Antibiotic resistance and drug modification: Synthesis, characterization and bioactivity of newly modified potent ciprofloxacin derivatives

Development of new derivatives of commercial antibiotics using different organic reagents and testing these derivatives against different microorganisms are the main goals of this article. Thus, the antibiotic ciprofloxacin, CF, was acylated via reaction with ethyl cyanoacetate and ethyl acetoacetate in basic medium to give the cyanoacetylpiprazinyl dihydroquinoline derivative 3, and oxobutanoylpiprazinyl dihydroquinoline derivative 5, respectively. On the other hand, N-alkylated derivatives 8-10, were prepared through the reaction of CF with chloroacetonitrile, chloroacetyl acetone and chloroacetone in the presence of carbonate salt. In basic medium, both 3 and 10 were coupled with benzenediazonium chloride to afford hydrazono derivatives, which were then cyclized to give 4-(dihydropyridazinecarbonyl)piperazinyl-1,4-dihydroquinoline. Furthermore, compounds 3 and 10 were reacted with benylidenemalononitrile to produce 4H-pyan and pyrido[1,2-a]pyrazine derivatives, respectively. Both 3 and 10 were reacted with DMFDMA to give enaminone derivatives. These enaminones were cyclized to aminopyrimidine derivatives by reacting with urea or thiourea. X-ray, elemental analysis and spectral data were used to illustrate and confirm the structures of the isolated compounds. The bioactivities of the novel compounds were investigated against different gram-positive and gram-negative bacteria. In addition, these novel antibiotic derivatives were tested against ciprofloxacin-resistant bacteria isolated from patients aged 65-74 years. This study reveals that most of the modified drugs show high to moderate antibacterial activity. Additionally, these drugs show good effects against ciprofloxacin-resistant bacteria.