Synthesis and biological evaluation of novel aminoguanidine derivatives as potential antibacterial agents

Abstract

In an effort to identify novel antibacterial agents, we presented two series of aminoguanidine derivatives that were designed by incorporating 1,2,4-triazol moieties. All compounds exhibited strong in vitro antibacterial activity against a variety of testing strains. Compound 5f was identified as a potent antibacterial agent with a minimum inhibitory concentration (MIC) of 2-8 µg/mL against S. aureus, E. coli, S. epidermidis, B. subtilis, C. albicans, multi-drug resistant Staphylococcus aureus and multi-drug resistant Escherichia coli and low toxicity (Hela > 100 µM). Membrane permeability and transmission electron microscopy (TEM) image studies demonstrated that compound 5f permeabilized bacterial membranes, resulting in irregular cell morphology and the rapid death of bacteria. The results of the present study suggested that aminoguanidine derivatives with 1,2,4-triazol moieties were the intriguing scaffolds for the development of bactericidal agents.

Keywords: 1,2,4-triazol; Aminoguanidine derivatives; Antibacterial activity; Membrane permeability; TEM.

Fig. 1

Several molecules of previously reported compounds.

Fig. 2

Designed target compounds.

Fig. 3

(A) DIZ of S.aureus treated by Gatifoxacin, 5f and 1% DMSO respectively; (B) DIZ of E. coli treated by Gatifoxacin, 5f and 1% DMSO respectively.

Fig. 4

(A) the outer membrane probed with NPN; (B) permeability of the inner membrane probed with PI.

Fig. 5

Transmission electron micrographs of (A) untreated E. coli ATCC 25,922; (B) treated with 5f. The arrows mark areas of membrane damage and cell content release. Scale bar 500 nm.

Scheme 1

Synthetic scheme for the compounds 4a-f, 5a-i and 9a-c. Reagents and conditions: a SOCl₂, DCM/DMF, reflux, 4 h; Pyridine, rt, 16 h; NaOH/H₂O, reflux, 3 h; b EtOH, MeONa, reflux, 48 h; c K₂CO₃, KI, acetone, reflux, 6 h; d aminoguanidine hicarbonate, EtOH, 50ºC, reflux, 10–12 h.