Indole hybrid quinolone compounds, methods of making and using the same

Abstract

The present application relates to a kind of indole hybrid quinolone compounds and its preparation method and application, as shown in general formula I, the compound has certain inhibitory activity to gram-positive bacteria and gram-negative bacteria, can be used for preparing antibacterial drug, can also be used as DNA intercalator, and preparation raw material is simple, cheap and easy to obtain, and it has important significance to the application of anti-infection.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, and relates to indole-hybridized quinolone compounds, as well as the preparation method and application of such compounds. Background Technology

[0002] Bacterial infections are the leading cause of most hospital-acquired infections, resulting in high morbidity and mortality rates annually and posing a serious threat to human health. Quinolones, as one of the most important first-line broad-spectrum synthetic antibiotics, have been widely used to treat infections caused by various microorganisms due to their strong antibacterial activity, low toxicity, and good pharmacokinetics. However, the long-term widespread use and even abuse of these drugs has led to serious drug resistance problems, posing a significant challenge to anti-infective therapy.

[0003] Indole alkaloids are widely distributed in nature, and the presence of nitrogen-containing heterocycles in their molecular structure endows these compounds with significant biological activity. Indole alkaloids exhibit antibacterial activity through various mechanisms, including inhibition of efflux pumps, biofilms, DNA gyrases, topoisomerase IV, and methicillin-resistant Staphylococcus aureus pyruvate kinase. They play an important role in the development of novel antibacterial drugs and possess a wide variety of structures and mechanisms.

[0004] Acrylonitrile contains unsaturated vinyl (C=C) and cyano (C≡N) bonds, which readily form electron-deficient reactive intermediates, enhancing their affinity for binding to biomolecules and thus inactivating or damaging bacterial DNA. The cyano group is generally considered to be a bioisostere of carbonyl, hydroxyl, carboxyl, and halogen atoms. The nitrogen atom in the cyano group contains unshared electron pairs, which can act as hydrogen bond acceptors to form hydrogen bonds, thereby exerting an antibacterial effect.

[0005] To discover new quinolones with a broad antibacterial spectrum and the ability to overcome drug resistance, extensive research both domestically and internationally has focused on their structural modification in order to obtain more effective quinolone antibacterial drugs. Among these modifications, the C-7 position of quinolones is considered the most important and significant modification site. Studies have shown that C-7 modification can significantly affect the interaction with DNA gyrases and ultimately influence biological activity. Summary of the Invention

[0006] In view of this, one objective of the present invention is to provide an indole-hybridized quinolone compound and its pharmaceutically acceptable salt; a second objective of the present invention is to provide a method for preparing the indole-hybridized quinolone compound and its pharmaceutically acceptable salt; a third objective of the present invention is to provide the application of the indole-hybridized quinolone compound and its pharmaceutically acceptable salt in the preparation of antibacterial drugs; and a fourth objective of the present invention is to provide the application of the indole-hybridized quinolone compound and its pharmaceutically acceptable salt in the preparation of DNA intercalating agents. This provides more efficient and safe candidate drugs for clinical antimicrobial therapy, helping to solve increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and emerging harmful microorganisms.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] 1. Indole-hybridized quinolones and their pharmaceutically acceptable salts, with structures shown in general formula I:

[0009]

[0010] In the formula,

[0011] R 1 It can be ethyl, alkenyl, alkynyl, ester, cyano, carboxyl, aryl, cycloalkyl, or heterocyclic.

[0012] R 2 It can be hydrogen, alkyl, cyanalkyl, hydroxyalkyl, alkenylalkyl, aralkyl, alkynylalkyl, etheralkyl, carboxylalkyl, esteralkyl, carbonylalkyl, or heterocyclic alkyl;

[0013] X 1 X 2 X 3 X 4 X 5 It can be hydrogen, halogen, cyano, alkyl, methoxy, or nitro.

[0014] 2. The indole-hybridized quinolone compounds and their pharmaceutically acceptable salts, characterized in that:

[0015] R 1 It can be ethyl, alkenyl, alkynyl, or aromatic;

[0016] R 2 It can be hydrogen, alkyl, cyano, alkoxy, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl, or heterocyclic; X 1 It is hydrogen;

[0017] X 2 It is chlorine;

[0018] X 3 It is chlorine or nitro;

[0019] X 4 It is fluorine;

[0020] X 5 It is a methyl group.

[0021] Preferably, it is any one of the following compounds:

[0022]

[0023] Preferably, the pharmaceutically acceptable salt is a hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate, or acetate.

[0024] 2. A method for preparing indole-hybridized quinolone compounds, the method being as follows:

[0025] a. Preparation of intermediate II: Intermediate II is obtained by reacting different types of halogenated compounds with 3-indolecarboxaldehyde compounds;

[0026]

[0027] in:

[0028] R 1 It can be ethyl, alkenyl, alkynyl, or aromatic;

[0029] R 2 It can be hydrogen, alkyl, cyano, alkoxy, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl, or heterocyclic; X 1 It is hydrogen;

[0030] X 2 It is chlorine;

[0031] X 3 It is chlorine or nitro;

[0032] X 4 It is fluorine;

[0033] X 5 It is a methyl group.

[0034] b. Preparation of indole-hybridized quinolone compounds as shown in general formula I: Intermediates II and III are dissolved in ethanol, and piperidine is added dropwise to obtain indole-hybridized quinolone compounds as shown in general formula I.

[0035]

[0036] Preferred,

[0037] In step a, the molar ratio of the intermediate 3-indolecarboxaldehyde compound, the halogenated compound, and cesium carbonate is 1:1.5:1.5, and the reaction is specifically carried out in acetonitrile as solvent at 80°C for 4–10 h.

[0038] In step b, the molar ratio of intermediates II and III to piperidine is 1.5:1.0:0.5; the reaction is specifically carried out in ethanol as solvent at 50-80°C for 4-10 h.

[0039] 3. The application of the indole-hybridized quinolone compounds and their pharmaceutically acceptable salts in the preparation of DNA intercalators, wherein the DNA is calf thymus DNA or DNA extracted from bacteria.

[0040] Preferably, the bacteria are one or more of the following: methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, or Acinetobacter baumannii.

[0041] 4. Preparations containing the aforementioned indole-hybridized quinolone compounds and their pharmaceutically acceptable salts.

[0042] Preferably, the preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

[0043] The beneficial effects of this invention are as follows: Utilizing the principle of drug design and synthesis, this invention designs and synthesizes a series of novel indole-hybridized quinolones by introducing an acrylonitrile fragment at the C-7 position of quinolones to bridge indole compounds through different modifications of 3-indole-formaldehyde compounds. In vitro antimicrobial activity tests have shown that these compounds exhibit certain inhibitory activity against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii). These compounds can be used to prepare antibacterial drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial therapy, and helping to solve increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms, and newly emerging harmful microorganisms. Furthermore, the indole-hybridized quinolone compounds of the present invention can also be used to prepare DNA intercalating agents. Attached Figure Description

[0044] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided for illustration:

[0045] Figure 1This refers to the competitive interaction between compound I-18 and neutral red with methicillin-resistant Staphylococcus aureus DNA, respectively. Detailed Implementation

[0046] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0047] Example 1, Preparation of Intermediate II:

[0048]

[0049] Compound II was prepared according to the method described in the reference "Costi, R.; Crucitti, GC; Pescatori, L.; Messire, A.; Scipione, L.; Tortorella, S.; Amoroso, A.; Crespan, E.; Campiglia, P.; Maresca, B.; Porta, A.; Granata, I.; Novellino, E.; Gouge, J.; Delarue, M.; Maga, G.; Di Santo, R. New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyltransferase: discover yaracterization, crystal structure in complex with the target. J. Med. Chem. 2013, 56, 7431–41.", in yield of 63.0–85.0%, as a pale yellow solid.

[0050] Example 2, Preparation of Intermediate III:

[0051]

[0052] Intermediate III was prepared according to the method described in the reference "Charushin, VN; Mochulskaya, NN; Antipin, FV; Kotovskaya, SK; Nosova, EV; Ezhikova, MA; Kodess, MI; Kravchenko, MA Synthesis antimycobacterial evaluation of new (2-oxo-2H-chromen-3-yl) substituted fluoroquinolones. J. Fluorine. Chem. 2018, 208, 15–23.", in yield of 73.5–92.3%, as a white solid.

[0053] Example 3, Preparation of compound I-1:

[0054]

[0055] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Indole-3-carboxaldehyde (79 mg) was then added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-1 (108 mg), with a yield of 73.8%. Melting point: >300 °C 1 H NMR (600MHz, DMSO-d6) δ9.07(1H),8.52(1H),8.30(1H),8.21(1H),8.10(1H),7.96(1H),7.56(1H),7.27(1H),7.23(1H),4.70(2H),1.49(3H)ppm.

[0056] Example 4, Preparation of compound I-2:

[0057]

[0058] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-isopropyl-1H-indole-3-carboxaldehyde (137 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-2 (133 mg), with a yield of 81.7%. Melting point: 242–244 °C. 1H NMR(600MHz,DMSO-d6)δ14.93(1H),9.07(1H),8.59(1H),8.27(1H),8.21(1H),8.09(1H), 7.99(1H),7.71(1H),7.34(1H),7.28(1H),4.94(1H),4.70(2H),1.57(6H),1.49(3H)ppm.

[0059] Example 5, Preparation of compound I-3:

[0060]

[0061] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(diethoxymethyl)-1H-indole-3-carboxaldehyde (143 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-3 (155 mg), with a yield of 82.1%. Melting point: 215–217 °C. 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.56(1H),8.27(1H),8.25(1H),8.12(1H),7.97(1H),7.69 (1H),7.33(1H),7.27(1H),4.81(1H),4.72(2H),4.47(2H),3.67(2H),3.46(2H),1.49(3H),1.07(6H)ppm.

[0062] Example 6, Preparation of compound I-4:

[0063]

[0064] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-allyl-1H-indole-3-carboxaldehyde (101 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-4 (125 mg), with a yield of 77.7%. Melting point: 264–266 °C. 1H NMR(600MHz,DMSO-d6)δ14.95(1H),9.10(1H),8.53(1H),8.30(1H),8.26(1H),8.14(1H),8.01(1H), 7.62(1H),7.33(1H),7.28(1H),6.09(1H),5.25(1H),5.14(1H),5.07(2H),4.72(2H),1.49(3H)ppm.

[0065] Example 7, Preparation of compound I-5:

[0066]

[0067] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(prop-2-en-1-yl)-1H-indole-3-carboxaldehyde (100 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-5 (120 mg), with a yield of 74.9%. Melting point: 266–268 °C. 1 H NMR(600MHz,DMSO-d6)δ14.95(1H),9.11(1H),8.55(1H),8.32(1H),8.29(1H),8.16(1H),δ8. 05(1H),7.94(1H),7.39(1H),7.38–7.31(1H),5.95(2H),4.72(2H),2.67(1H),1.49(3H)ppm.

[0068] Example 8, Preparation of compound I-6:

[0069]

[0070] Intermediate III-1 (0.100 g, 0.36 mmol) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 min. Compound 2-(3-formyl-1H-indol-1-yl)acetonitrile (101 mg) was added, and the mixture was refluxed at 80 °C for 10 h. The reaction was separated by column chromatography to obtain a yellow solid I-6 (133 mg), yield 82.8%. Melting point: 286–288 °C; 1 H NMR(600MHz,DMSO-d6)δ14.91(1H),9.09(1H),8.64(1H),8.31–8.25(2H),8.13(1 H),8.05(1H),7.75(1H),7.45(1H),7.36(1H),5.83(2H),4.72(1H),1.50(3H)ppm.

[0071] Example 9, Preparation of compound I-7:

[0072]

[0073] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-(2-hydroxyethyl)-1H-indole-3-carboxaldehyde (103 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-7 (130 mg), with a yield of 80.0%. Melting point: 276–278 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.56(1H),8.27(1H),8.22(1H),8.11(1H),7.98 (1H),7.66(1H),7.32(1H),7.27(1H),5.02(1H),4.71(1H),4.42(2H),3.79(2H),1.49(3H)ppm.

[0074] Example 10, Preparation of compound I-8:

[0075]

[0076] Intermediate III-1 (100 mg), piperidine (16 mg) as catalyst, stirred at 80 °C for 15 minutes, then compound 1-propyl-1H-indole-3-carboxaldehyde (102 mg) was added, and the reaction was continued under reflux at 80 °C for 10 hours. The mixture was separated by column chromatography to obtain a yellow solid I-8 (120 mg), yield 76.7%. Melting point: 240–242 °C; 1 H NMR(600MHz,DMSO-d6)δ14.96(1H),9.09(1H),8.52(1H),8.28(1H),8.24(1H),8.12(1H),7.99( 1H),7.68(1H),7.33(1H),7.27(1H),4.71(2H),4.36(2H2),1.85(2H),1.49(3H),0.90(3H)ppm.

[0077] Example 11, Preparation of compound I-9:

[0078]

[0079] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-hexyl-1H-indole-3-carboxaldehyde (125 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-9 (150 mg), with a yield of 84.7%. Melting point: 226–228 °C. 1 H NMR(600MHz,DMSO-d6)δ14.92(1H),9.05(1H),8.49(1H),8.24(1H),8.20(1H),8.06(1H),7.96(1H),7. 64(1H),7.32(1H),7.26(1H),4.69(1H),4.36(2H),1.82(2H),1.49(3H),1.30–1.27(6H),0.85(3H)ppm.

[0080] Example 12, Preparation of compound I-10:

[0081]

[0082] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-decyl-1H-indole-3-carboxaldehyde (156 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-10 (110 mg), with a yield of 54.1%. Melting point: 158–160 °C; 1 H NMR(600MHz,DMSO-d6)δ14.95(1H),9.09(1H),8.51(1H),8.26(1H),8.23(1H),8.12(1H),7.99(1H), 7.65(1H),7.33(1H),7.27(1H),4.71(2H),4.37(2H),1.82(2H),1.49(3H),1.25(14H),0.83(3H)ppm.

[0083] Example 13, Preparation of compound I-11:

[0084]

[0085] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-hexadecyl-1H-indole-3-carboxaldehyde (272 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-11 (180 mg), with a yield of 78.9%. Melting point: 111–113 °C. 1H NMR(600MHz,DMSO-d6)δ14.95(1H),9.10(1H),8.52(1H),8.28(1H),8.24(1H),8.12(1H),7.99(1H),7.66(1H),7 .33(1H),7.27(1H),4.72(1H),4.38(2H),1.81(2H),1.49(3H),1.31–1.25(4H),1.24–1.16(22H),0.83(3H)ppm.

[0086] Example 14, Preparation of compound I-12:

[0087]

[0088] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(cyclopropylmethyl)-1H-indole-3-carboxaldehyde (109 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-12 (130 mg), with a yield of 78.3%. Melting point: 260–262 °C. 1 H NMR(600MHz,DMSO-d6)δ14.95(1H),9.08(1H),8.64(1H),8.28(1H),8.23(1H),8.10(1H),7.99(1H),7.70(1H ),7.33(1H),7.27(1H),4.71(1H),4.26(2H),1.49(3H),1.37–1.33(1H),0.61–0.58(2H),0.48–0.46(2H)ppm.

[0089] Example 15, Preparation of compound I-13:

[0090]

[0091] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-(cyclopentylmethyl)-1H-indole-3-carboxaldehyde (124 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-13 (145 mg), with a yield of 82.2%. Melting point: 250–252 °C; 1H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.53(1H),8.27(1H),8.24(1H),8.11(1H),7.98(1H),7.69(1H),7.3 3(1H),7.27(1H),4.71(1H),4.32(2H),2.43(1H),1.70–1.60(4H),1.57–1.51(2H),1.49(3H),1.34–1.27(2H)ppm.

[0092] Example 16, Preparation of compound I-14:

[0093]

[0094] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(cyclohexylmethyl)-1H-indole-3-carboxaldehyde (132 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-14 (150 mg), with a yield of 82.7%. Melting point: 240–242 °C. 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.47(1H),8.27(1H),8.24(1H),8.10(1H),7.98(1H),7.67(1H),7.32(1H),7.2 6(1H),4.71(1H),4.23(2H),1.89–1.80(1H),1.70–1.65(2H),1.61–1.53(3H),1.49(3H),1.17–1.14(3H),1.09–1.02(2H)ppm.

[0095] Example 17, Preparation of compound I-15:

[0096]

[0097] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-(2-morpholinoethyl)-1H-indole-3-carboxaldehyde (141 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-15 (155 mg), with a yield of 85.3%. Melting point: 227–229 °C. 1H NMR(600MHz,DMSO-d6)δ14.92(1H),9.07(1H),8.68(1H),8.26(1H),8.22(1H),8.11(1H),7.96(1H), 7.67(1H),7.32(1H),7.26(1H),4.71(2H),4.47(2H),3.59(4H),2.73(2H),2.47(4H),1.50(3H)ppm.

[0098] Example 18, Preparation of compound I-16:

[0099]

[0100] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-(3-morpholinoethyl)-1H-indole-3-carboxaldehyde (149 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-16 (166 mg), with a yield of 86.1%. Melting point: 218–220 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.54(1H),8.27(1H),8.23(1H),8.11(1H),7.98(1H),7.67 (1H),7.33(1H),7.27(1H),4.71(2H),4.43(2H),3.59(4H),2.32(4H),2.21(2H),1.98(2H),1.49(3H)ppm.

[0101] Example 19, Preparation of compound I-17:

[0102]

[0103] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, tert-butyl 2-(3-formyl-1H-indol-1-yl)acetate (141 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-17 (150 mg), with a yield of 85.1%. Melting point: 218–220 °C. 1H NMR(600MHz,DMSO-d6)δ14.96(1H),9.09(1H),8.54(1H),8.29(1H),8.27(1H),8.14(1H), 8.00(1H),7.53(1H),7.33(1H),7.28(1H),5.30(2H),4.72(1H),1.50(3H),1.45(9H)ppm.

[0104] Example 20, Preparation of compound I-18:

[0105]

[0106] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Ethyl 2-(3-formyl-1H-indol-1-yl)acetate (126 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-18 (150 mg), with a yield of 84.4%. Melting point: 255–257 °C. 1 H NMR(600MHz,DMSO-d6)δ14.95(1H),9.10(1H),8.57(1H),8.27(1H),8.21(1H),8.13(1H),8.00 (1H),7.57(1H),7.33(1H),7.28(1H),5.42(2H),4.72(2H),4.20(2H),1.49(3H),1.24(3H)ppm.

[0107] Example 21, Preparation of compound I-19:

[0108]

[0109] Compound II-5b (100 mg, 0.21 mmol) was mixed with 5 mL of methanol and 1 mL of NaOH (1 mol / L) solution and stirred at room temperature for 10 h. The crude product was purified by silica gel column chromatography to give the target compound I-19 (56 mg). Yield: 59.4%. Melting point: 295–297 °C. 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),13.19(1H),9.09(1H),8.55(1H),8.29(1H),8.26(1H) ,8.15(1H),8.00(1H),7.57(1H),7.32(1H),7.28(1H),5.31(2H),4.72(2H),1.50(3H)ppm.

[0110] Example 22, Preparation of compound I-20:

[0111]

[0112] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 2-(3-formyl-1H-indol-1-yl)acetamide (111 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-20 (130 mg), with a yield of 77.8%. Melting point: >300 °C; 1 H NMR(600MHz,DMSO-d6)δ14.93(1H),9.09(1H),8.52(1H),8.28(1H),8.24(1H),8.13(1H),8.00 (1H),7.80(1H),7.51(1H),7.39(1H),7.33(1H),7.28(1H),5.07(2H),4.72(2H),1.49(3H)ppm.

[0113] Example 23, Preparation of compound I-21:

[0114]

[0115] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 2-(3-formyl-1H-indol-1-yl)-N,N-diisopropylacetamide (157 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-21 (140 mg), with a yield of 83.8%. Melting point: 255–257 °C. 1 H NMR(600MHz,DMSO-d6)δ14.96(1H),9.08(1H),8.47(1H),8.28(1H),8.22(1H),8.11(1H),7.98(1H), 7.43(1H),7.30(1H),7.26(1H),5.37(2H),4.71(2H),4.13(1H),3.54(1H),1.49(3H),1.28(12H)ppm.

[0116] Example 24, Preparation of compound I-22:

[0117]

[0118] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-(2-oxo-2-(pyrrolidone-1-yl)ethyl)-1H-indole-3-carboxaldehyde (140 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-22 (143 mg), with a yield of 76.5%. Melting point: 280–282 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.09(1H),8.49(1H),8.30(1H),8.26(1H),8.15(1H),7.99(1H ),7.56(1H),7.34–7.21(2H),5.34(2H),4.72(2H),3.64(4H),1.98(2H),1.84(2H),1.50(3H)ppm.

[0119] Example 25, Preparation of compound I-23:

[0120]

[0121] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound 1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-indole-3-carboxaldehyde (147 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-23 (155 mg), with a yield of 80.7%. Melting point: 266–268 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.48(1H)),8.29(1H),8.24(1H),8.14(1H) ,7.98(1H),7.51(1H),7.28(2H),5.44(2H),4.71(2H),3.56(4H),1.65(4H),1.50(5H)ppm.

[0122] Example 26, Preparation of compound I-24:

[0123]

[0124] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(2-morpholino-2-oxyethyl)-1H-indole-3-carboxaldehyde (148 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-24 (156 mg), with a yield of 81.0%. Melting point: 278–280 °C;1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.10(1H),8.49(1H),8.30(1H),8.27(1H),8.15(1H),7.99(1H),7.54(1H),7.3 1(1H),7.26(1H),5.48(2H),4.73(2H),4.32(2H),3.82–3.67(2H),3.64–3.59(2H),3.47–3.43(2H),1.50(3H)ppm.

[0125] Example 27, Preparation of compound I-25:

[0126]

[0127] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Then, compound N,N-dicyclohexyl-2-(3-formyl-1H-indol-1-yl)acetamide (200 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-25 (173 mg), with a yield of 76.2%. Melting point: 200–202 °C. 1 H NMR(600MHz,DMSO-d6)δ14.97(1H),9.11(1H),8.49(1H),8.31(1H),8.25(1H),8.15(1H),8.00(1H ),7.46(1H),7.30(2H),5.44(2H),4.73(2H),3.66(2H),1.80(4H),1.70–1.37(14H),1.21(5H)ppm.

[0128] Example 28, Preparation of compound I-26:

[0129]

[0130] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(2-oxo-3-phenylpropyl)-1H-indole-3-carboxaldehyde (129 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-26 (131 mg), with a yield of 73.1%. Melting point: 270–272 °C. 1H NMR(600MHz,DMSO-d6)δ14.94(1H),9.10(1H),8.67(1H),8.30(1H),8.26(1H),8.14(1H ),8.01(1H),7.61(1H),7.43(2H),7.32–7.27(4H),5.68(2H),4.72(2H),1.49(3H)ppm.

[0131] Example 29, Preparation of compound I-27:

[0132]

[0133] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 min. 1-(3-(2,4-dichlorophenyl)-2-oxopropyl)-1H-indole-3-carboxaldehyde (166 mg) was added, and the mixture was refluxed for another 10 hours. The resulting solution was separated by column chromatography to obtain a yellow solid I-27 (168 mg), with a yield of 82.2%. Melting point: 254–256 °C. 1 H NMR(600MHz,DMSO-d6)δ14.95(1H),9.11(1H),8.61(1H),8.31(1H),8.27(1H),8.15(1H),8.03(1H),7.75(1H),7.59(1H),7.43(1H),7.31 2H),7.01(1H),5.75(2H),4.72(2H),1.49(3H)ppm.

[0134] Example 30, Preparation of compound I-28:

[0135]

[0136] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(3-(2,4-difluorophenyl)-2-oxopropyl)-1H-indole-3-carboxaldehyde (148 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-28 (160 mg), with a yield of 78.0%. Melting point: >300 °C; 1 H NMR(600MHz,DMSO-d6)δ14.92(1H),9.09(1H),8.62(1H),8.28(1H),8.26(1H),8.13(1H)),8.00 (1H),7.68(1H),7.42(1H),7.33(2H),7.28(1H),7.11(1H),5.70(2H),4.71(1H),1.49(3H)ppm.

[0137] Example 31, Preparation of compound I-29:

[0138]

[0139] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(3-(3-chlorophenyl)-2-oxopropyl)-1H-indole-3-carboxaldehyde (148 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-29 (160 mg), with a yield of 83.4%. Melting point: 280–282 °C. 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.10(1H),8.67(1H),8.30(1H),8.26(1H),8.14(1H ),8.01(1H),7.61(1H),7.43(2H),7.32–7.27(4H),5.68(2H),4.72(2H),1.49(3H)ppm.

[0140] Example 32, Preparation of compound I-30:

[0141]

[0142] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(3-(4-nitrophenyl)-2-oxopropyl)-1H-indole-3-carboxaldehyde (153 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-30 (165 mg), with a yield of 84.3%. Melting point: >300 °C; 1 H NMR(600MHz,DMSO-d6)δ14.97(1H),9.12(1H),8.73(1H),8.33(1H),8.29(1H),8.24(1H),8.26–8.21(2H), 8.17(1H),8.06–8.01(1H),7.60–7.56(1H),7.51–7.47(2H),7.29(2H),5.88(2H),4.73(2H),1.49(3H)ppm.

[0143] Example 33, Preparation of compound I-31:

[0144]

[0145] Intermediate III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Compound 1-(2-oxo-3-(p-tolyl)propyl)-1H-indole-3-carboxaldehyde (136 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-31 (155 mg), with a yield of 84.1%. Melting point: 260–262 °C. 1 H NMR(400MHz,DMSO-d6)δ8.67(1H),8.60(s1H),8.22(1H),8.04–7.79(3H),7.6 1(1H),7.26(2H),7.20–7.14(4H),5.59(2H),4.47(2H),2.26(3H),1.42(3H).

[0146] Example 34, Preparation of compound I-32:

[0147]

[0148] Compound III-2 (100 mg), with hexahydropyridine (14 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-1H-indol-1-yl)ethyl acetate (110 mg) prepared by chemical reaction was added. The reaction was further refluxed at 80 °C for 10 hours, and the yellow solid I-32 (135 mg) was obtained by column chromatography, with a yield of 80.4%. Melting point: 248–250 °C; 1 H NMR(600MHz,DMSO-d6)δ14.91(1H),9.09(1H),8.58(1H),8.33(1H),8.15(1H),8.08(1H),7.99(1H), 7.58(1H),7.33(1H),7.29(1H),5.42(1H),5.30(2H),4.20(2H),1.89(3H),1.76(3H),1.24(3H)ppm.

[0149] Example 35, Preparation of compound I-33:

[0150]

[0151] Compound III-3 (100 mg), with hexahydropyridine (16 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-1H-indol-1-yl)ethyl acetate (122 mg) prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The product was separated by column chromatography to obtain a yellow solid I-33 (124 mg), with a yield of 70.9%. Melting point: 245–247 °C; 1H NMR(600MHz,DMSO-d6)δ14.68(1H),9.22(1H),8.59(1H),8.31(1H),8.28(1H),8.15(1H),7.96 (1H),7.58(1H),7.34(1H),7.30(1H),5.63(2H),5.43(2H),4.20(2H),3.86(1H),1.25(2H)ppm.

[0152] Example 36, Preparation of compound I-34:

[0153]

[0154] Compound III-4 (100 mg), with hexahydropyridine (15 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-1H-indol-1-yl)ethyl acetate (120 mg) prepared by chemical reaction was added. The reaction was further refluxed at 80 °C for 10 hours, and the yellow solid I-34 (130 mg) was obtained by column chromatography, with a yield of 74.7%. Melting point: 257–259 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.08(1H),8.56(1H),8.27(2H),8.26(1H),8.14(1H),7.99(1H), 7.57(1H),7.33(1H),7.28(1H),5.42(2H),4.66(2H),4.20(2H),1.91(2H),1.24(3H),0.94(3H)ppm.

[0155] Example 37, Preparation of compound I-35:

[0156]

[0157] Compound III-5 (100 mg), with hexahydropyridine (13 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-1H-indol-1-yl)ethyl acetate (110 mg) prepared by chemical reaction was added. The reaction was further refluxed at 80 °C for 10 hours, and the yellow solid I-35 (127 mg) was obtained by column chromatography, with a yield of 75.9%. Melting point: 268–270 °C; 1H NMR(600MHz,DMSO-d6)δ14.93(1H),9.09(1H),8.57(1H),8.29(1H),8.24(1H),8.14(1H),7.98(1H),7.58(1H ),7.33(1H),7.28(1H),5.42(2H),4.68(2H3),4.20(2H),1.89(2H),1.40–1.33(4H),1.24(3H),0.88(3H)ppm.

[0158] Example 38, Preparation of compound I-36:

[0159]

[0160] Compound III-6 (100 mg), with hexahydropyridine (12 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and then ethyl 2-(3-formyl-1H-indol-1-yl)acetate (97 mg) prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The resulting yellow solid, I-36 (110 mg), was obtained by column chromatography, with a yield of 69.0%. Melting point: 254–256 °C; 1 H NMR(600MHz,DMSO-d6)δ14.93(1H),9.08(1H),8.57(1H),8.28(1H),8.23(1H),8.14(1H),7.98(1H),7.57(1H), 7.33(1H),7.27(1H),5.42(2H),4.68(2H),4.20(2H),1.88(2H),1.38–1.31(4H),1.28–1.18(9H),0.80(3H)ppm.

[0161] Example 39, Preparation of compound I-37:

[0162]

[0163] Compound III-7 (100 mg), with hexahydropyridine (13 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and then ethyl 2-(3-formyl-1H-indol-1-yl)acetate (103 mg) prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The resulting yellow solid, I-37 (140 mg), was obtained by column chromatography, with a yield of 85.8%. Melting point: 270–272 °C; 1H NMR(600MHz,DMSO-d6)δ14.85(1H),9.31(1H),8.53(1H),8.51(1H),8.13(2H),8.01(1H),7.91–7.86(1H,) ,7.82(1H),7.67(1H),7.59–7.55(1H),7.38(1H),7.33(2H),6.09(2H),5.41(2H),4.19(2H),1.24(3H)ppm.

[0164] Example 40, Preparation of compound I-38:

[0165]

[0166] Compound III-8 (100 mg), with hexahydropyridine (13 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-1H-indol-1-yl)ethyl acetate (103 mg) prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The product was separated by column chromatography to obtain a yellow solid I-38 (136 mg), yielding 83.2%. Melting point: 266–268 °C; 1 H NMR(600MHz,DMSO-d6)δ14.84(1H),9.33(1H),8.54(1H),8.16–8.11(2H),7.96(1H),7.82–7.79(1H) ),7.59–7.56(1H),7.42–7.37(5H),7.35–7.32(2H),5.98(2H),5.41(2H),4.19(2H),1.24(2H)ppm.

[0167] Example 41, Preparation of compound I-39:

[0168]

[0169] Compound III-9 (100 mg), with hexahydropyridine (12 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and then ethyl 2-(3-formyl-1H-indol-1-yl)acetate (99 mg) of the intermediate prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The resulting solid was separated by column chromatography to obtain a yellow solid I-39 (122 mg), with a yield of 75.8%. Melting point: 255–257 °C; 1H NMR(600MHz,DMSO-d6)δ14.87(1H),9.30(1H),8.54(1H),8.15-8.10(3H),7.94(1H),7.80(1H),7. 58(1H),7.34(2H),7.29(2H),7.22(2H),5.92(2H),5.40(2H),4.19(2H),2.31(3H),1.24(2H)ppm.

[0170] Example 42, Preparation of compound I-40:

[0171]

[0172] Compound III-10 (100 mg), with hexahydropyridine (11 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-1H-indol-1-yl)ethyl acetate (93 mg) prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The resulting yellow solid, I-40 (132 mg), was obtained by column chromatography, with a yield of 83.4%. Melting point: 243-245 °C. 1 H NMR(600MHz,DMSO-d6)δ14.75(1H),9.26(1H),8.55(1H,ndole-H),8.13(3H , ),7.85(1H),7.58(1H),7.49(1H),7.39–7.28(3H),7.09(1H),6.01(2H),5.41(1H),4.20(2H),1.24(2H)ppm.

[0173] Example 43, Preparation of compound I-41:

[0174]

[0175] Compound III-11 (100 mg), with hexahydropyridine (11 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and then ethyl 2-(3-formyl-1H-indol-1-yl)acetate (86 mg) of the intermediate prepared by chemical reaction was added. The reaction was continued under reflux at 80 °C for 10 hours. The resulting yellow solid, I-41 (99 mg), was obtained by column chromatography, with a yield of 64.9%. Melting point: >300 °C; 1H NMR(600MHz,DMSO-d6)δ14.81(1H),9.33(1H),8.55(1H),8.15(1H),8.07(1H),7.95(1H),7.80(1H) ,7.76(1H),7.63(1H),7.57(1H),7.37–7.28(3H),5.97(1H,2H),5.41(2H),4.19(2H),1.24(2H)ppm.

[0176] Example 44, Preparation of compound I-42:

[0177]

[0178] Compound III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Ethyl 2-(4-chloro-3-formyl-1H-indol-1-yl) compound (145 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The resulting product was separated by column chromatography to obtain a yellow solid I-42 (150 mg), with a yield of 78.8%. Melting point: 279–281 °C. 1 H NMR(600MHz,DMSO-d6)δ14.93(1H),9.10(1H),8.60(1H),8.29(1H),8.28(1H),8.14–8. 12(2H),7.63(1H),7.33(1H),5.44(2H),4.73(1H),4.19(2H),1.50(3H),1.24(3H)ppm.

[0179] Example 45, Preparation of compound I-43:

[0180]

[0181] Compound III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Ethyl 2-(5-chloro-3-formyl-1H-indol-1-yl) compound (145 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-43 (144 mg), with a yield of 75.7%. Melting point: >300 °C; 1 H NMR(600MHz,DMSO-d6)δ14.93(1H),9.10(1H),8.60(1H),8.29(1H),8.28(1H),8.14–8. 12(2H),7.63(1H),7.33(1H),5.44(2H),4.73(1H),4.19(2H),1.50(3H),1.24(3H)ppm.

[0182] Example 46, Preparation of compound I-44:

[0183]

[0184] Compound III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Ethyl 2-(5-nitro-3-formyl-1H-indol-1-yl) compound (151 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was then separated by column chromatography to obtain a yellow solid I-44 (100 mg), with a yield of 51.1%. Melting point: >300 °C; 1 H NMR(600MHz,DMSO-d6)δ14.91(1H),9.12(1H),9.07(1H),8.75(1H),8.48(1H),8.33 (1H),8.18(2H),7.84(1H),5.54(2H),4.74(2H),4.21(2H),1.50(3H),1.25(3H)ppm.

[0185] Example 47, Preparation of compound I-45:

[0186]

[0187] Compound III-1 (100 mg) and piperidine (16 mg) were stirred in 10 mL of ethanol at 80 °C for 15 minutes. Ethyl 2-(6-fluoro-3-formyl-1H-indol-1-yl) compound (136 mg) was added, and the mixture was refluxed at 80 °C for 10 hours. The reaction was separated by column chromatography to obtain a yellow solid I-45 (150 mg), with a yield of 81.4%. Melting point: 251–253 °C. 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.10(1H),8.55(1H),8.32–8.24(2H),8.14(1H),8.03 –7.98(1H),7.55(1H),7.16(1H),5.62(2H),4.72(2H),4.20(2H),1.49(3H),1.25(3H)ppm.

[0188] Example 48, Preparation of compound I-46:

[0189]

[0190] Compound III-1 (100 mg), with hexahydropyridine (16 mg) as a catalyst, was stirred at 80 °C for 15 minutes, and the intermediate 2-(3-formyl-7-methyl-1H-indol-1-yl)ethyl acetate (134 mg) prepared by chemical reaction was added. The reaction was further refluxed at 80 °C for 10 hours, and the yellow solid I-46 (147 mg) was obtained by column chromatography, with a yield of 80.4%. Melting point: 260-262 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.09(1H),8.47(1H),8.27(1H),8.24(1H),8.13(1H),7.82 (1H),7.14(1H),7.05(1H),5.57(2H),4.72(2H),4.23(2H),2.58(3H),1.49(3H),1.24(3H)ppm.

[0191] Example 49: In vitro antimicrobial activity of indole-hybridized quinolones:

[0192] Adopting clinical laboratory standards that comply with those set by the U.S. National Clinical Laboratory Committee. The 96-well microdilution method of the Standards Institute (CLSI) was used to examine the minimum inhibitory concentration (MIC) of indole-hybridized quinolones prepared in Examples 3–48 against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii). The test compound was dissolved in a small amount of dimethyl sulfoxide, then diluted with water to prepare a solution with a concentration of 1.28 mg / mL, and then diluted with culture medium to 128 μg / mL. The solution was incubated at 35°C for 24–72 hours. After thoroughly mixing the culture plate on a shaker, the MIC was measured at a wavelength of 590 nm. The results are shown in Tables 1–2.

[0193] Table 1. In vitro antibacterial activity (MIC, μg / mL) of indole-hybridized quinolones prepared in Examples 3–48

[0194]

[0195] As shown in Table 1, the compounds in this invention exhibited certain inhibitory effects against the tested Gram-positive bacteria. In particular, the hydroxyethyl-substituted indolequinolone compound I-7 showed excellent inhibitory activity against MRSA, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus aureus 29213, with MIC values ​​of 2, 0.5, 0.25, and 0.5 μg / mL, respectively; the ethyl acetate-substituted indolequinolone compound I-18 also showed excellent inhibitory activity against MRSA, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus aureus 25923, with MIC values ​​of 0.25, 0.25, 0.5, and 0.25 μg / mL, respectively. These results were significantly superior to the inhibitory activity of the reference drug norfloxacin against MRSA, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus aureus 25923 (MIC values ​​of 8, 8, 8, and 1 μg / mL, respectively). Some compounds showed antibacterial activity comparable to, or even stronger than, the reference drug norfloxacin.

[0196] Table 2. In vitro antibacterial activity (MIC, μg / mL) of indole-hybridized quinolone compounds prepared in Examples 3–48

[0197]

[0198]

[0199] As shown in Table 2, the compounds in this invention exhibit certain inhibitory effects on the tested Gram-negative bacteria. In particular, the cyanoethyl-modified indolequinolone compound I-6 showed excellent inhibitory activity against Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa 27853, and Acinetobacter baumannii, with MIC values ​​of 0.5, 0.25, 1, 0.5, and 0.5 μg / mL, respectively. The ethyl acetate-modified indolequinolone compound I-18 also showed excellent inhibitory activity against Klebsiella pneumoniae, Escherichia coli, Escherichia coli 25922, Pseudomonas aeruginosa, and Pseudomonas aeruginosa 27853, with MIC values ​​of 1, 0.25, 0.25, 0.5, and 2 μg / MIC, respectively. The inhibitory activity of the compound against the reference drug norfloxacin was significantly superior to that against Klebsiella pneumoniae, Escherichia coli, Escherichia coli 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa 27853, and Acinetobacter baumannii (MIC values ​​of 4, 2, 4, 4, and 32 μg / mL, respectively). Some compounds showed antibacterial activity comparable to, or even stronger than, that of norfloxacin.

[0200] Example 50: Pharmaceutical uses of indole-hybridized quinolone compounds:

[0201] Based on the above antimicrobial activity test results, the indole-hybridized quinolone compounds of the present invention exhibit good antibacterial activity and can be formulated into antibacterial drugs for clinical use. These drugs can be single-component formulations, such as those composed of a single-structure indole-hybridized quinolone compound and pharmaceutically acceptable excipients; or they can be compound formulations, such as those composed of a single-structure indole-hybridized quinolone compound, existing antibacterial active ingredients (e.g., sulfamethoxazole, fluconazole, fosfluconazole, itraconazole, etc.), and pharmaceutically acceptable excipients, or composed of several indole-hybridized quinolone compounds with different structures and pharmaceutically acceptable excipients. The formulation types include, but are not limited to, tablets, capsules, powders, granules, drop pills, injections, powder for injection, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches, and various sustained-release, controlled-release formulations and nano-formulations.

[0202] 1. Preparation of Compound I-1 tablets

[0203] Prescription: 10g of compound I-1, 50g of corn starch, 187g of lactose, 3.0g of magnesium stearate, and an appropriate amount of 70% ethanol solution, to make 1000 tablets.

[0204] Preparation: Dry corn starch at 105℃ for 5 hours for later use; mix compound I-1 with lactose and corn starch evenly, prepare a soft mass with 70% ethanol solution, sieve to make wet granules, add magnesium stearate, compress into tablets to obtain the product; each tablet weighs 250mg and contains 10mg of active ingredient.

[0205] 2. Preparation of Compound I-6 Capsules

[0206] Prescription: Compound I-6 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5g, talc (100 mesh) 2.0g, sweetener 1.25g, orange flavoring 0.25g, coloring as needed, water as needed, to make 1000 capsules.

[0207] Preparation method: The prescribed amount of compound I-6 is micronized and pulverized into an extremely fine powder, and then mixed with the prescribed amounts of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, sweetener, orange flavor and coloring. The mixture is then softened with water, granulated through a 12-14 mesh sieve, dried at 40-50℃, sieved and granulated, and filled into empty capsules to obtain the product; each capsule weighs 50mg and contains 25mg of active ingredient.

[0208] 3. Preparation of Compound I-7 Granules

[0209] Prescription: Compound I-7 26g, dextrin 120g, sucrose 280g.

[0210] Preparation method: Mix compound I-7, dextrin, and sucrose evenly, wet granulate, dry at 60℃, and package to obtain the final product.

[0211] 4. Preparation of Compound I-17 Injection

[0212] Prescription: Compound I-17 10g, propylene glycol 500mL, water for injection 500mL, to prepare a total of 1000mL.

[0213] Preparation: Weigh compound I-17, add propylene glycol and water for injection, stir to dissolve, then add 1g of activated carbon, stir thoroughly and let stand for 15 minutes, filter with a 5μm titanium rod to remove carbon, then filter with microporous membranes with pore sizes of 0.45μm and 0.22μm in sequence, and finally fill into 10mL ampoules and sterilize with flowing steam at 100℃ for 45 minutes to obtain the product.

[0214] 5. Preparation of Compound I-19 Powder for Injection

[0215] Preparation method: The intermediate I-19 aseptic powder is dispensed under aseptic conditions to obtain the product.

[0216] 6. Preparation of Compound I-26 Eye Drops

[0217] Prescription: Compound I-26 3.78g, sodium chloride 0.9g, boric acid buffer solution as needed, distilled water to 1000mL.

[0218] Preparation: Weigh compound I-26 and sodium chloride and add them to 500 mL of distilled water. After complete dissolution, adjust the pH to 6.5 with boric acid buffer solution, add distilled water to 1000 mL, stir well, filter through a microporous membrane, fill into containers, seal, and sterilize with flowing steam at 100°C for 1 hour to obtain the final product.

[0219] 7. Preparation of Compound I-34 Liniment

[0220] Prescription: Compound I-34 4g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.

[0221] Preparation: Dissolve camphor in a 95% (v / v) ethanol solution and set aside; liquefy potassium soap by heating and set aside; weigh compound I-34, add potassium soap solution and camphor ethanol solution while stirring continuously, then gradually add distilled water, and after complete emulsification, add distilled water to the total volume to obtain the final product.

[0222] 8. Preparation of Compound I-36 Suppositories

[0223] Prescription: Compound I-36 4g, gelatin 14g, glycerin 70g, distilled water to 100mL, 100 tablets (metric).

[0224] Preparation: Weigh gelatin and glycerin, add distilled water to 100mL, heat in a water bath at 60℃ until melted into a paste, add compound I-36, stir well, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain the product.

[0225] 9. Preparation of Compound I-42 Ointment

[0226] Prescription: Compound I-42 0.5–2g, cetyl alcohol 6–8g, white petrolatum 8–10g, liquid paraffin 8–19g, monoglyceride 2–5g, polyoxyethylene (40) stearate 2–5g, glycerin 5–10g, ethylparaben 0.1g, distilled water to 100g.

[0227] Preparation: Cetyl alcohol, white petrolatum, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate are heated and completely melted, then mixed and kept at 80°C to prepare the oil phase. Ethylparaben is added to glycerol and distilled water and heated to 85°C to dissolve. The oil phase is then added while stirring continuously. After emulsification, compound I-45 is added, stirred and cooled to obtain the final product.

[0228] 10. Preparation formula of compound I-45 aerosol: 2.5g of compound I-45, 3g of Span20, 4g of talc (100 mesh), and appropriate amount of trichlorofluoromethane.

[0229] Preparation method: Place compound I-45, Span20 and talc powder in a vacuum drying oven and dry for several hours. Cool to room temperature in a desiccator and pulverize into fine powder using an air jet mill. Mix well according to the prescription amount, pour into a sealed container, and add trichlorofluoromethane to the specified amount to obtain the final product.

[0230] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. Indole-hybridized quinolone compounds and their pharmaceutically acceptable salts, characterized in that, It is any one of the following compounds:

2. The indole-hybrid quinolone compound and pharmaceutically acceptable salt thereof according to claim 1, characterized by: The pharmaceutically usable salt is a hydrochloride, nitrate, or acetate.

3. The use of the indole-hybridized quinolone compounds and their pharmaceutically acceptable salts as described in any one of claims 1-2 in the preparation of antibacterial drugs.

4. Use according to claim 3, characterized in that: The bacteria are selected from one or more of Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, or Acinetobacter baumannii.

5. Use according to claim 4, characterized in that, The Staphylococcus aureus is methicillin-resistant Staphylococcus aureus, Staphylococcus aureus ATCC 25923, or Staphylococcus aureus ATCC 29213; the Escherichia coli is Escherichia coli ATCC 25922; and the Pseudomonas aeruginosa is Pseudomonas aeruginosa ATCC 27853.

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