Novel inhibitor of bacterial sphingomyelinase, SMY-540, developed based on three-dimensional structure analysis

Figures & data

Figure 1. The structure of RY221B-a and its synthetic analogues.

Table 1. Summary of the inhibitory effects of RY221B-a analogues on hydrolysis of SMase*.

Inhibitor	IC50 (μM)	Inhibition type	Ki (μM)
RY221B-a	1.2	Competitive	5.2
RY221B-b	>20	–	–
SMY-584	>20	–	–
SMY-632	>20	–	–
SMY-471	0.9	Competitive	2.8
SMY-579	18.3	–	–
SMY-540	0.8	Competitive	1.3
SMY-610	3.3	–	–
SMY-469a	>20	–	–
TOM-2-7	>20	–	–
TOM-2-18	>20	–	–
TOM-2-37	>20	–	–

*The inhibition kinetics of the compounds with an IC₅₀ less than 1.5 μM were analyzed using Lineweaver-Burk plots.

Figure 2. Docking simulation analysis of Bc-SMase and SMY-540. (A) Simulation analysis of the docking of SMY-540 to Bc-SMase. The most stable structure of SMY-540 on the molecular electrostatic potential surface is shown. The red and blue surfaces indicate the negative and positive electrostatic potential surfaces, respectively. (B) Interactions between Bc-SMase and SMY-540 at the catalytic site. The gray, white, red and purple in the compound indicate carbon, hydrogen, oxygen and nitrogen, respectively. Mg²⁺ is represented by green. Please view colour online.

Figure 3. Effect of SMY-540 on the lethality of B. cereus in mice. Mice were intravenously injected with 0.1 or 0.5 mg/kg SMY-540 emulsion. B. cereus (JMU-06B-35, 1.0 × 10⁷CFU/mouse) was intraperitoneally administered to each mouse 3 h after injection. Mice were monitored every 2 h, for 100 h after administration of B. cereus. The duration of the experiment was set at 100 h. ○, Saline; ▪, B. cereus; ▴, 0.1 mg/kg SMY-540 + B. cereus; •, 0.5 mg/kg SMY-540 + B. cereus.

Scheme A1. Syntheses of RY-221-Ba, SMY-584 and SMY-610.

Scheme A2. Synthesis of SMY-632.

Scheme A3. Syntheses of SMY-579 and SMY-471.

Scheme A4. Synthesis of SMY-540.

Scheme A5. Synthesis of SMY-469a.

Scheme A6. Syntheses of TOM-2-7, TOM-2-18 and TOM-2-37.