(+/-)-marinopyrrole A for resisting methicillin-resistant staphylococcus aureus (MRSA) and synthesized derivative thereof

Abstract

Disclosed are synthesized derivatives of a natural product, (±)-marinopyrrole A, shown as structural formula I, which have inhibition activities on gram-positive bacteria, such as methicillin sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), oxacilline-resistant Staphylococcus aureus (ORSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and the like. Furthermore, the methods for preparing (±)-marinopyrrole A and the derivatives thereof are disclosed. According to the study of antibacterial activity in vitro, the synthesized derivatives of the natural product (±)-marinopyrrole A have excellent antibiotic activities on the gram-positive bacteria, such as methicillin sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), oxacilline-resistant Staphylococcus aureus (ORSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and the like, and have potential prospects in clinical application.

Description

technical field

[0001] The present invention relates to the preparation of natural product (±)-marinopyrrole A used for the treatment of Gram-positive bacterial infections such as methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, and vancomycin-resistant Enterococcus synthetic derivatives. In addition, the present invention also relates to the preparation method of marinopyrrole A and its new synthetic derivatives. Background technique

[0002] The emergence and treatment of antibiotic resistance has been a problem that has plagued the medical field for many years, among which the drug resistance caused by Methicillin-resistant Staphylococcus aureus (MRSA) is one of the medical problems in recent years. Methicillin-resistant Staphylococcus aureus is a unique strain derived from a variety of Staphylococcus aureus. Cephalosporin antibiotics with β-lactam structure. The bacterial infection mainly comes from ...

Examples

Embodiment 1

[0053] Implementation Example 1 Preparation of Compound 5

[0054]

[0055] Compound 2 (2.00 g, 10.50 mmol) was dissolved in 20 mL of toluene, and compound 3 (3.40 g, 15.74 mmol) and p-toluenesulfonic acid (26 mg, 0.14 mmol) were added in sequence. The reaction solution was refluxed for 10 h, cooled to room temperature, adjusted to pH=7 with saturated sodium bicarbonate solution, extracted the aqueous phase (3×20 mL) with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product Separation and purification by silica gel column (10% ethyl acetate / petroleum ether) gave light yellow powdery solid 4 (2.40 g, yield 82%). Mp 70-71.6°C; 1 H NMR (CDCl 3 , 400MHz) δ1.11(t, J=7.2Hz, 3H), 1.23(t, J=7.2Hz, 3H), 4.10-4.19(m, 4H), 6.26(dd, J=4.0, 2.8Hz, 1H ), 6.31(t, J=2.8Hz, 1H), 6.89(t, J=1.6Hz, 1H), 6.91(t, J=3.2Hz, 1H), 7.07(dd, J=4.0, 2.0Hz, 1H ), 9.32 (br, s, 1H) ppm; 13 C NMR (C...

Embodiment 2

[0056] Implementation Example 2 Preparation of Compound 5

[0057]

[0058] Compound 4 (2.00 g, 7.25 mmol) was dissolved in 20 mL of dry CH 2 Cl 2 , DMAP (4.40g, 36.07mmol) and DIPEA (4.70g, 36.43mmol) were added at 0°C, and p-toluenesulfonyl chloride (11.50g, 72.33mmol) was slowly added after stirring for 10min, and the reaction solution rose to room temperature. After reacting for 8 h, the reaction solution was poured into water, and the 2 Cl 2 The aqueous phase was extracted (3×25 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated and purified on a silica gel column (5% ethyl acetate / petroleum ether) to obtain a pale yellow solid 5 (2.96 g, yield 95%). Mp 87-89°C; 1 H NMR (400MHz, CDCl 3 )δ0.91(t, J=7.2Hz, 3H), 0.94(t, J=7.2Hz, 3H), 2.44(s, 3H), 3.97(q, J=7.2Hz, 2H), 4.07(q, J=7.2Hz, 2H), 6.22(dd, J=4, 2.8Hz, 1H), 6.37(d, J=3.6Hz, 1H), 6.81(dd,...

Embodiment 3

[0059] Implementation Example 3 Preparation of Compound 6

[0060]

[0061] In an ice-water bath, under nitrogen protection, DIBAL (4.67mL, 4.70mmol) was slowly added dropwise to compound 5 (500mg, 1.16mmol) in dry CH 2 Cl 2 (5 mL) solution. After the dropwise addition, the reaction solution was raised to room temperature to continue the reaction for 6 h, and then the solution was washed with saturated Na 2 SO 4 The solution quenched the reaction and a large amount of white precipitate formed. The precipitate was removed by filtration, the filter cake was washed with ethyl acetate (3×50 mL), the filtrates were combined, the solvent was evaporated under reduced pressure, and the crude product was separated and purified on a silica gel column (33% ethyl acetate / petroleum ether) to obtain a white solid 6 (370 mg, yield 92%). Mp 103-106°C; 1 H NMR (400MHz, CDCl 3 )δ2.44(s, 3H), 2.63(br, s, 1H), 3.48(br, s, 1H), 4.31(s, 2H), 4.42(s, 2H), 6.19(t, J=3.6Hz , 1H), 6.29(dd, J...

technical field

[0001] The present invention relates to the preparation of natural product (±)-marinopyrrole A used for the treatment of Gram-positive bacterial infections such as methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, and vancomycin-resistant Enterococcus synthetic derivatives. In addition, the present invention also relates to the preparation method of marinopyrrole A and its new synthetic derivatives. Background technique

[0002] The emergence and treatment of antibiotic resistance has been a problem that has plagued the medical field for many years, among which the drug resistance caused by Methicillin-resistant Staphylococcus aureus (MRSA) is one of the medical problems in recent years. Methicillin-resistant Staphylococcus aureus is a unique strain derived from a variety of Staphylococcus aureus. Cephalosporin antibiotics with β-lactam structure. The bacterial infection mainly comes from ...

Examples

Embodiment 1

[0053] Implementation Example 1 Preparation of Compound 5

[0054]

[0055] Compound 2 (2.00 g, 10.50 mmol) was dissolved in 20 mL of toluene, and compound 3 (3.40 g, 15.74 mmol) and p-toluenesulfonic acid (26 mg, 0.14 mmol) were added in sequence. The reaction solution was refluxed for 10 h, cooled to room temperature, adjusted to pH=7 with saturated sodium bicarbonate solution, extracted the aqueous phase (3×20 mL) with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product Separation and purification by silica gel column (10% ethyl acetate / petroleum ether) gave light yellow powdery solid 4 (2.40 g, yield 82%). Mp 70-71.6°C; 1 H NMR (CDCl 3 , 400MHz) δ1.11(t, J=7.2Hz, 3H), 1.23(t, J=7.2Hz, 3H), 4.10-4.19(m, 4H), 6.26(dd, J=4.0, 2.8Hz, 1H ), 6.31(t, J=2.8Hz, 1H), 6.89(t, J=1.6Hz, 1H), 6.91(t, J=3.2Hz, 1H), 7.07(dd, J=4.0, 2.0Hz, 1H ), 9.32 (br, s, 1H) ppm; 13 C NMR (C...

Embodiment 2

[0056] Implementation Example 2 Preparation of Compound 5

[0057]

[0058] Compound 4 (2.00 g, 7.25 mmol) was dissolved in 20 mL of dry CH 2 Cl 2 , DMAP (4.40g, 36.07mmol) and DIPEA (4.70g, 36.43mmol) were added at 0°C, and p-toluenesulfonyl chloride (11.50g, 72.33mmol) was slowly added after stirring for 10min, and the reaction solution rose to room temperature. After reacting for 8 h, the reaction solution was poured into water, and the 2 Cl 2 The aqueous phase was extracted (3×25 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated and purified on a silica gel column (5% ethyl acetate / petroleum ether) to obtain a pale yellow solid 5 (2.96 g, yield 95%). Mp 87-89°C; 1 H NMR (400MHz, CDCl 3 )δ0.91(t, J=7.2Hz, 3H), 0.94(t, J=7.2Hz, 3H), 2.44(s, 3H), 3.97(q, J=7.2Hz, 2H), 4.07(q, J=7.2Hz, 2H), 6.22(dd, J=4, 2.8Hz, 1H), 6.37(d, J=3.6Hz, 1H), 6.81(dd,...

Embodiment 3

[0059] Implementation Example 3 Preparation of Compound 6

[0060]

[0061] In an ice-water bath, under nitrogen protection, DIBAL (4.67mL, 4.70mmol) was slowly added dropwise to compound 5 (500mg, 1.16mmol) in dry CH 2 Cl 2 (5 mL) solution. After the dropwise addition, the reaction solution was raised to room temperature to continue the reaction for 6 h, and then the solution was washed with saturated Na 2 SO 4 The solution quenched the reaction and a large amount of white precipitate formed. The precipitate was removed by filtration, the filter cake was washed with ethyl acetate (3×50 mL), the filtrates were combined, the solvent was evaporated under reduced pressure, and the crude product was separated and purified on a silica gel column (33% ethyl acetate / petroleum ether) to obtain a white solid 6 (370 mg, yield 92%). Mp 103-106°C; 1 H NMR (400MHz, CDCl 3 )δ2.44(s, 3H), 2.63(br, s, 1H), 3.48(br, s, 1H), 4.31(s, 2H), 4.42(s, 2H), 6.19(t, J=3.6Hz , 1H), 6.29(dd, J...

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