Synergism of fused bicyclic 2-aminothiazolyl compounds with polymyxin B against Klebsiella pneumoniae

Abstract

A series of fused bicyclic 2-aminothiazolyl compounds were synthesized and evaluated for their synergistic effects with polymyxin B (PB) against Klebsiella pneumoniae (SIPI-KPN-1712). Some of the synthesized compounds exhibited synergistic activity. When 4 μg ml^-1 compound B1 was combined with PB, it showed potent antibacterial activity, achieving 64-fold reduction of the MIC of PB. Furthermore, compound B1 showed prominent synergistic efficacy in both concentration gradient and time-kill curves in vitro. In addition, B1 combined with PB also exhibited synergistic and partial synergistic effect against E. coli (ATCC25922 and its clinical isolates), Acinetobacter baumannii (ATCC19606 and its clinical isolates), and Pseudomonas aeruginosa (Pae-1399).

Fig. 1. Design strategy for the target thiazole compounds A–C.

Scheme 1. Synthesis of intermediates. (i) KSCN, acetone, Ar, r.t., 1 h; (ii) EA, reflux, 2 h; (iii) NaOH, EtOH, reflux, 2 h.

Scheme 2. Synthesis of compounds A–C. (i) R₂OH, MW, 15–30 min. (ii) H₂O, reflux, 12 h. (iii) CuSO₄, Et₃N, 80 °C, 5 h.

Fig. 2. Time-kill curves of PB and B1 alone and in combination at different concentrations against SIPI-KPN-1712.