Design, synthesis, and evaluation of curcumin analogues as potential inhibitors of bacterial sialidase

Abstract

Sialidases are key virulence factors that remove sialic acid from the host cell surface glycan, unmasking receptors that facilitate bacterial adherence and colonisation. In this study, we developed potential agents for treating bacterial infections caused by Streptococcus pneumoniae Nan A that inhibit bacterial sialidase using Turmeric and curcumin analogues. Design, synthesis, and structure analysis relationship (SAR) studies have been also described. Evaluation of the synthesised derivatives demonstrated that compound 5e was the most potent inhibitor of S. pneumoniae sialidase (IC₅₀ = 0.2 ± 0.1 µM). This compound exhibited a 3.0-fold improvement in inhibitory activity over that of curcumin and displayed competitive inhibition. These results warrant further studies confirming the antipneumococcal activity 5e and indicated that curcumin derivatives could be potentially used to treat sepsis by bacterial infections.

Keywords: Curcumin; Nan A; sepsis; sialidase.

Scheme 1.

Designed strategies for the synthesis of curcumin analogues.

Scheme 2.

Reagent and conditions for synthesis of 3: (i) 1, B₂O₃, ethyl acetate, 90 °C; (ii) 2, n-(BuO)₃B, ethyl acetate, 90 °C; (iii) n-BuNH₂, ethyl acetate, 90 °C; (iv) hydrochloric acid (1M, aq.), 50 °C; synthesis of 4: (i) 3, B₂O₃, ethyl acetate, 90 °C; (ii) 2, n-(BuO)₃B, ethyl acetate, 90 °C; (iii) n-BuNH₂, ethyl acetate, 90 °C; (iv) hydrochloric acid (1M, aq.), 50 °C; synthesis of 4f: 1, 2, B₂O₃, morpholine, AcOH, 40 min, microwave irradiation (300 W).

Scheme 3.

Reagent and conditions for synthesis of asymmetrical curcumin derivatives 5: (i) 3, B₂O₃, ethyl acetate, 90 °C; (ii) 2, n-(BuO)₃B, ethyl acetate, 90 °C; (iii) n-BuNH₂, ethyl acetate, 90 °C; (iv) hydrochloric acid (1M, aq.), 50 °C.

Scheme 4.

Reagent and conditions for synthesis of curcumin derivatives 4c, 4d, and 6–8: (A) 4a, CH₃I, K₂CO₃, acetone, reflux; (B): 4a, BBr₃, –78 °C to ambient temperature, N₂ (g), H₂O; (C) 4a, H₂/Pd-C (10 wt. % of palladium), MeOH, 0 °C to ambient temperature; (D) 4a, Ac₂O, DMAP, pyridine, ambient temperature; (E) 4a, NH₂NH₂ ^.H₂O, AcOH, reflux.

Figure 1.

Graphical determination of the inhibition type for compounds 4a, 4e, 5q, and 5e. Lineweaver–Burk (A–D) plots for the inhibitory activity of compounds 4a, 4e, 5q, and 5e, respectively, against S. pneumoniae Nan A hydrolysis activity in the presence of different substrate concentrations.