N-functionalized indole compounds as antimicrobial agents and process for preparation thereof

Abstract

N-Functionalized Indole Compounds as Antimicrobial Agents and Process for Preparation Thereof The present invention relates to novel N-functionalized indole compounds and their synthesis using ionic liquids as green reagents and / or solvents in a two to four-step process. The compounds exhibit potent antibacterial activity against multi-drug resistant and susceptible gram-positive bacteria, including Staphylococcus aureus and Enterococcus sp. Synergistic effects are observed when combined with gentamicin or levofloxacin, including activity against resistant MRSA (NRS 119). In-vivo efficacy is demonstrated in a murine skin infection model via topical and oral administration.

Description

[0001] N-Functionalized Indole Compounds as Antimicrobial Agents and Process for Preparation Thereof FIELD OF THE INVENTION The present invention relates to N-functionalized indole compounds having activity against antimicrobial resistance (AMR) microbial strains. The present invention particularly relates to N-functionalized indole compounds having activity against Staphylococcus aureus. The present invention also relates to process for the preparation of N-functionalized indole compounds. The potential of such a molecule can be further increased when combined with existing antibiotics. The present invention also discloses a synergistic combination of functionalized indole compounds with antibiotics like Gentamicin and levofloxacin. BACKGROUND OF THE INVENTION Antimicrobial resistance (AMR) existed before the antimicrobials were synthesized, produced, and commercialized. Staphylococcus aureus has been resistant to penicillin lived since penicillin clinical usage was introduced. The way antibiotics were misused in the current scenario will become one of the causes of the expansion of multidrug-resistant (MDR) strains, which will be responsible for~ 700,000 annual deaths and a US$ 100 trillion losses to the global economy by 2050. In 2017, the World Health Organization (WHO) released a priority list for antibiotic-resistant pathogens, consisting of 12 families of bacteria that can be considered the greatest threat to human health. S. aureus resistance to methicillin and vancomycin is placed a high priority for which new antibiotics are sought. Methicillin-resistant S. aureus (MRSA) can cause 64% more death when compared to drug-sensitive infections. Thus, MRSA infections, which can cause many serious diseases, has become a significant threat to human health. The discovery and development of new antibiotics must be accelerated against drug-resistant S. aureus specially to treat MRSA infections before it becomes too late and most warranted to date. Design of small molecules have been used for the treatment of a vast array of diseases including microbial infections. Indole is one of the most valuable privileged heterocyclic compounds in synthetic as well as medicinal chemistry owing to their omnipresence in many drugs and drug- like molecules with wide range of biological activities such as antibacterials antitumor and antiinflammatory. Particularly, 3- sulfenyl indole derivatives has a wide range of pharmaceutical activities such as anticancer, respiratory disorder, antiviral, antibacterial, and COX-2 inhibitors. Anand Kumar et al, disclosed arylthioindoles having the following structural scaffold and its use for treating various diseases including HIV, heart diseases, cancer and bacterial infection (ACS Omega (2020), 5(13), 7627-7635). Li, Shengyi et al, disclosed the synthesis of 3- sulfenylindoles via a cellulose-derived Fe3O4@Pd nanoparticles catalysed heterogeneously. This approach provided an effective synthetic route to an important class of indole derivatives and featured high efficiency, easy operation, good practicality and environmental friendliness. The compounds were found to show antitumor, anti- HIV and antibacterial activity (Catalysis Letters (2020), 150(8), 2409-2414). Golzar, N et al, disclosed CuI catalysed synthesis of 3- sulfenylindoles involving the reaction of aryl halides with indole derivatives in the presence of thiourea and hexachloroethane in DMSO. The compound showed therapeutic value in treating cancer, HIV, heart disease, allergies, obesity and several bacterial infections. (New Journal of Chemistry (2017), 41(20), 11921-11925). Liu, Cong-Rong et al, disclosed derivatives which were synthesized from by-product promoted regioselective sulfenylation of indoles with sulfonic acids which possessed anti-cancer, anti-bacterial properties and were also found to be useful in treating obesity and certain allergic conditions (D16: Organic & Biomolecular Chemistry (2015), 13(8), 2251-2254). Prasad .C et al, disclosed methods comprising metal free sulfenylation and bis-sulfenylation of indoles for the synthesis of 3-arylthioindoles which were found to be useful in the treatment of HIV, cancer, cardiovascular, and bacterial diseases. (Organic & Biomolecular Chemistry (2013), 11(46), 8036-8040). Silveira et al, disclosed a method for the preparation of 3-sulfenyl indoles along with the use of disclosed derivatives in the treatment of several diseases such as bacterial infection, HIV, obesity, heart diseases, and allergies (Tetrahedron Letters (2010), 51(15), 2014-2016). The newly published scientific articles [10.1002 / ddr.22123 Drug development Research Volume85, Issue1 February 2024] by the inventors from CSIR-CDRI 3-sulfenyl indole class for anti-bacterial / anti-microbial activity. Hemiaminals of pyrazole and imidazole group showed enhanced the antimicrobial activity against S. aureus over parent heterocycles. Herein we disclose the development of a sustainable approach for the synthesis of novel N-functionalized indole compounds and their study against drug-resistant S. aureus and structure-activity relationship (SAR). Preclinical parameters such as MIC, cytotoxicity, Combination studies, Time-kill kinetics, Biofilm inhibition as well as eradication assays and PAE of hit molecule, (5-bromo-3-((4- bromophenyl)thio)-1H-indol-1-yl)methanol (Example 10) were determined in this study, followed by In-vivo efficacy of the compound in murine skin infection model alone and combination with levofloxacin against S. aureus NRS 119 a levofloxacin resistant strain. OBJECTS OF THE INVENTION The main objective of the present invention is to provide novel N-functionalized indoles as new potent molecules which can be utilized as an antibacterial drug against different MDR strains of gram-positive bacteria S. aureus and Enterococcus sp alone and in combination with existing antibiotics Gentamicin and levofloxacin. Another objective of the invention is to provide a process for the preparation of N- functionalized indole compounds and derivatives. SUMMARY OF THE INVENTION Accordingly, the invention provides N-functionalized indole derivatives of Formula 1 exhibiting antibacterial activity against gram-positive MDR strains (Staphylococcus aureus and Enterococcus sp), either alone or in combination with gentamicin and levofloxacin. Wherein; X is S, Se, SO, SO2, O, CH2, CH2-S, NHSO2 R1is selected from the group consisting of benzyl, naphthyl, group selected from C1 to C10 alkyl groups A, B, C, D and E are independently selected from the groups consisting of hydrogen, halogen, alkyl or alkoxy, CF3; R2is hydrogen, halogen, CN, NO2,alkyl, alkoxy, carboxylic acid, ester, amide; R3is hydrogen, aryl, alkyl, carboxylic acid, ester, amide; Y is hydrogen, tosyl, or ; n = 1 to 4 and Z is selected from the group consisting of hydrogen, OH, CN, , , , carboxylic acid, amide, hydrazide, , , cyclic and acyclic amines, , their amine salts, where R4is selected form hydrogen, alkyl group , Y and R3are connected through [-(CH2)n-N-C-] where n = 1-3 In another embodiment, the invention provides a process for the preparation of compound of formula 1a, comprising: (a) reacting an indole of formula 2 with thiol of formula 3 in the presence of a base in an aprotic solvent to obtain a compound of formula 4; (b) reacting the compound of formula 4 with formaldehyde and catalysts tetra-butyl ammonium fluoride (TBAF) in (1-hexyl-3-methyl-1H-imidazol-3-ium bromide = [hmim]Br) HMIM to obtain the compound of formula 1a and oxidation of compound 1a with mCPBA to obtain its corresponding oxides of formula 1aa. Wherein R1, R2and R3are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1ab, comprising: (a) reacting an indole of formula 2 with diselenide of formula 5 in the presence of a base in an aprotic solvent to obtain a compound of formula 6; (b) reacting the compound of formula 6 with formaldehyde and catalyst tetra-butyl ammonium fluoride (TBAF) in (1-hexyl-3-methyl-1H-imidazol-3-ium bromide = [hmim]Br) HMIM to obtain the compound of formula 1ab. Wherein R1, R2and R3are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1b, comprising: reacting the compound of formula 4 with compound of formula 7 in the presence of a base to obtain the compound of formula 1b. Wherein R1, R2, R3and Y are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1c, comprising: a) reacting a substituted 3-formylindole of formula 8 with tosyl hydrazine followed by treatment with substituted arylboronic acid or thiophenols in the presence of a base in 1,4-dioxane to obtain a compound of formula 9; b) reacting compound of formula 9 with formaldehyde / TBAF / HMIMBr or substituted halides in the presence a base to obtain the compound of formula 1c. Wherein R1, R2, R3and Y are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1d, comprising: a) reacting an indole of formula 2 with tosylchloride, NBS, triethylamine and then with substituted phenols or sulphonamides in a sequential manner in the presence of a base followed by aromatization with Lewis acid and detosylation with Cs2CO3 to obtain a compound of formula 10. b) reacting compound of formula 10 with formaldehyde / TBAF / HMIMBr or substituted halides in the presence a base to obtain the compound of formula 1d. Wherein R1, R2, R3and Y are as defined above BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Time Kill kinetics of Example 10 alone against S. aureus ATCC 29213 Figure 2: Time Kill kinetics of Example 10 in combination with gentamicin and levofloxacin against S. aureus ATCC 29213 Figure 3: Time Kill kinetics of Example 10 in combination against NRS119 with Levofloxacin Figure 4: Biofilm inhibition and eradication of Example 10 against pre-formed biofilm using S. aureus ATCC 29213 Figure 5: Example 10 does not induce resistance using S. aureus ATCC 29213 Figure 6: Intracellular activity of Example 10 against S. aureus ATCC 29213 Figure 7: Example 10 leads to membrane damage (1) DiSC3 assay indicating membrane damage; (2) SEM confirming cellular lysis. Figure 8: In vivo infection model with Example 10 in topical infection model Figure 8 (a)Topical model with S. aureus ATCC 29213 treated topically Figure 8 (b)Topical model with MRSA NRS 119 treated topically Figure 8 (c)Topical model with S. aureus ATCC 29213 treated orally Figure 9: Scanning electron microscopic visualization of treated S. aureus cells with Example 10. The panel on the top is untreated S. aureus cells and stained green indicating live cells while the panel on left is S. aureus treated with Example 10 and stained red indicating dead cells. Similarly, the panel on bottom right is electron microscopic images of S. aureus untreated indicating live cells whereas the bottom left is damaged cells with contents leaking out as shown by arrows. DETAILED DESCRIPTION OF THE INVENTION Multi-drug resistant strains (MDR) are microorganisms which are resistant to more than one antibiotic. Infections with MDR strains are hard to treat since few or no treatment options remain, and it spreads antibiotic resistance. Therefore, antibiotics that are more toxic have to be used for curing infections and have become one of the most important threats to public health. Methicillin-resistant S. aureus (MRSA) is amongst the most prevalent community associated MDR bacterial infections. Currently, existing drugs in combination with new, potent anti-bacterial leads can be tested against these bacterial strains, which will be more cost- effective. The present invention provides N-functionalized indole derivatives of Formula 1 exhibiting antibacterial activity against gram-positive MDR strains (Staphylococcus aureus and Enterococcus sp), either alone or in combination with gentamicin and levofloxacin. The potential of such a molecule can be further increased when combined with existing antibiotics. A synergistic combination disclosed herein with Gentamicin and levofloxacin reveals the potency of 1 as an efficient anti-bacterial drug. Formula 1 Wherein X is S, Se, SO, SO2, O, CH2, CH2-S, NHSO2 R1is selected from the group consisting of benzyl, naphthyl, group selected from C1 to C10 alkyl groups A, B, C, D and E are independently selected from the groups consisting of hydrogen, halogen, alkyl or alkoxy, CF3; R2is hydrogen, halogen, CN, NO2, alkyl, alkoxy, carboxylic acid, ester, amide; R3is hydrogen, aryl, alkyl, carboxylic acid, ester, amide; Y is hydrogen, tosyl, or ; n = 1 to 4 and Z is selected from the group consisting of hydrogen, OH, CN, , , carboxylic acid, amide, hydrazide, , , cyclic and acyclic amines, , and their amine salts, where R4is selected form hydrogen, alkyl group , , , , Y and R3are connected through [-(CH2)n-N-C-] where n = 1-3 In an embodiment of the present invention, the compound of general Formula I is selected from the compounds listed in Table 1 consisting of:

[0002] In another embodiment, the invention provides a process for the preparation of compound of formula 1a, comprising: (a) reacting an indole of formula 2 with thiol of formula 3 in the presence of a base in an aprotic solvent to obtain a compound of formula 4; (b) reacting the compound of formula 4 with formaldehyde and catalysts tetra-butyl ammonium fluoride (TBAF) in (1-hexyl-3-methyl-1H-imidazol-3-ium bromide = [hmim]Br) HMIM to obtain the compound of formula 1a and oxidation of compound 1a with mCPBA to obtain its corresponding oxides of formula 1aa. Wherein R1, R2and R3are as defined above. In another embodiment, the invention provides a process for the preparation of compound of formula 1ab, comprising: (a) reacting an indole of formula 2 with diselenide of formula 5 in the presence of a base in an aprotic solvent to obtain a compound of formula 6; (b) reacting the compound of formula 6 with formaldehyde and catalyst tetra-butyl ammonium fluoride (TBAF) in (1-hexyl-3-methyl-1H-imidazol-3-ium bromide = [hmim]Br) HMIM to obtain the compound of formula 1aa. Wherein R1, R2and R3are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1b, comprising: reacting the compound of formula 4 with compound of formula 7 in the presence of a base to obtain the compound of formula 1b. wherein R1, R2, R3and Y are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1c, comprising: a) reacting a substituted 3-formylindole of formula 8 with tosyl hydrazine followed by treatment with substituted arylboronic acid or thiophenols in the presence of a base in 1,4-dioxane to obtain a compound of formula 9; b) reacting compound of formula 9 with formaldehyde / TBAF / HMIMBr or substituted halides in the presence a base to obtain the compound of formula 1c. Wherein R1, R2, R3and Y are as defined above In another embodiment, the invention provides a process for the preparation of compound of formula 1d, comprising: a) reacting an indole of formula 2 with tosylchloride, NBS, triethylamine and then with substituted phenols or sulphonamides in a sequential manner in the presence of a base followed by aromatization with Lewis acid and detosylation with Cs2CO3to obtain a compound of formula 10. b) reacting compound of formula 10 with formaldehyde / TBAF / HMIMBr or substituted halides in the presence a base to obtain the compound of formula 1d. wherein R1, R2, R3and Y are as defined above In an embodiment of the present invention, the base used is selected from the group comprising sodium hydroxide, potassium carbonate, sodium hydride, and triethylamine. In an embodiment of the present invention, the aprotic solvent is selected from the group comprising dimethyl sulfoxide, dimethylformamide, acetonitrile, and tetrahydrofuran. In another embodiment, the synthesis of the compounds of general formulae (1a, 1aa, 1b, 1c, and 1d) is schematically represented below. Scheme 1: Scheme 2: Scheme 3: Scheme 4: Scheme 5: General Experimental Procedure for the Synthesis of Functionalized Indoles For general formula 1a and 1aa: A mixture of indoles (1.0 mmol), thiols or diselenide (2 mmol), and NaOH (2 mmol) in 8 mL DMSO was stirred in a 25 mL round-bottom flask at 70 °C for 6 h. The reaction progress was monitored by TLC (25% ethyl acetate in hexane). After completion of the reaction, the mixture was diluted with 10 mL of water and extracted with (3 x 25 mL) EtOAc. Now, combine the organic layer, dry over anhydrous Na2SO4, and concentrate by rotavapor. The crude product was purified by column chromatography, if needed (using 10-30% ethyl acetate in hexane) to give corresponding sulfenyl indoles. In the subsequent step, sulfenylindoles (1 mmol), formaldehyde (4 mmol), and TBAF (20 mol%) were heated in 0.5 mL neutral ionic liquid (1-hexyl-3-methyl-1H-imidazol-3-ium bromide=[hmim]Br) at 50 °C temperature for 2-100 h. The reaction progress was monitored by TLC (20-40% ethyl acetate in hexane). After completion of the reaction mixture was diluted with 10 mL water and extracted with (3 x 25 mL) EtOAc. Now, combined the organic layer, dry over anhydrous Na2SO4, and concentrate by rotavapor. The crude product was purified by column chromatography using 10-30% ethyl acetate in hexane as eluent resulting pure products of HPLC purity >90-98% and with 70-95% yield. Corresponding oxides of formula 1a were synthesized using m-CPBA in DCM. For general formula 1b: Added base K2CO3 (2-5 equiv.) to the solution containing functionalized (NH)-indoles of formula 4 in acetonitrile, stirred the reaction mixture at 60 °C to reflux temperature for 30 minutes, then alkylating agents (Y-halides) were added and heated at 60 °C to refluxing temperature till the completion of starting materials. Solvent was evaporated, diluted with DCM and partitioned with water and dried over anhydrous Na2SO4. After evaporation, pure products were obtained either through recrystallization with suitable solvents or column chromatography. For general formula 1c: To a solution of TsNHNH2 (1 equiv.) in ethanol, indole- 3carboxyaldehyde (1 equiv.) and p-toluenesulfonic acid (10 mol%) were added, and the reaction mixture was stirred at RT till completion of starting material. A minimum amount of methanol was added to the mixture, and then water was added to precipitate the hydrazine in pure form. Indole-3-tosylhydrazones (1 equiv.) was then treated with substituted boronic acids / thiols (1.5 equiv.) and K2CO3(2.0 equiv.) in 1,4-dioxane and stirred the reaction mixture at 100 °C till completion of reaction. Reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure. The desired C3-functionalized indole products 7 were obtained after column chromatography or recrystallization. Further N- alkylation / functionalization was done as Scheme 1a / 1b. For general formula 1d: Sodium hydride (1.2 equiv.) was carefully added to a solution of substituted indole in anhydrous DMSO at 0°C and stirred for 30 minutes. Then p-TsCl (1 equiv.) dissolved in anhydrous ether was dropped into the resulting solution at 0°C, and the mixture was stirred at room temperature for one hour to complete the reaction then added ice cold water. After evaporating ether, solid precipitate was filtered through sintered funnel. The solid N-tosylindole was dissolved in acetone & H2O and NBS (1.1 equiv.) was added portion- wise, and the mixture was stirred at RT till the consumption of N-tosylindole. Triethylamine (1.1 equiv.) was added & stirred further at RT to form salt, white precipitate. Salt was then treated with substituted phenols or sulphonamides (2-5 equiv.) in the presence of triethylamine in ethyl acetate and was heated under reflux till the completion of reaction, the mixture extracted with ethyl acetate-water. Combined the organic layer was dried over anhydrous Na2SO4. The product dissolved in ethyl acetate was then treated with BF3-OEt2 and heated at 50 °C till the completion of reaction. Reaction was neutralized with NaHCO3 aq., and extracted with ethyl acetate. The organic layer was dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography or recrystallization. Tosyl group was deported using Cs2CO3 (3 equiv.) in THF-MeOH mixture at RT. After the completion of reaction, solvent was evaporated, and water added to the mixture, stirred for some time, resulting formation of precipitate, washed with water and filtered, dried over vacuum to obtain product 8. EXAMPLE-1:(3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol: White solid(311 mg, yield: 93%);Rf= 0.45 (8:2 EA / hexane); M.P.108-109 ℃; HPLC purity; 99%;1H NMR (400 MHz, DMSO-d6):δ 7.87 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.42 – 7.37 (m, 3H), 7.28 – 7.24 (m, 1H), 7.15 – 7.11 (m, 1H), 7.00 – 6.96 (m, 2H), 6.62 (s, 1H), 5.59 (s, 2H).13C NMR (100 MHz, DMSO-d6): δ 138.5, 136.4, 135.3, 131.7, 129.2, 127.5, 122.6, 120.9, 118.5, 117.8, 111.5, 98.9, 69.1. HRMS (ESI): m / z calculated for C15H13BrNOS [M+H]+: 333.9896; found: 333.9889. EXAMPLE-2:(3-((4-bromophenyl)thio)-5-methyl-1H-indol-1-yl)methanol: Off-white solid (314 mg, yield: 90%);Rf= 0.45 (8:2 EA / hexane); M.P. 99-101 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3):δ 7.43 (t, J = 3.6 Hz, 2H), 7.34 (s, 1H), 7.27 – 7.25 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 5.64 (d, J = 6.2 Hz, 2H), 2.59 (t, J = 6.8 Hz, 1H), 2.42 (s, 3H).13C NMR (125 MHz, CDCl3): δ 138.6, 134.9, 133.7, 131.8, 131.3, 130.4, 127.5, 125.2, 119.6, 118.5, 110.0, 102.0, 70.3, 21.6. HRMS (ESI):m / z calculated for C16H15BrNOS [M+H]+: 348.0052; found: 348.0021. EXAMPLE-3:(3-((4-bromophenyl)thio)-5-methoxy-1H-indol-1-yl)methanol: White solid (339 mg, yield: 93%);Rf= 0.5 (7:3 EA / hexane); M.P.118-120 ℃; HPLC purity; 97%;1H NMR (400 MHz, CDCl3):δ 7.44 – 7.42 (m, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.97 – 6.94 (m, 4H), 5.62 (d, J = 6.8 Hz, 2H), 3.79 (s, 3H), 2.68 (t, J = 7.2 Hz, 1H).13C NMR (100 MHz, CDCl3): δ 155.8, 138.4, 134.0, 131.8, 131.5, 131.0, 127.5, 118.5, 113.9, 111.3, 101.9, 101.4, 70.5, 56.0. HRMS (ESI): m / z calculated for C16H15BrNO2S [M+H]+: 364.0001; found: 364.0025. EXAMPLE-4:(3-((4-bromophenyl)thio)-5-fluoro-1H-indol-1-yl)methanol: White solid (300 mg, yield: 85%); Rf = 0.45 (8:2 EA / hexane); M.P.181-183 ℃; HPLC purity; 100%;1H NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.70 (dd, J = 8.9, 4.4 Hz, 1H), 7.44 – 7.40 (m, 2H), 7.16 – 7.10 (m, 1H), 7.08 (dd, J = 9.3, 2.5 Hz, 1H), 7.00 – 6.97 (m, 2H), 6.67 (t, J = 7.3 Hz, 1H), 5.59 (d, J = 7.3 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 158.3 (d, J1= 233.8 Hz), 138.2, 137.2, 133.1, 131.9, 130.2 (d, J4= 9.9 Hz), 127.7, 118.2, 113.1 (d, J5= 9.6 Hz), 111.0 (d, J2= 25.9 Hz), 103.4 (d, J3= 23.8 Hz), 99.2 (d, J6= 4.6 Hz), 69.5.19F NMR (375 MHz, DMSO- d6): δ -122.4. HRMS (ESI): m / z calculated for C15H12BrFNOS [M+H]+: 351.9802; found: 351.9824. EXAMPLE-5: (3-((4-bromophenyl)thio)-5-chloro-1H-indol-1-yl)methanol: White solid (313 mg, yield: 85%); Rf= 0.5 (7:3 EA / hexane); M.P. 155-157 ℃; HPLC purity; 100%;1H NMR (400 MHz, DMSO-d6):δ 7.96 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.35 (d, J = 1.7 Hz, 1H), 7.29 (dd, J = 8.7, 2.0 Hz, 1H), 7.00 – 6.97 (m, 2H), 6.70 (t, J = 7.0 Hz, 1H), 5.59 (d, J = 6.6 Hz, 2H).13C NMR (100 MHz, DMSO-d6): δ 138.0, 136.9, 134.8, 131.8, 130.5, 127.5, 125.8, 122.6, 118.0, 117.5, 113.3, 98.7, 69.3. HRMS (ESI):m / z calculated forC15H12BrClNOS [M+H]+: 367.9506; found: 367.9513. EXAMPLE-6:(3-((4-bromophenyl)thio)-5-iodo-1H-indol-1-yl)methanol: Brown solid (415 mg, yield: 93%);Rf = 0.5 (7:3 EA / hexane); M.P.89-91 ℃; HPLC purity; 98%;1H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.68 (t, J = 0.9 Hz, 1H), 7.55 (s, 2H), 7.44 – 7.41 (m, 2H), 6.99 – 6.96 (m, 2H), 6.69 (s, 1H), 5.58 (s, 2H).13C NMR (100 MHz, DMSO-d6):δ 138.0, 136.3, 135.5, 131.8, 131.8, 130.6, 127.4, 126.6, 118.0, 114.0, 98.1, 85.1, 69.3. HRMS (ESI):m / z calculated for C15H12BrINOS [M+H]+: 459.8862; found: 459.8877. EXAMPLE-7:3-((4-bromophenyl)thio)-1-(hydroxymethyl)-1H-indole-5-carbonitrile: White solid (310 mg, yield: 86%);Rf= 0.45 (6:4 EA / hexane); M.P.151-152 ℃; HPLC purity; 99%;1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H) 7.87 – 7.87 (m, 1H), 7.66 (dd, J = 8.6, 1.6 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.04 – 7.01 (m, 2H), 6.82 (t, J = 7.4 Hz, 1H), 5.66 (d, J = 7.4 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 138.3, 138.0, 137.7, 132.1, 129.3, 128.2, 125.7, 123.9, 120.2, 118.6, 113.2, 103.5, 100.9, 69.6.HRMS (ESI):m / z calculated for C16H12BrN2OS [M+H]+: 358.9848; found: 358.9857. EXAMPLE-8:(3-((4-bromophenyl)thio)-5-nitro-1H-indol-1-yl)methanol: Yellow solid (266 mg, yield: 70%);Rf= 0.5 (6:4 EA / hexane); M.P. 150-153 ℃; HPLC purity; 96%;1H NMR (400 MHz, DMSO-d6):δ 8.24 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 8.17 (dd, J = 9.0, 2.3 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.06 – 7.03 (m, 2H), 6.89 (t, J = 7.4 Hz, 1H), 5.68 (d, J = 7.0 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 142.2, 139.4, 139.1, 137.4, 132.1, 128.8, 127.9, 118.5, 118.0, 114.9, 112.6, 102.1, 69.8.HRMS (ESI): m / z calculated for C15H12BrN2O3S [M+H]+: 378.9747; found: 378.9772. EXAMPLE-9:(4-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol: Pink solid (356 mg, yield: 86%);Rf= 0.45 (7:3 EA / hexane); M.P. 131-132 ℃; HPLC purity; 99%;1H NMR (400 MHz, CDCl3):δ 7.50 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.30 – 7.27 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 6.96 – 6.93 (m, 2H), 5.64 (d, J = 6.8 Hz, 2H), 2.78 (t, J = 7.2 Hz, 1H).13C NMR (100 MHz, CDCl3):δ 140.2, 137.7, 136.0, 131.8, 127.6, 127.3, 126.6, 124.4, 118.5, 114.9, 109.8, 103.3, 70.4. HRMS (ESI): m / z calculated for C15H12Br2NOS [M+2+H]+: 413.9001; found: 413.8978. EXAMPLE-10:(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol: White solid (391 mg, yield: 93%); Rf= 0.45 (7:3 EA / hexane); M.P.151-152 ℃; HPLC purity; 100%;1H NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.44 – 7.39 (m, 3H), 7.00 – 6.97 (m, 2H), 6.71 (t, J = 6.6 Hz, 1H), 5.60 (s, 2H).13C NMR (100 MHz, DMSO-d6):δ 138.0, 136.8, 135.1, 131.8, 131.1, 127.5, 125.1, 120.5, 118.0, 113.7, 98.5, 69.3. HRMS (ESI): m / z calculated for C15H12Br2NOS [M+H]+: 411.9001; found: 411.9020. EXAMPLE-11:(6-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol: White solid (373 mg, yield: 90%); Rf= 0.45 (7:3 EA / hexane); M.P. 136-138 ℃; HPLC purity; 98%;1H NMR (400 MHz, CDCl3):δ 7.72 (d, J = 1.4 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31 – 7.25 (m, 3H), 6.96 – 6.92 (m, 2H), 5.63 (d, J = 6.8 Hz, 2H), 2.70 (t, J = 7.0 Hz, 1H).13C NMR (125 MHz, CDCl3):δ 137.8, 137.4, 133.9, 131.9, 129.0, 127.8, 125.1, 121.4, 118.9, 117.4, 113.6, 103.4, 70.4. HRMS (ESI): m / z calculated for C15H12Br2NOS [M+2+H]+: 413.9001; found: 413.8992. EXAMPLE-12:(5-bromo-3-((2-bromophenyl)thio)-1H-indol-1-yl)methanol: White solid (361 mg, yield: 87%);Rf= 0.45 (7:3 EA / hexane); M.P. 128-130 ℃; HPLC purity; 94%;1H NMR (400 MHz, DMSO-d6):δ 7.99 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 7.9, 1.2 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 8.7, 1.9 Hz, 1H), 7.17 (td, J = 7.5, 1.3 Hz, 1H), 7.05 (td, J = 7.7, 1.6 Hz, 1H), 6.74 (t, J = 7.0 Hz, 1H), 6.54 (dd, J = 8.0, 1.6 Hz, 1H), 5.62 (d, J = 6.7 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 139.3, 137.2, 135.2, 132.7, 131.1, 128.2, 126.5, 126.0, 125.3, 120.4, 119.0, 113.8, 97.9, 69.4. HRMS (ESI): m / z calculated for C15H12Br2NOS [M+2+H]+: 413.9001; found: 413.8981. EXAMPLE-13:(5-bromo-3-(p-tolylthio)-1H-indol-1-yl)methanol: White solid (321 mg, yield: 92%);Rf = 0.45 (7:3 EA / hexane); M.P.102-104 ℃; HPLC purity; 99%;1H NMR (400 MHz, CDCl3): δ 7.74 (t, J = 1.3 Hz, 1H), 7.42 (s, 1H), 7.38 (d, J = 0.9 Hz, 2H), 7.03 – 7.7.01 (m, 2H), 7.00 – 6.98 (m, 2H), 5.60 (d, J = 2.9 Hz, 2H), 2.64 (s, 1H), 2.26 (s, 3H).13C NMR (125 MHz, CDCl3):δ 135.4, 135.2, 134.6, 134.2, 132.2, 129.8, 126.8, 126.3, 122.7, 115.1, 111.8, 103.8, 70.3, 21.0. HRMS (ESI): m / z calculated for C16H14BrNOSNa [M+Na]+: 369.9872; found: 369.9881. EXAMPLE-14:(5-bromo-3-((4-methoxyphenyl)thio)-1H-indol-1-yl)methanol: White solid (256 mg, yield: 70%); Rf = 0.45 (7:3 EA / hexane); M.P.79-80 ℃; HPLC purity; 98%;1H NMR (400 MHz, CDCl3):δ 7.75 (t, J = 1.2 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J = 1.1 Hz, 2H), 7.15 – 7.12 (m, 2H), 6.77 – 6.73 (m, 2H), 5.60 (s, 2H), 3.74 (s, 3H), 2.74 (s, 1H).13C NMR (125 MHz, CDCl3):δ 158.3, 135.2, 133.8, 132.1, 129.3, 128.6, 126.3, 122.7, 115.0, 114.8, 111.8, 105.0, 70.3, 55.5. HRMS (ESI): m / z calculated for C16H15BrNO2S [M+H]+: 364.0001; found: 364.0024. EXAMPLE-15:(5-bromo-3-((3-methoxyphenyl)thio)-1H-indol-1-yl)methanol: White solid (339 mg, yield: 93%); Rf = 0.45 (8:2 EA / hexane); M.P. 110-112 ℃; HPLC purity; 99%;1H NMR (400 MHz, CDCl3):δ 7.75 – 7.74 (m, 1H), 7.45 (s, 1H), 7.42 – 7.37 (m, 2H), 7.12 – 7.07 (m, 1H), 6.69 – 6.66 (m, 1H), 6.64 – 6.61 (m, 2H), 5.63 (d, J = 6.8 Hz, 2H), 3.70 (s, 3H), 2.72 (t, J = 7.3 Hz, 1H).13C NMR (125 MHz, CDCl3): δ 160.1, 140.0, 135.3, 134.6, 132.3, 129.8, 126.5, 122.7, 118.6, 115.2, 112.1, 111.9, 110.6, 102.8, 70.4, 55.4. HRMS (ESI): m / z calculated for C16H15BrNO2S [M+H]+: 364.0001; found: 364.0002. EXAMPLE-16:(5-bromo-3-((4-chlorophenyl)thio)-1H-indol-1-yl)methanol: White solid (332 mg, yield: 90%);Rf= 0.5 (7:3 EA / hexane); M.P.132-133 ℃; HPLC purity; 99%;1H NMR (400 MHz, CDCl3):δ 7.70 (s, 1H), 7.47 (s, 1H), 7.41 (s, 2H), 7.16 – 7.12 (m, 2H), 7.02 – 6.99 (m, 2H), 5.64 (d, J = 5.2 Hz, 2H), 2.65 (t, J = 6.8 Hz, 1H).13C NMR (125 MHz, CDCl3): δ 137.1, 135.3, 134.6, 132.0, 131.2, 129.1, 127.5, 126.6, 122.6, 115.3, 112.0, 102.7, 70.4. HRMS (ESI): m / z calculated for C15H12BrClNOS [M+2+H]+: 369.9506; found: 369.9478. White solid (314 mg, yield: 89%); Rf = 0.45 (7:3 EA / hexane); M.P.106-108 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3):δ 7.71 (t, J = 1.1 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J = 1.1 Hz, 2H), 7.11 – 7.06 (m, 2H), 6.92 – 6.86 (m, 2H), 5.62 (d, J = 7.0 Hz, 2H), 2.72 (t, J = 7.4 Hz, 1H).13C NMR (125 MHz, CDCl3):δ 161.3 (d, J1= 243.1 Hz), 135.2, 134.3, 133.2 (d, J4= 3.1 Hz), 132.0, 128.4 (d, J3= 7.8 Hz), 126.5, 122.6, 116.1 (d, J2= 21.9 Hz), 115.2, 111.9, 103.7, 70.3.19F NMR (375 MHz, CDCl3):δ -117.4. HRMS (ESI): m / z calculated for C15H12BrFNOS [M+H]+: 351.9802; found: 351.9794. EXAMPLE-18:(5-bromo-3-(phenylthio)-1H-indol-1-yl)methanol: White solid (294 mg, yield: 88%);Rf = 0.45 (7:3 EA / hexane); M.P.130-132 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3):δ 7.74 – 7.74 (m, 1H), 7.46 (s, 1H), 7.43 – 7.38 (m, 2H), 7.20 – 7.16 (m, 2H), 7.10 – 7.06 (m, 3H), 5.64 (d, J = 7.1 Hz, 2H), 2.66 (t, J = 7.5 Hz, 1H).13C NMR (100 MHz, CDCl3):δ 138.4, 135.3, 134.5, 132.3, 129.0, 126.4, 126.3, 125.4, 122.7, 115.2, 111.9, 103.1, 70.4. HRMS (ESI):m / z calculated for C15H13BrNOS [M+H]+: 333.9896; found: 333.9840. EXAMPLE-19:(5-bromo-3-(naphthalen-2-ylthio)-1H-indol-1-yl)methanol: White solid(346 mg, yield: 90%);Rf = 0.45 (7:3 EA / hexane); M.P.147-148 ℃; HPLC purity; 100%;1H NMR (400 MHz, DMSO-d6):δ 8.00 (s, 1H), 7.83 – 7.79 (m, 2H), 7.70 – 7.68 (m, 2H), 7.58 (s, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.47 – 7.39 (m, 3H), 7.23 (dd, J = 8.6, 1.6 Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 5.62 (d, J = 7.3 Hz, 2H).13C NMR (100 MHz, DMSO-d6): δ 136.7, 135.7, 135.1, 133.3, 131.4, 131.0, 128.6, 127.7, 126.8, 126.8, 125.5, 125.1, 124.5, 123.4, 120.6, 113.7, 113.6, 99.3, 69.4. HRMS (ESI): m / z calculated for C19H15BrNOS [M+H]+: 384.0052; found: 384.0068. EXAMPLE-20: (3-(benzylthio)-5-bromo-1H-indol-1-yl)methanol: Yellowish viscous(314 mg, yield: 90%);Rf= 0.45 (7:3 EA / hexane); HPLC purity; 89%;1H NMR (400 MHz, CDCl3):δ 7.70 (dd, J = 1.8, 0.7 Hz, 1H), 7.35 (dd, J = 8.6, 1.8 Hz, 1H), 7.32 (dd, J = 8.6, 0.6 Hz, 1H), 7.22 – 7.19 (m, 3H), 7.06 – 7.04 (m, 2H), 6.95 (s, 1H), 5.48 (d, J = 6.8 Hz, 2H), 3.82 (s, 2H), 2.49 (t, J = 7.2 Hz, 1H).13C NMR (125 MHz, CDCl3):δ 138.8, 134.9, 133.8, 132.5, 129.2, 128.4, 127.1, 126.0, 122.5, 114.8, 111.6, 105.4, 70.1, 41.2. HRMS (ESI):m / z calculated for C16H15BrNOS [M+H]+: 348.0052; found: 348.0031. EXAMPLE-21:(5-bromo-3-((2,4,5-trichlorophenyl)thio)-1H-indol-1-yl)methanol: White solid (315 mg, yield: 72%); Rf= 0.45 (7:3 EA / hexane); M.P. 164-165 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3): δ 7.69 – 7.68 (m, 1H), 7.51 (s, 1H), 7.48 – 7.45 (m, 2H), 7.44 (s, 1H), 6.64 (s, 1H), 5.68 (d, J = 3.7 Hz, 2H), 2.77 (t, J = 6.5 Hz, 1H).13C NMR (125 MHz, CDCl3):δ 138.6, 135.5, 135.4, 131.8, 131.6, 130.7, 129.3, 129.0, 127.1, 127.0, 122.3, 115.8, 112.3, 100.0, 70.6. HRMS (ESI): m / z calculated for C15H10BrCl3NOS [M+H]+: 435.8727; found: 435.8734. EXAMPLE-22:(5-bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indol-1-yl)methanol: White solid (326 mg, yield: 81%);Rf= 0.45 (7:3 EA / hexane); M.P.134-136 ℃; HPLC purity; 98%;1H NMR (400 MHz, DMSO-d6):δ 8.00 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.7, 1.9 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 6.74 (s, 1H), 5.62 (d, J = 2.2 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 144.5, 137.1, 135.2, 131.1, 125.8 (q, J3= 3.2 Hz), 125.5 (q, J2= 31.7 Hz), 125.3, 124.3 (q, J1= 270.0 Hz), 120.5, 113.9, 113.8, 97.4, 69.4.19F NMR (375 MHz, DMSO-d6):δ -56.0. HRMS (ESI):m / z calculatedfor C16H12BrF3NOS [M+H]+: 401.9770; found: 401.9810. EXAMPLE-23:(5-bromo-3-(thiazol-2-ylthio)-1H-indol-1-yl)methanol: White solid (301 mg, yield: 88%); Rf = 0.45 (7:3 EA / hexane); M.P.156-157 ℃; HPLC purity; 98%;1H NMR (400 MHz, DMSO-d6):δ 8.08 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 3.4 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.48 (d, J = 3.4 Hz, 1H), 7.43 (dd, J = 8.7, 1.9 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 5.61 (d, J = 7.4 Hz, 2H).13C NMR (100 MHz, DMSO-d6): δ 168.7, 143.5, 137.2, 135.2, 130.7, 125.6, 120.8, 120.7, 114.3, 114.0, 98.4, 69.6. HRMS (ESI):m / z calculated for C12H10BrN2OS2 [M+H]+: 340.9412; found: 340.9422. EXAMPLE-24:(5-bromo-3-(pyridin-2-ylthio)-1H-indol-1-yl)methanol: White solid (293 mg, yield: 87%);Rf = 0.45 (7:3 EA / hexane); M.P. 120-122 ℃; HPLC purity; 97%;1H NMR (400 MHz, DMSO-d6):δ 8.38 – 8.36 (m, 1H), 7.94 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.55 (td, J = 7.7, 1.9 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.7, 1.9 Hz, 1H), 7.10 – 7.07 (m, 1H), 6.74 – 6.70 (m, 2H), 5.60 (d, J = 7.4 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 161.1, 149.3, 137.2, 136.8, 135.1, 131.4, 125.1, 120.6, 120.0, 119.2, 113.7, 113.7, 98.0, 69.4. HRMS (ESI):m / z calculated for C14H12BrN2OS [M+H]+: 334.9848; found: 334.9849. EXAMPLE-25:(3-(benzo[d]thiazol-2-ylthio)-5-bromo-1H-indol-1-yl)methanol: White solid (372 mg, yield: 95%);Rf = 0.45 (7:3 EA / hexane); M.P. 127-129 ℃; HPLC purity; 98%;1H NMR (400 MHz, DMSO-d6):δ 8.18 (s, 1H), 7.85 – 7.81 (m, 2H), 7.74 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 8.8, 1.9 Hz, 1H), 7.45 – 7.41 (m, 1H), 7.31 – 7.27 (m, 1H), 6.85 (t, J = 7.4 Hz, 1H), 5.64 (d, J = 7.4 Hz, 2H).13C NMR (100 MHz, DMSO-d6): δ 171.8, 154.0, 137.7, 135.1, 134.9, 130.7, 126.3, 125.6, 124.2, 121.7, 121.2, 120.5, 114.4, 114.0, 96.9, 69.6. HRMS (ESI):m / z calculated for C16H12BrN2OS2[M+H]+: 390.9569; found: 390.9581. EXAMPLE-26:(5-bromo-3-(ethylthio)-1H-indol-1-yl)methanol: White solid (238 mg, yield: 83%);Rf= 0.5 (7:3 EA / hexane); M.P. 63-65 ℃; HPLC purity; 96%;1H NMR (400 MHz, CDCl3): δ 7.87 – 7.78 (m, 1H), 7.38 – 7.32 (m, 2H), 7.28 (s, 1H), 5.56 (d, J = 6.1 Hz, 2H), 2.78 (t, J = 6.9 Hz, 1H), 2.69 (q, J = 7.4 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3):δ 135.0, 133.3, 132.6, 126.0, 122.5, 114.7, 111.7, 105.9, 70.1, 30.4, 15.3. HRMS (ESI):m / z calculated for C11H13BrNOS [M+H]+: 285.9896; found: 285.9868. EXAMPLE-27:(5-bromo-3-(dodecylthio)-1H-indol-1-yl)methanol: Brown solid (331 mg, yield: 77%); Rf= 0.45 (8:2 EA / hexane); M.P. 56-58 ℃; HPLC purity; 93%;1H NMR (400 MHz, CDCl3):δ7.88 – 7.87 (m, 1H), 7.36 (d, J = 1.8 Hz, 2H), 7.29 (s, 1H), 5.58 (s, 2H), 2.67 (t, J = 7.3 Hz, 2H), 1.57 – 1.49 (m, 3H), 1.40 – 1.33 (m, 2H), 1.30 – 1.24 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H).13C NMR (100 MHz, CDCl3):δ 135.0, 133.0, 132.6, 126.0, 122.6, 114.6, 111.6, 106.5, 70.2, 36.6, 32.1, 30.0, 29.8, 29.8, 29.7, 29.7, 29.5, 29.4, 28.7, 22.8, 14.3. HRMS (ESI):m / z calculatedfor C21H33BrNOS [M+H]+: 426.1461; found: 426.1424. EXAMPLE-28:(3-((4-bromophenyl)thio)-2-phenyl-1H-indol-1-yl)methanol: White viscous(312 mg, yield: 76%); Rf= 0.45 (8:2 EA / hexane); HPLC purity; 95%;1H NMR (400 MHz, CDCl3):δ 7.60 – 7.56 (m, 2H), 7.49 – 7.46 (m, 5H), 7.38 – 7.34 (m, 1H), 7.25 – 7.22 (m, 3H), 6.92 – 6.88 (m, 2H), 5.60 (s, 2H), 2.59 (s, 1H).13C NMR (100 MHz, CDCl3):δ 145.5, 138.7, 136.8, 131.8, 130.7, 129.9, 129.4, 128.7, 127.4, 123.8, 122.1, 120.1, 118.3, 110.1, 101.7, 67.9. HRMS (ESI): m / z calculated for C21H17BrNOS [M+H]+: 410.0209; found: 410.0228. EXAMPLE-29:ethyl 1-(hydroxymethyl)-3-(phenylthio)-1H-indole-2-carboxylate: White solid (230 mg, yield: 70%); Rf = 0.45 (8:2 EA / hexane); M.P.87-89 ℃; HPLC purity; 98%;1H NMR (400 MHz, CDCl3):δ 7.60 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.20 – 7.16 (m, 3H), 7.15 – 7.12 (m, 2H), 7.11 – 7.07 (m, 1H), 5.78 (d, J = 6.8 Hz, 2H), 4.63 (t, J = 8.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).13C NMR (125 MHz, CDCl3): δ 163.2, 138.0, 138.0, 130.0, 128.9, 128.9, 127.3, 126.6, 125.5, 122.1, 122.1, 113.0, 110.5, 68.6, 62.1, 14.1. HRMS (ESI):m / zcalculated for C18H17NO3SNa [M+Na]+: 350.0821; found : 350.0830. EXAMPLE-30:(5-fluoro-3-(phenylselanyl)-1H-indol-1-yl)methanol: Brown solid (282 mg, yield: 88%); Rf= 0.5 (7:3 EA / hexane); M.P. 87-90 ℃; HPLC purity; 96%;1H NMR (400 MHz, CDCl3):δ 7.49 (s, 1H), 7.45 (dd, J = 8.9, 4.1 Hz, 1H), 7.28 – 7.22 (m, 3H), 7.17 – 7.09 (m, 3H), 7.04 (td, J = 9.0, 2.5 Hz, 1H), 5.64 (s, 2H), 2.76 (s, 1H).13C NMR (125 MHz, CDCl3):δ 159.1 (d, J1= 235.7 Hz), 135.5, 133.0 (d, J4= 23.1 Hz), 132.2 (d, J5= 10.0 Hz), 129.2, 129.1, 126.1, 111.7 (d, J2= 26.3 Hz), 111.1 (d, J6= 9.5 Hz), 106.0 (d, J3= 24.0 Hz), 98.4 (d, J7= 4.7 Hz), 70.3.19F NMR (375 MHz, CDCl3):δ -122.2. HRMS (ESI): m / z calculated for C15H13FNOSe [M+H]+: 322.0141; found: 322.0151. EXAMPLE-31:(5-bromo-3-((4-bromophenyl)sulfonyl)-1H-indol-1-yl)methanol: White solid(305 mg, yield: 79%); Rf=0.5 (6:4 EA / hexane); M.P.192-193 ℃; HPLC purity; 94%;1H NMR (400 MHz, DMSO-d6):δ 8.39 (s, 1H), 7.93 – 7.89 (m, 3H), 7.82 – 7.79 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.8, 1.9 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 5.60 (d, J = 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d6):δ 142.1, 135.5, 134.7, 132.7, 128.3, 127.1, 126.3, 125.4, 120.8, 115.4, 114.4, 113.3, 70.1. HRMS (ESI):m / z calculated for C15H12Br2NO3S [M+H]+= 443.8899; found = 443.8895. EXAMPLE-32:5-bromo-3-((4-bromophenyl)thio)-1-methyl-1H-indole: White solid (up to 83% yield);Rf = 0.45 (9:1 EA / hexane); M.P.144-147 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.7, 1.8 Hz, 1H), 7.32 (s, 1H), 7.29 – 7.24 (m, 3H), 6.94 – 6.90 (m, 2H), 3.84 (s, 3H).13C NMR (100 MHz, CDCl3):δ 138.6, 136.4, 136.4, 131.9, 131.5, 127.5, 125.9, 122.2, 118.6, 114.6, 111.5, 100.0, 33.5. HRMS(ESI): m / z calculated for C15H12Br2NS [M+H]+: 395.9052; found: 395.9064. EXAMPLE-33:5-bromo-1-methyl-3-(p-tolylthio)-1H-indole: White solid(90% yield); Rf=0.45 (9:1 EA / hexane); M.P.119-122 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3):δ 7.74 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 8.6, 1.9 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.01 – 6.97 (m, 4H), 3.82 (s, 3H), 2.25 (s, 3H).13C NMR (100 MHz, CDCl3):δ 136.3, 136.1, 135.5, 135.0, 131.7, 129.7, 126.4, 125.7, 122.4, 114.3, 111.4, 101.3, 33.4, 21.0. EXAMPLE-34:5-bromo-1-ethyl-3-(p-tolylthio)-1H-indole: White solid (90% yield);Rf=0.5 (9:1 EA / hexane); M.P.64-66 ℃; HPLC purity; 99%;1H NMR (400 MHz, CDCl3):δ 7.74 (d, J = 1.9 Hz, 1H), 7.37 (s, 1H), 7.34 (dd, J = 8.7, 1.9 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.99 (s, 4H), 4.18 (q, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.50 (t, J = 7.3 Hz, 3H).13C NMR (125 MHz, CDCl3):δ 135.6, 135.4, 134.9, 134.4, 131.9, 129.7, 126.3, 125.5, 122.5, 114.2, 111.4, 101.3, 41.7, 21.0, 15.4. HRMS (ESI):m / z calculated for C17H17BrNS [M+2+H]+: 348.0260; found:348.0236. EXAMPLE-35:5-bromo-1-(oxiran-2-ylmethyl)-3-(phenylthio)-1H-indole: White solid (50% yield); Rf = 0.45 (6:4 EA / H); M.P: 82-84 ℃; HPLC purity; 100%;1H NMR (400 MHz, CDCl3):δ 7.74 (d, J = 1.7 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J = 8.7, 1.8 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.19 – 7.15 (m, 2H), 7.09 – 7.05 (m, 3H), 4.50 (dd, J = 15.3, 2.7 Hz, 1H), 4.14 (dd, J = 15.3, 5.7 Hz, 1H), 3.32 – 3.29 (m, 1H), 2.85 (t, J = 4.3 Hz, 1H), 2.48 (dd, J = 4.6, 2.5 Hz, 1H).13C NMR (100 MHz, CDCl3):δ 138.9, 136.1, 135.7, 131.8, 129.0, 126.1, 126.0, 125.2, 122.6, 114.7, 111.7, 101.9, 50.7, 48.5, 45.2. HRMS (ESI):m / z calculated for C17H15BrNOS [M+H]+: 360.0052; found: 360.0063. EXAMPLE-36:2-(5-bromo-3-(p-tolylthio)-1H-indol-1-yl)ethan-1-ol: Pink viscous (312 mg, 86% yield); Rf = 0.45(6:4 EA / H); HPLC purity; 97%;1H NMR (400 MHz, CDCl3):δ 7.75 (d, J = 1.8 Hz, 1H), 7.43 (s, 1H), 7.34 (dd, J = 8.7, 1.8 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.02 – 6.97 (m, 4H), 4.27 (t, J = 5.1 Hz, 2H), 3.99 – 3.96 (m, 2H), 2.26 (s, 3H), 1.65 (s, 1H).13C NMR (125 MHz, CDCl3): δ 135.8, 135.6, 135.2, 135.1, 131.9, 129.7, 126.5, 125.8, 122.6, 114.4, 111.6, 102.0, 61.9, 49.2, 21.0. HRMS (ESI):m / z calculated for C17H17BrNOS [M+2+H]+: 364.0209; found: 364.0209. EXAMPLE-37:3-(5-bromo-3-(p-tolylthio)-1H-indol-1-yl)propan-1-ol: White viscous (251 mg, 66% yield); Rf = 0.45(6:4 EA / H); HPLC purity; 95%;1H NMR (400 MHz, CDCl3):δ 7.74 (dd, J = 1.8, 0.5 Hz, 1H), 7.39 (s, 1H), 7.34 (dd, J = 8.8, 1.8 Hz, 1H), 7.30 (dd, J = 8.6, 0.5 Hz, 1H), 6.98 (s, 4H), 4.31 (t, J = 6.7 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H), 2.26 (s, 3H), 2.11 – 2.04 (m, 2H).13C NMR (125 MHz, CDCl3): δ 135.7, 135.5, 135.3, 135.0, 131.8, 129.7, 126.3, 125.6, 122.5, 114.2, 111.6, 101.5, 59.1, 43.2, 32.5, 21.0. HRMS (ESI):m / z calculated for C18H19BrNOS [M+H]+: 376.0365; found: 376.0373. EXAMPLE-38: (5-chloro-3-((2,4-dichlorophenyl)thio)-1H-indol-1-yl)methanol: White Solid (74% yield); Rf = 0.3 (2:8 EA / H); HPLC purity; 98%;1H NMR (500 MHz, CDCl3): δ 7.51 – 7.49 (m, 3H), 7.36 (d, J = 2.30 Hz, 1H), 7.30 (dd, J = 8.70, 2.15 Hz, 1H), 6.94 (dd, J = 8.55, 2.10 Hz, 1H), 6.54 (d, J = 8.55 Hz, 1H), 5.67 (s, 2H), 2.78 (s, 1H);13C NMR (125 MHz, CDCl3): δ 136.6, 135.3, 135.1, 131.3, 131.0, 130.9, 129.3, 128.0, 127.5, 127.3, 124.2, 119.4, 111.8, 100.8, 70.5. EXAMPLE-39: 5-bromo-3-((4-bromophenyl)thio)-2-phenyl-1H-indole: Greenish white solid (50% yield); Rf = 0.2 (1:9 EA / H); HPLC purity; 97%;1H NMR (500 MHz, CDCl3): δ 8.64 (s, 1H), 7.73 – 7.70 (m, 3H), 7.46 – 7.40 (m, 3H), 7.37 – 7.32 (m, 2H), 7.28 (d, J = 8.60 Hz, 2H), 6.92 (d, J = 8.55 Hz, 2H);13C NMR (125 MHz, CDCl3): δ 143.6, 138.2, 134.6, 132.9, 132.1, 130.8, 129.4, 129.1, 128.2, 127.2, 126.6, 122.4, 118.6, 114.9, 112.9, 98.6. Mass (ESI): m / z calculated for C20H13Br2NS [M-H]- : 455.91; found: 456. EXAMPLE-40: 5-bromo-3-((2,4-difluorophenyl)thio)-2-phenyl-1H-indole: White Solid (50% yield); Rf = 0.2 (1:10 EA / H); HPLC purity; 100%;1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 7.75 – 7.72 (m, 3H), 7.48 – 7.41 (m, 3H), 7.37 (dd, J = 8.55, 1.95 Hz, 1H), 7.32 (d, J = 8.55 Hz, 1H), 6.83 – 6.79 (m, 1H), 6.72 – 6.67 (m, 1H), 6.64 – 6.60 (m, 1H);13C NMR (125 MHz, CDCl3): δ 162.1 (d, J5 = 10.96 Hz), 160.1 (d, J3 = 11.42 Hz), 158.2 (d, J4 = 11.41 Hz), 143.8, 134.6, 131.9 (d, J1 = 273.08 Hz), 129.4, 129.1, 128.6 (d, J6 = 4.1 Hz), 128.5 (d, J6 = 4.1 Hz), 128.2, 126.7, 122.4, 121.3, 121.1, 114.9, 112.9, 112.0 (d, J1 = 3.66 Hz), 111.8 (d, J7 = 3.7 Hz), 104.3 (t, J2 = 25.6 Hz), 97.3. Mass (ESI):m / z calculated for C20H12BrF2NS [M- H]- : 413.98; found: 414. Example 41: 3-((4-bromophenyl)thio)-5-chloro-1H-indole-2-carboxylic acid: Light brownish white solid (53% yield); Rf = 0.25 (5:5 EA / H); HPLC purity; 98%;1H NMR (500 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.53 (d, J = 8.65 Hz, 1H), 7.40 – 7.38 (m, 2H), 7.36 (d, J = 2.15 Hz, 1H), 7.29 (dd, J = 8.70, 2.15 Hz, 1H), 7.00 – 6.97 (m, 2H);13C NMR (100 MHz, DMSO-d6): δ 162.0, 137.9, 134.3, 131.7, 130.3, 128.1, 125.6, 124.9, 118.7, 117.8, 115.0, 103.7. Mass (ESI): m / z calculated for C15H9BrClNO2S [M-H]-: 379.9; found: 380. Example 42: 5-bromo-3-((4-bromophenyl)thio)-1-(prop-2-yn-1-yl)-1H-indole: Light yellowish white solid (95% yield); Rf = 0.3 (1:19 EA / H); HPLC purity; 99%;1H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 1.95 Hz, 1H), 7.50 (s, 1H), 7.40 (dd, J = 8.70, 1.85 Hz, 1H), 7.33 (d, J = 8.75 Hz, 1H), 7.28 – 7.27 (m, 2H), 6.93 (d, J = 8.55 Hz, 2H), 4.90 (d, J = 2.60 Hz, 2H), 2.50 (t, J = 2.60 Hz, 1H);13C NMR (125 MHz, CDCl3): δ 138.1, 135.4, 134.8, 131.9, 131.8, 127.6, 126.3, 122.5, 118.8, 115.0, 111.7, 101.4, 76.5, 75.1, 36.6. Example 43: 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)acetonitrile: White solid (97% yield); Rf = 0.3 (2:8 EA / H); HPLC purity; 100%;1H NMR (500 MHz, CDCl3): δ 7.72 (s, 1H), 7.48 (d, J = 8.75 Hz, 1H), 7.40 (s, 1H), 7.33 – 7.30 (m, 3H), 6.95 (d, J = 8.70 Hz, 2H), 5.04 (s, 2H);13C NMR (125 MHz, CDCl3): δ 137.1, 135.3, 134.2, 132.1, 131.7, 128.0, 127.4, 123.1, 119.3, 116.0, 113.6, 111.1, 104.5, 34.8. Mass (ESI): m / z calculated for C16H10Br2N2S [M-H]- : 418.89; found: 419. Example 44: 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)ethan-1-amine hydrochloride: White solid (91% yield); HPLC purity; 100%;1H NMR (500 MHz, DMSO- d6): δ 8.26 (s, 3H), 7.97 (s, 1H), 7.74 (d, J = 8.70 Hz, 1H), 7.48 (d, J = 2.00 Hz, 1H), 7.43 – 7.40 (m, 3H), 7.03 (d, J = 8.55 Hz, 2H), 4.56 (t, J = 6.40 Hz, 2H), 3.29 (t, J = 6.40 Hz, 2H);13C NMR (125 MHz, DMSO-d6): δ 137.9, 137.2, 135.8, 131.8, 130.9, 127.6, 125.2, 120.6, 118.0, 113.6, 113.3, 98.6, 43.6, 38.5. Mass (ESI): m / z calculated for C16H15Br2ClN2S [M-H]- : 458.9; found: 459. Example 45: White solid (90% yield); Rf = 0.3 (1.5:8.5 EA / H);1H NMR (400 MHz, CDCl3): δ 11.38 (s, 1H), 8.37 (t, J = 5.8 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.72 Hz, 1H), 7.37-7.35 (m, 2H), 7.29-7.26 (m, 2H), 6.92-6.89 (m, 2H), 4.38 (t, J = 6.4 Hz, 2H), 3.80 (q, J = 6.2 Hz, 2H), 1.52 (s, 9H), 1.42 (s, 9H). Mass (ESI): m / z calculated for C27H32Br2N4O4S [M+H]+: 667.05; found: 667.1. Example 46: 8-bromo-10-((4-bromophenyl)thio)-1,2,3,4-tetrahydro-2l4-pyrazino[4,3- a]indole: White solid (65% yield);1H NMR (500 MHz, DMSO-d6): δ 9.51 (s, 1H), 7.61 (d, J = 8.70 Hz, 1H), 7.53 (s, 1H), 7.43 – 7.40 (m, 3H), 7.03 (d, J = 8.55 Hz, 2H), 4.51 (s, 2H), 4.43 (t, J = 5.50 Hz, 2H), 3.74 (t, J = 5.50 Hz, 2H);13C NMR (125 MHz, DMSO-d6): δ 136.8, 135.1, 132.0, 131.9, 130.4, 127.8, 125.3, 120.1, 120.1, 118.4, 114.4, 112.8, 72.5, 63.1, 39.8. Mass (ESI):m / z calculated for C17H14Br2N2S [M+H]+: 436.92; found: 436.9. Examples 47: tert-butyl (Z)-((8-bromo-10-((4-bromophenyl)thio)-3,4-dihydropyrazino[1,2- a]indol-2(1H)-yl)((tert-butoxycarbonyl)imino)methyl)carbamate: Yellowish white solid (88%); Rf = 0.3 (2:8 EA / H);1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 7.69 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.08 Hz, 2H), 7.22 (d, J = 8.64 Hz, 1H), 6.87 (d, J = 8.08 Hz, 2H), 4.86 (s, 2H), 4.28 (t, J = 4.82 Hz, 2H), 4.11 (brs, 2H), 1.48 (s, 18H). Mass (ESI): m / z calculated for C28H32Br2N4O4S [M+H]+:679.05; found: 679.0. Example 48: 2-(5-bromo-3-(4-bromophenoxy)-1H-indol-1-yl)ethan-1-amine hydrochloride: White solid (74% yield);1H NMR (400 MHz, DMSO-d6): δ 8.20 (s, 3H), 7.66 (d, J = 9.28 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.56 Hz, 2H), 7.36-7.34 (m, 2H), 7.03 (d, J = 8.56 Hz, 2H), 4.45 (t, J = 6.08 Hz, 2H), 3.25 (t, J = 5.92 Hz, 2H).13C NMR (125 MHz, DMSO-d6): 158.1, 133.0, 132.5, 132.0, 124.9, 122.0, 112.0, 119.3, 118.1, 113.9, 112.8, 112.2, 43.3, 38.7. HRMS (ESI): m / z calculated for C16H14Br2N2O [M+H]+: 408.9473; found 408.9535. Example 49: ethyl 3-((5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methyl)-1H- pyrrole-2-carboxylate: Light greenish white solid (88% yield); Rf = 0.3 (3:7 EA / H); HPLC purity; 98%;1H NMR (500 MHz, CDCl3): δ 9.10 (s, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.34 (s, 2H), 7.27 (d, J = 8.25 Hz, 2H), 6.91 (d, J = 8.55 Hz, 2H), 6.83 (s, 1H), 5.93 (s, 1H), 5.55 (s, 2H), 4.37 (q, J = 7.15 Hz, 2H), 1.35 (t, J = 7.15 Hz, 3H);13C NMR (125 MHz, CDCl3): δ 160.8, 138.7, 136.0, 135.9, 131.8, 131.5, 127.3, 126.4, 125.8, 122.3, 122.2, 119.3, 118.5, 114.5, 112.1, 111.1, 99.9, 60.8, 43.4, 14.6. Mass (ESI): m / z calculated for C22H18Br2N2O2S [M-H]- : 530.9; found: 531. Example 50: 3-((5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methyl)-1H-pyrrole-2- carboxylic acid: White solid (96% yield); Rf = 0.3 (5:5 EA / H); HPLC purity; 98%;1H NMR (500 MHz, DMSO-d6): δ 11.61 (s, 1H), 7.91 (s, 1H), 7.58 (d, J = 8.70 Hz, 1H), 7.41 (d, J = 2.15 Hz, 1H), 7.37 – 7.34 (m, 2H), 7.27 (dd, J = 8.70, 2.15 Hz, 1H), 6.91 – 6.88 (m, 2H), 6.77 – 6.76 (m, 1H), 5.87 – 5.86 (m, 1H), 5.56 (s, 2H);13C NMR (125 MHz, DMSO-d6): δ 162.7, 138.4, 137.3, 135.6, 131.8, 130.8, 127.3, 125.4, 125.0, 122.2, 120.5, 119.9, 117.9, 113.6, 113.4, 110.0, 97.6, 42.8. Mass (ESI): m / z calculated for C20H14Br2N2O2S [M-H]- : 502.9; found: 503. Example 51: 5-bromo-3-(4-bromobenzyl)-1H-indole: Reddish white solid (84% yield); Rf = 0.3 (2:8 EA / H); HPLC purity; 99%;1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.59 (d, J = 1.96 Hz, 1H), 7.41 – 7.38 (m, 2H), 7.27 (dd, J = 8.68, 1.84 Hz, 1H), 7.28 (d, J = 8.44 Hz, 1H), 7.13 – 7.10 (m, 2H), 6.91 (d, J = 2.44 Hz, 1H); 4.00 (s, 2H);13C NMR (125 MHz, CDCl3): δ 139.8, 135.2, 131.6, 130.4, 129.2, 125.2, 123.7, 121.7, 120.0, 115.0, 112.9, 112.7, 30.9. Mass (ESI): m / z calculated for C15H11Br2N [M-H]-: 361.9; found: 362. Example 52: 5-bromo-3-(((4-bromophenyl)thio)methyl)-1H-indole: Red viscous oil (83% yield); Rf = 0.3 (2:8 EA / H); HPLC purity; 95%;1H NMR (500 MHz, CDCl3): δ 8.03 (s, 1H), 7.79 (s, 1H), 7.36 (d, J = 8.55 Hz, 2H), 7.30 (d, J = 8.55 Hz, 1H), 7.22 (d, J = 8.55 Hz, 1H), 7. 17 (d, J = 8.55 Hz, 2H), 7.02 (s, 1H), 4.24 (s, 2H);13C NMR (125 MHz, CDCl3): δ 135.9, 135.0, 132.0, 131.8, 128.5, 125.5, 124.5, 121.9, 120.4, 113.2, 112.9, 111.4, 30.1. Mass (ESI): m / z calculated for C15H11Br2NS [M-H]- : 393.9; found: 393.9. Example 53: 5-bromo-3-(4-bromophenoxy)-1-tosyl-1H-indole: White solid (85% yield); Rf = 0.7 (1:9 EA / H); HPLC purity; 99%;1H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 8.70 Hz, 1H), 7.70 (d, J = 8.40 Hz, 2H), 7.47 – 742 (m, 4H), 7.25 – 7.21 (m, 3H), 6.88 (d, J = 9.05 Hz, 2H), 2.37 (s, 3H);13C NMR (125 MHz, CDCl3): δ 156.5, 145.6, 140.0, 134.6, 133.0, 132.8, 130.2, 128.9, 127.0, 126.2, 121.6, 118.9, 117.3, 116.4, 115.9, 114.3, 21.8. Mass (ESI): m / z calculated for C21H15Br2NO3S [M-H]- : 517.9; found: 518. Example 54: 5-bromo-3-(4-bromophenoxy)-1H-indole: White solid (86% yield); Rf = 0.2 (1:9 EA / H); HPLC purity; 98%;1H NMR (500 MHz, CDCl3): δ 7.91 (s, 1H), 7.50 (s, 1H), 7.37 (d, J = 9.05 Hz, 2H), 7.31 (d, J = 8.65 Hz, 1H), 7.25 (d, J = 8.55 Hz, 1H), 7.06 (d, J = 2.75 Hz, 1H), 6.88 (d, J = 9.05 Hz, 2H);13C NMR (125 MHz, CDCl3): δ 158.3, 134.2, 133.0, 132.6, 126.1, 122.2, 120.7, 117.7, 114.9, 114.6, 113.4, 113.3. Mass (ESI): m / z calculated for C14H9Br2NO [M-H]- : 363.9; found: 364. Example 55: 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)acetic acid: Reddish white solid (80% yield); Rf = 0.3 (7:3 EA / H);1H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.55 (d, J = 8.68 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 8.52 Hz, 2H), 7.36 (dd, J = 8.68, 1.84 Hz, 1H), 6.97 (d, J = 8.56 Hz, 2H), 5.12 (s, 2H);13C NMR (125 MHz, DMSO-d6): 169.9, 138.2, 138.1, 136.3, 131.8, 130.6, 127.3, 125.2, 120.4, 118.0, 113.5, 113.4, 98.3, 47.6. Mass (ESI): m / z calculated for C16H11Br2NO2S [M-H]- : 437.8; found: 437.9. Example 56: 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)acetamide: White solid (92% yield); Rf = 0.3 (6:4 EA / H);1H NMR (500 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.85 Hz, 2H),7.42 (d, J = 8.55 Hz, 2H), 7.37 (dd, J = 8.70, 2.00 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J = 8.55 Hz, 2H), 4.19 (s, 2H);13C NMR (100 MHz, DMSO-d6): δ 168.7, 138.4, 138.2, 136.3, 131.8, 130.7, 127.4, 125.0, 120.4, 117.9, 113.4, 113.2, 97.9, 48.7. Mass (ESI): m / z calculated for C16H12Br2N2OS [M-H]- : 436.9; found: 436.9. Example 57: 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)acetohydrazide: White solid (93% yield); Rf = 0.3 (6:4 EA / H);1H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 7.85 (s, 1H), 7.50 (d, J = 8.56 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.56 Hz, 2H), 7.38 (d, J = 8.68 Hz, 1H), 6.99 (d, J = 8.56 Hz, 2H), 4.88 (s, 2H), 4.34 (s, 2H). Mass (ESI): m / z calculated for C16H13Br2N3OS [M-H]- : 451.9; found: 451.9. Example 58: (Z)-2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)-N' hydroxyacetimidamide: White solid (88% yield); Rf = 0.3 (3:7 EA / H);1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 7.91 (s, 1H), 7.61 (d, J = 8.80 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.56 Hz, 2H), 7.37 (d, J = 8.68 Hz, 1H), 6.99 (d, J = 8.56 Hz, 2H), 5.65 (s, 2H), 4.81 (s, 2H).13C NMR (100 MHz, DMSO-d6): δ 148.6, 138.1, 137.9, 135.9, 131.8, 130.8, 127.4, 125.0, 120.4, 118.0, 113.8, 113.5, 97.8, 46.9. Mass (ESI):m / z calculated for C16H13Br2N3OS [M+H]+: 453.9; found: 454.0. Biological Screening: The minimum inhibitory concentration (MIC) of the compound against gram-positive Staphylococcus aureus ATCC 29213 was tested by broth dilution method, which was found to be 1 µg / mL. Further, the selectivity index (SI) was measured as 50, which is a ratio of CC50 and MIC. The higher SI suggest that the compound is highly selective against the corresponding bacterial strain. Cytotoxicity of the compound were studied against Vero cells for identifying how many viable cells are remaining after the treatment with the compound using Doxorubicin as positive control. Activity against Methicillin resistant (MRSA), Methicillin susceptible (MSSA) and Vancomycin resistant (VRSA) Staphylococcus aureus were checked in comparison with the existing drugs and found that the compound does not change their MIC against both the bacterial strains. Same was observed for Enterococcus strains including Vancomycin-Resistant Enterococci (VRE). Extremely fast Bactericidal properties of compound were confirmed by the time kill kinetic studies. 1x and 10x MIC of the compound showed excellent bactericidal property in comparison with Vancomycin and Levofloxacin. Biofilms are formed by complex bacterial communities, which are considered the most perplexing areas of modern medicine. Bacteria within the biofilm are adaptively resistant to antibiotic treatment and it can take up to 1000 times more antibiotic to kill cells within the biofilm when compared to planktonic bacterial cells. Biofilm inhibition assay of Example 10 revealed that it has the ability to inhibit both preformed biofilm as well as not allow new biofilm to form which is much better than controls. Synergy studies were done using Checkerboard assay by measuring the Fractional Inhibitory Concentrations (FIC) index of the compound in combination with existing drugs. Combination of compounds with the drugs Gentamicin and levofloxacin increases the inhibitory activity. Also, the combination of the mentioned molecule with gentamicin and levofloxacin reduces the CFU of bacteria to zero at 24 h which confirms the high bactericidal potential of the combination, even against gentamicin and levofloxacin resistant strains. When tested for generation of resistance, Example 10 did not induce resistance in S. aureus even after multiple exposures for 40 days while levofloxacin induced stable resistance. The in vivo studies of the compound were conducted using skin infection model with S. aureus ATCC 29213 and MRSA NRS 119 showed that it works perfectly as either a 1% drug ointment applied BD topically and also when given orally at 100 and 200 mpk. In both cases, the reduction in CFU is comparable or better than controls. Table 2: MIC of (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (Example 10) analogs against ESKAPE pathogen panel

[0003] Table 3: Selectivity Index of (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (Example 10) analogs

[0004] Table 4: MRSA / VRSA panel with (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1- yl)methanol (Example 10)

[0005] Table 5: Enterococcus sp panel with (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1- yl)methanol (Example 10) Table 6: PMBN assay with (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (Example 10) Table 7: Combination studies with (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1- yl)methanol (Example 10) Table 8: Post Antibiotic Effect (PAE) of Example 10

[0006] Table 9: MIC of Example 10 against S. pneumonia ADVANTAGES OF THE INVENTION • MDR bacterial strains are the common cause of severe infections in public health. Infections caused by MDR strains of Staphlylococcus aureus like MRSA, VRSA etc. is widespread. People with MRSA are estimated to be 64% more likely to die than people with a non-resistant form of the infection. In this scenario, the disclosed molecule is showing excellent activity against different MRSA and VRSA strains. The lead molecule, (5-bromo-3-((4- bromophenyl)thio)-1H-indol-1-yl)methanol (Example 10) is also capable of inhibiting the biofilm as well as eradicating, which is more resistant to antibiotic treatment representing the efficiency of the disclosed molecule as an anti-bacterial agent. • In addition, the combination of the molecule with the existing drugs Gentamicin and levofloxacin also giving better result. The combination with levofloxacin reduces the CFU of bacteria to zero at 24 h which confirms the high bactericidal potential of the combination even against MRSA NRS 119. • The present invention is the synthesis of functionalized indole compounds. The process for the synthesis of title molecules are also new using ionic liquid as a green reagent / solvent.

Claims

WE CLAIM:

1. An antibacterial drug N-functionalized indoles and derivatives thereof of formula 1, comprising:wherein X is S, Se, SO, SO2, O, CH2, CH2-S, NHSO2 R1is selected from the group consisting of benzyl, naphthyl,, , , , or alkyl group selected from C1 to C10 alkyl groups A, B, C, D and E are independently selected from the groups consisting of hydrogen, halogen, alkyl or alkoxy, CF3; R2is hydrogen, halogen, CN, NO2, alkyl, alkoxy, carboxylic acid, ester, amide; R3is hydrogen, aryl, alkyl, carboxylic acid, ester, amide; Y is hydrogen, tosyl, or; n = 1 to 4 and Z is selected from the groupconsisting of hydrogen, OH, CN,, carboxylic acid, amide, hydrazide, ,, cyclic and acyclic amines,th4eir amine salts, where R is selected form hydrogen, alkyl group , ,Y and R3are connected through [-(CH2)n-N-C-] where n = 1-3 2. The compound as claimed in claim 1, wherein the representative compounds are selected from the group consisting of: (3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (3-((4-bromophenyl)thio)-5-methyl-1H-indol-1-yl)methanol (3-((4-bromophenyl)thio)-5-methoxy-1H-indol-1-yl)methanol (3-((4-bromophenyl)thio)-5-fluoro-1H-indol-1-yl)methanol (3-((4-bromophenyl)thio)-5-chloro-1H-indol-1-yl)methanol (3-((4-bromophenyl)thio)-5-iodo-1H-indol-1-yl)methanol 3-((4-bromophenyl)thio)-1-(hydroxymethyl)-1H-indole-5-carbonitrile (3-((4-bromophenyl)thio)-5-nitro-1H-indol-1-yl)methanol (4-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (6-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-((2-bromophenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-(p-tolylthio)-1H-indol-1-yl)methanol (5-bromo-3-((4-methoxyphenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-((3-methoxyphenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-((4-chlorophenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-((4-fluorophenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-(phenylthio)-1H-indol-1-yl)methanol(5-bromo-3-(naphthalen-2-ylthio)-1H-indol-1-yl)methanol (3-(benzylthio)-5-bromo-1H-indol-1-yl)methanol (5-bromo-3-((2,4,5-trichlorophenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-((4-(trifluoromethyl)phenyl)thio)-1H-indol-1-yl)methanol (5-bromo-3-(thiazol-2-ylthio)-1H-indol-1-yl)methanol (5-bromo-3-(pyridin-2-ylthio)-1H-indol-1-yl)methanol (3-(benzo[d]thiazol-2-ylthio)-5-bromo-1H-indol-1-yl)methanol (5-bromo-3-(ethylthio)-1H-indol-1-yl)methanol 5-bromo-3-(dodecylthio)-1H-indol-1-yl)methanol (3-((4-bromophenyl)thio)-2-phenyl-1H-indol-1-yl)methanol ethyl 1-(hydroxymethyl)-3-(phenylthio)-1H-indole-2-carboxylate 5-fluoro-3-(phenylselanyl)-1H-indol-1-yl)methanol (5-bromo-3-((4-bromophenyl)sulfonyl)-1H-indol-1-yl)methanol 5-bromo-3-((4-bromophenyl)thio)-1-methyl-1H-indole 5-bromo-1-methyl-3-(p-tolylthio)-1H-indole 5-bromo-1-ethyl-3-(p-tolylthio)-1H-indole 5-bromo-1-(oxiran-2-ylmethyl)-3-(phenylthio)-1H-indole 2-(5-bromo-3-(p-tolylthio)-1H-indol-1-yl)ethan-1-ol 3-(5-bromo-3-(p-tolylthio)-1H-indol-1-yl)propan-1-ol (5-chloro-3-((2,4-dichlorophenyl)thio)-1H-indol-1-yl)methanol 5-bromo-3-((4-bromophenyl)thio)-2-phenyl-1H-indole 5-bromo-3-((2,4-difluorophenyl)thio)-2-phenyl-1H-indole 5-bromo-3-((4-bromophenyl)thio)-1-(prop-2-yn-1-yl)-1H-indole 5-bromo-3-(4-bromobenzyl)-1H-indole 5-bromo-3-(((4-bromophenyl)thio)methyl)-1H-indole ethyl 3-((5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methyl)-1H-pyrrole-2- carboxylate 3-((5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)methyl)-1H-pyrrole-2- carboxylic acid 5-bromo-3-(4-bromophenoxy)-1-tosyl-1H-indole 5-bromo-3-(4-bromophenoxy)-1H-indole 3-((4-bromophenyl)thio)-5-chloro-1H-indole-2-carboxylic acid 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)acetonitrile 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)ethan-1-amine hydrochloride1-(2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)ethyl)guanidine 8-bromo-10-((4-bromophenyl)thio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole 8-bromo-10-((4-bromophenyl)thio)-3,4-dihydropyrazino[1,2-a]indole-2(1H)- carboximidamide 2-(5-bromo-3-((4-bromophenyl)thio)-1H-indol-1-yl)acetimidamide 3. A process for the preparation of the compound of formula 1a & 1aa as claimed in claim 1, comprising the steps of: (a) reacting an indole of formula 2 with thiol of formula 3 in the presence of a base in an aprotic solvent to obtain a compound of formula 4; and (b) reacting the compound of formula 4 with formaldehyde and catalysts tetra-butyl ammonium fluoride (TBAF) in (1-hexyl-3-methyl-1H-imidazol-3-ium bromide = [hmim]Br) HMIM to obtain the compound of formula 1a and oxidation of compound 1a with mCPBA to obtain its corresponding oxides of formula 1aa.

4. A process for the preparation of compound of formula 1ab as claimed in claim 1, comprising the steps of: (a) reacting an indole of formula 2 with diselenide of formula 5 in the presence of a base in an aprotic solvent to obtain a compound of formula 6; and (b) reacting the compound of formula 6 with formaldehyde and catalyst tetra-butyl ammonium fluoride (TBAF) in (1-hexyl-3-methyl-1H-imidazol-3-ium bromide = [hmim]Br) HMIM to obtain the compound of formula 1ab.

5. A process for the preparation of compound of formula 1b as claimed in claim 1, comprising the step of: reacting the compound of formula 4 with compound of formula 7 in the presence of a base to obtain the compound of formula 1b.

6. A process for the preparation of compound of formula 1c as claimed in claim 1, comprising the steps of:(a) reacting a substituted 3-formylindole of formula 8 with tosyl hydrazine followed by treatment with substituted arylboronic acid or thiophenols in the presence of a base in 1,4-dioxane to obtain a compound of formula 9; and (b) reacting compound of formula 9 with formaldehyde / TBAF / HMIMBr or substituted halides in the presence a base to obtain the compound of formula 1c.

7. A process for the preparation of compound of formula 1d as claimed in claim 1, comprising the steps of: (a) reacting an indole of formula 2 with tosylchloride, NBS, triethylamine and then with substituted phenols or sulphonamides in a sequential manner in the presence of a base followed by aromatization with Lewis acid and detosylation with base to obtain a compound of formula 10; and (b) reacting compound of formula 9 with formaldehyde / TBAF / HMIMBr or substituted halides in the presence a base to obtain the compound of formula 1c.

8. The process as claimed in claims 3, 4, 5, 6, and 7 wherein the base used is selected from sodium hydroxide, potassium and cesium carbonate, and triethyl amine.

9. The process as claimed in claim 3, wherein the aprotic solvent is selected from dimethyl sulfoxide, dimethylformamide, acetonitrile and tetrahydrofuran.

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