Enhanced antibacterial efficacy of new benzothiazole phthalimide hybrid compounds/methyl-β-cyclodextrin inclusion complexes compared to the free forms: Insights into the possible mode of action.

With the aim to gain further insights into the possible mechanism(s) involved in the cyclodextrin (CD)-mediated enhancement of antimicrobial activity, herein we report the preparation and fully characterization of a series of phenoxy-benzothiazole-phthalimide hybrid compounds and the corresponding complexes with methyl-β-CD (Me-β-CD). Next, these complexes were tested against selected Gram positive and Gram-negative bacterial strains and the observed antibacterial activity compared to those of the free forms. Results from 1H NMR and molecular modeling studies showed that in solution the chloro substituted compounds may give inclusion complex of 1:2 Drug-CD stoichiometry besides the 1:1 complexes, while the para-methyl derivative and the unsubstituted compound may provide complexes of 1:1 stoichiometry only. The antimicrobial tests against selected Gram positive and Gram-negative bacterial strains showed that the most active agents were the chloro substituted compounds/Me-β-CD complexes. Hence, it seems that improving of the efficacy of antimicrobial agents by CD complexation may be accomplished by formation of higher order complexes. Further, the hypothesized mode of action of CDs in reducing the minimal inhibition concentration (MIC) values of antimicrobials should be related to their ability to make permeable the bacterial cell wall. This is now substantiated by the observed increased uptake of Propidium iodide in S. aureus ATCC 29213 strain incubated with the para-chloro substituted benzothiazole-phthalimide compound/Me-β-CD complex compared to the corresponding free form. Overall, such strategy to take advantage of inclusion complexes of higher order may constitute a promising methodology to overcome the microbial resistance issue.