natural anti-oxidants with mark able anti-bacterial action ,while paracetamol is a centrally non - steroidal anti-inflammatory drugs (NSAIDs) ,the up-to-date  studies of paracetamol referred to it has a good anti-bacterial action. Design of the new analogous of gatifloxacin with quiaicol&paracetamol respectively with complementary anti-bacterial action to synergize the therapeutic action and impair the microbial mechanism of resistance that is the major challenges of the most anti-bacterial antibiotic.      

Methods: The hydroxyl  functional  groupe  of (quaiacol ,parcetamol), was conjugated to chloroacetyl chloride via  a nucleophilic substitution profile reaction respectively, to produce an  intermediates (IA-IB), which were further  reacted with a carboxyl  functional  group of Gatifloxacin to produce  the designed  compounds (I-II) having an ester linkage as mutual prodrug.

Results: The Antibacterial activity effect of the designed compounds (I-II) has been investigated for in vitro inhibitory anti-bacterial  action against Gram-(+) bacteria like Staphylococcus aureus and Escherichia coli  as Gram-negative bacteria; using the diffusion of the spots procedure. All the tested compounds show a remarkable antibacterial activity toward the tested bacteria.

Conclusion: The synthesized  designated mutual prodrugs were synthesized ,characterized and identified by using  FT-IR spectroscopic analysis, 1H-NMR spectroscopic analysis, and important physicochemical properties. The antibacterial assay of the  designated compounds report different  activities toward the two types of pathogenic bacteria which are Staphylococcus aureus and Escherichia coli. Compounds [I, II] revealed that Staphylococcus aureus was sensitive to synthesized designated compounds but Escherichia coli report  a reverse activity with some resistance for antibacterial drugs .