An efficient synthesis of bis(indolyl)methanes and evaluation of their antimicrobial activities

Abstract

A versatile and efficient method has been developed for the synthesis of bis(indolyl)methanes by using aluminium triflate (0.5 mol%) as a novel catalyst. Further, some of the synthesized compounds were evaluated for their efficacy as antibacterial and antifungal activities. Most of the compounds have shown moderate to good inhibitory activity.

• Bis(indolyl)methanes
• aluminium triflate
• antibacterial activity
• antifungal activity

Introduction

Indole derivatives are found to exhibit a wide spectrum of pharmacological activities such as cytotoxic [1, 2], antitumour [3], antiviral [3], antimicrobial [4] and anti-inflammatory activities [5]. Bis(indolyl)methanes (BIMs), which contain two indole or substituted indole units in a molecule, are found in bioactive metabolites of terrestrial and marine origin [6–8]. Over the past few years, much attention has been given for the search of specific bis(indole) secondary metabolites in view of their novel structural feature and broad spectrum of biological activities [9]. Recently, some bis(indole) alkaloids have been isolated from plants (I and II) and sponges (III and IV) wherein, two indole units are joined through different heterocyclic moieties. Further, such molecules have been also designed and synthesized that exhibit promising antibacterial, as well as antifungal activities ([10–13]; Figure 1).

Figure 1.  Chemical structures of bis(indole) alkaloids, I. , II isolated from Aspidosperma ramiflorum and III, IV from sponge Spongosorites sp., nifuroxazide (V) and nitrofuryl BIM (3q).

Nitrofurans and isosteric nitrothiophenes are heterocyclic compounds that have been well documented as potential antimicrobial agents 14–18. In spite of extensive research work that has been carried out in this class of compounds, there is still scope for the development of new molecules based on this type of heterocyclic systems [19–23]. It is well established that the activity of such nitroheterocycles is mainly due to the metabolic reduction of their nitro functionality by nitroreductase enzyme [24]. Moreover, a number of other furan derivatives have also exhibited antibacterial activity [25,26]. Therefore, in view of these findings, we have designed some new bisindoles by employing a new methodology. Furthermore, these compounds have been evaluated for their efficacy as antibacterial and antifungal agents.

It is well known in the literature that the reaction of indole with aromatic or aliphatic aldehydes and ketones produce azafulvenium salts, and this can undergo further addition with the second indole molecule to afford BIM [27]. Several other methods have been reported in the literature for the synthesis of BIMs using protic acid (e.g. HCl; [28–30]) or Lewis acids (e.g. AlCl₃, BF₃; [31,32]). These reactions have also been investigated using various triflates and chlorides 33–36]. More recently, Bhuyan and co-workers [37] have reported the synthesis of BIMs in protic solvents like methanol and water. However, this method requires longer reaction time (1–20 h) and heterocyclic moieties like furfural 2-aldehyde, thiophene 2-aldehyde and aliphatic aldehydes did not react with indole in aqueous media, whereas in methanol low yields (16–65%) have been obtained. In today's context, if water can be replaced instead of organic solvents, it is significant from the environmental concerns point of view. However, this replacement is difficult for mainly two reasons; firstly, most of the organic substances are insoluble in water and secondly, many reactive substrates, reagents as well as catalysts are decomposed or deactivated by water. In recent years, aluminium triflouromethanesulfonate has been used for various transformations in organic synthesis [38–42]. Therefore, based on the versatility and usefulness of this catalyst, herein, we report a new and efficient method for the synthesis of BIMs catalyzed by 0.5 mol% Al(OTf)₃. Further, these compounds have been evaluated for their antimicrobial activity against various antibacterial and antifungal strains. Most of these compounds have shown good antibacterial and antifungal activities.

Materials and methods

Chemistry

¹H and ¹³C NMRs were recorded on a Bruker UXNMR/XWIN-NMR (200 MHz) or Varian VXR-Unity (400 MHz) with TMS (0 ppm) as an internal standard. Coupling constants are reported in Hertz. EI mass spectra were recorded on a VG-7070H Micromass mass spectrometer at 200°C, 70 eV, with a trap current of 200 μA and 4 kV of acceleration voltage. LC–MS were recorded on instrument LC-MSD-Trap-SL and ESI MS on Micro mass, Quattro LC using ESI⁺ software with capillary voltage 3.98 kV. Melting points were determined with an Electrothermal melting point apparatus and are reported uncorrected. IR spectra (KBr) were measured with a Thermo Nicolet Nexus 670 Spectrometer (ν_max in cm^{− 1}). Analytical TLC of all reactions was performed on Merck prepared plates (silica gel 60 F-254 on glass). Column chromatography was performed using Acme silica gel. Starting materials were purchased from Sigma-Aldrich (Poole, UK). MeCN was distilled from CaH₂ and dried over 4 Å molecular sieves. Micro analytical data (C, H and N) agreed with the proposed structures within ± 0.4% of the theoretical values. All the standard organisms were obtained from IMTECH Chandigarh, and nutrient agar and potato dextrose agar (PDA) were procured from Himedia Laboratories, Mumbai, India.

General procedure for the synthesis of bis(indolyl) methanes (3a–v)

To a mixture of indole (217 mg, 1 mmol), substituted aldehydes (0.5 mmol) in acetonitrile (5 ml), aluminium triflate (0.5 mol%) was added and stirred at room temperature for the appropriate time (Tables I and II). After completion of the reaction as monitored by TLC, water was added to the reaction mixture and products were extracted into ethyl acetate (3 × 20 ml). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, concentrated in vacuum and purified by column chromatography, by using ethyl acetate–petroleum ether mixture as eluent to afford the desired products.

Table I.  Al(OTf)₃ catalysed synthesis of BIM derivatives (3a. –v) by the condensation of indole with various aldehydes.

Product	R	Time (min)	Yield (%)^a,b
3a	C6H5	14	95
3b	2-Cl–C6H4	4	92
3c	4-Cl–C6H4	6	90
3d	4-Br–C6H4	30	80
3e	2-NO2–C6H4	28	80
3f	3-NO2–C6H4	30	80
3g	4-NO2–C6H4	30	85
3h	4-Me–C6H4	20	95
3i	4-OMe–C6H4	12	92
3j	4-^iPr–C6H4	3	95
3k	3,4,5-tri-OMe–C6H2	25	80
3l	3,4-di-Cl–C6H3	30	85
3m	2-OH–C6H4	55	75
3n	4-OH–C6H4	45	80
3o	3-OMe-4-OH–C6H3	35	75
3p	2-Furyl	14	80
3q	5-Nitrofuryl	35	82
3r	2-Thienyl	25	80
3s	5-Nitrothienyl	60	80
3t	CH3	40	85
3u	C2H5	35	80
3v	C4H9	25	96

^a Yield obtained with 0.5 mol% Al(OTf)₃

^b Based on isolation by column chromatography and the products were characterized by NMR, IR and MS.

Table II.  Antibacterial activity^a of BIMs expressed in zone of inhibition in millimetres.

Compound	Gram-positive				Gram-negative
	B. Subtilis		S. aureus		E. coli		P. aeruginosa		P. oleovorians		K. pneumoniae
	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml
3a	8	9	10	12	10	11	9	10	10	11	–	–
3 g	9	10	10	11	9	10	8	10	8	9	–	–
3i	9	10	–	9	11	12	–	9	9	10	–	–
3p	11	14	14	16	12	14	12	14	13	14	11	12
3q	16	17	11	13	14	17	12	14	17	18	12	14
3r	8	10	10	11	11	13	9	10	9	10	–	–
3s	10	12	11	12	11	14	10	11	12	13	10	10
3t	15	16	14	16	17	17	10	11	15	16	12	14
3u	16	18	14	17	15	18	15	19	16	18	11	15
3v	12	13	13	14	12	13	10	13	12	13	11	12
Strept	19		21		29		24		29		23

^aThe tests were performed in duplicate and repeated thrice; –, bacteria are resistant to the compound at the concentrations; Strept, Streptomycin (50 μg/ml).

Spectral data for selected compounds

3,3′-Bis-indolyl phenylmethane (3a)

mp 148–150°C (lit.¹⁷ 150–152°C); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 7.77 (bs, 2H, NH), 7.15–7.35 (m, 9H), 7.10 (t, J = 8.13 Hz, 2H), 6.94 (t, J = 8.31 Hz, 2H), 6.57 (d, J = 2.26 Hz, 2H), 5.83 (s, 1H); ¹³C NMR (50 MHz, CDCl₃ + DMSO-d₆): δ 136.0, 133.8, 130.1, 129.7, 129.7, 129.4, 126.8, 124.5, 122.6, 119.5, 119.0, 113.2, 39.3; LC-MS m/z = 321.0 (M − 1)⁺, 345.1 (M + Na)⁺; IR (KBr) (ν_max/cm^{− 1}): 3395 (NH), 3050, 2924, 1596, 1455, 1088, 1004, 746. Anal. Calcd for C₂₃H₁₈N₂: C, 85.68; H, 5.63; N, 8.69. Found: C, 85.92; H, 5.54; N, 8.42.

3,3′-Bis-indolyl(4-nitrophenyl)methane (3g)

mp 219–221 (lit.^17e 217–219°C); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 10.50 (bs, 2H, NH), 8.15 (d, J = 8.56 Hz, 2H), 7.57 (d, J = 8.56 Hz, 2H), 7.39 (d, J = 7.81 Hz, 2H), 7.28 (d, J = 7.81 Hz, 2H), 7.09 (t, J = 7.81 Hz, 2H), 6.91 (t, J = 7.81 Hz, 2H), 6.73 (d, J = 2.34 Hz, 2H), 6.00 (s, 1H); ¹³C NMR (50 MHz, CDCl₃ + DMSO-d₆): δ 136.3, 134.2, 129.4, 129.0, 128.5, 124.1, 123.2, 122.4, 121.5, 118.4, 118.2, 112.5, 39.2; LC-MS m/z = 366 (M − 1)⁺; IR (KBr) (ν_max/cm^{− 1}): 3420 (NH), 3050, 2923, 1594, 1505, 1454, 1340, 1242, 1095, 1008, 743. Anal. Calcd for C₂₃H₁₇N₃: C, 75.19; H, 4.66; N, 11.44. Found: C, 75.44; H, 4.54; N, 11.68.

3,3′-Bis-indolyl(4-methoxyphenyl)methane (3i)

mp 183–185°C (lit.^17e 187–189°C); ¹H NMR (300 MHz, CDCl₃): δ 7.88 (bs, 2H, NH), 7.35 (q, J = 7.55 Hz, 4H), 7.23 (d, J = 8.30 Hz, 2H), 7.15 (t, J = 7.55 Hz, 2H), 6.98 (t, J = 7.55 Hz, 2H), 6.80 (d, J = 8.30 Hz, 2H), 6.62 (d, J = 2.26 Hz, 2H), 5.82 (s, 1H), 3.78 (s, 3H, –OCH₃); ¹³C NMR (75 MHz, CDCl₃): δ 143.7, 136.2, 133.6, 130.8, 130.2, 128.7, 126.8, 124.5, 122.6, 120.2, 119.6, 114.8, 55.4, 39.6; LC-MS m/z = 353.1 (M + 1)⁺, 375.0 (M + Na)⁺; IR (Neat) (ν_max/cm^{− 1}): 3394 (NH), 3054, 2925, 1608, 1507, 1554, 1336, 1241, 1090, 1025, 742. Anal. Calcd for C₂₄H₂₀N₂O: C, 81.79; H, 5.72; N, 7.95. Found: C, 81.92; H, 5.81; N, 7.60.

3,3′-Bis-indolyl furfurylmethane (3p)

mp > 300°C (lit.¹⁷>300°C); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 10.23 (bs, 2H, NH), 7.33 (q, J = 7.03 Hz, 5H), 7.02 (t, J = 7.03 Hz, 2H), 6.80–6.95 (m, 4H), 6.25 (q, J = 1.56 Hz, 1H), 6.00 (d, J = 3.12 Hz, 1H), 5.84 (s, 1H); ¹³C NMR (50 MHz, CDCl₃ + DMSO-d₆): δ 157.0, 140.5, 136.1, 126.1, 122.8, 120.8, 118.8, 118.2, 115.8, 110.9, 109.6, 105.7, 33.5; ESI MS m/z = 311.27 (M − 1)⁺; IR (KBr) (ν_max/cm^{− 1}): 3406 (NH), 3052, 2924, 1614, 1453, 1336, 1091, 1006, 739. Anal. Calcd for C₂₁H₁₆N₂O: C, 80.95; H, 5.26; N, 8.97. Found: C, 80.61; H, 5.17; N, 9.19.

3,3′-Bis-indolyl(5-nitrofurfuryl)methane (3q)

mp 97°C (charred); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 10.60 (bs, 2H, NH), 7.27–7.42 (m, 5H), 7.05 (t, J = 7.03 Hz, 2H), 6.85–6.99 (m, 4H), 6.32 (d, J = 3.90 Hz, 1H), 5.96 (s, 1H); ¹³C NMR (50 MHz, CDCl₃): δ 161.5, 150.4, 136.0, 126.9, 125.4, 123.1, 120.7, 118.2, 118.0, 112.8, 110.9, 109.9, 33.9; LC-MS m/z = 380 (M + Na)⁺; IR (KBr) (ν_max/cm^{− 1}): 3407 (NH), 3053, 2926, 1721, 1485, 1354, 1239, 1094, 1015, 741. Anal. Calcd for C₂₁H₁₅N₃O₃: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.32; H, 4.11; N, 11.79.

3,3′-Bis-indolyl thienylmethane (3r)

mp 155–157°C (lit.¹⁸ 150–153°C); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 10.21 (bs, 2H, NH), 7.35 (t, J = 8.57 Hz, 4H), 7.10–7.15 (m, 1H), 7.05 (dt, J = 7.85, 1.43 Hz, 2H), 6.85–6.95 (m, 6H), 6.10 (s, 1H); ¹³C NMR (50 MHz, CDCl₃ + DMSO-d₆): δ 143.2, 132.0, 126.2, 121.6, 121.2, 119.8, 118.6, 117.5, 115.3, 114.5, 106.5, 33.6; ESI MS m/z = 327.20 (M − 1)⁺; IR (KBr) (ν_max/cm^{− 1}): 3403 (NH), 3077, 2925, 1616, 1454, 1333, 1213, 1086, 1002, 744. Anal. Calcd for C₂₁H₁₆N₂S: C, 76.80; H, 4.91; N, 8.53. Found: C, 76.56; H, 4.74; N, 8.76.

3,3′-Bis-indolyl(5-nitrothienyl)methane (3s)

mp 181°C (charred); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 10.60 (bs, 2H, NH), 7.80 (d, J = 4.68 Hz, 1H), 7.39 (d, J = 8.59 Hz, 4H), 7.10 (t, J = 7.81 Hz, 2H), 6.90–7.02 (m, 5H), 6.14 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 15.9, 148.1, 135.7, 127.9, 125.1, 123.9, 122.7, 120.5, 117.9, 117.8, 115.4, 110.7, 35.2; LC-MS m/z = 396.9 (M + Na)⁺; IR (KBr) (ν_max/cm^{− 1}): 3444 (NH), 3056, 2922, 1525, 1458, 1335, 1212, 1090, 737. Anal. Calcd for C₂₁H₁₅N₃SO₂: C, 67.54; H, 4.05; N, 11.25. Found: C, 67.28; H, 4.12; N, 11.38.

3,3′-Bis-indolyl ethane (3t)

mp 153–155°C (lit.¹⁷ 148–150°C); ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 9.95 (bs, 2H, NH), 7.45 (d, J = 8.01 Hz, 2H), 7.28 (d, J = 8.01 Hz, 2H), 7.00 (t, J = 8.01 Hz, 2H), 6.91 (d, J = 2.18 Hz, 2H), 6.85 (d, J = 7.28 Hz, 2H), 4.60 (q, J = 6.55 Hz, 1H), 1.77 (d, J = 6.55 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 135.7, 125.5, 120.3, 119.7, 119.4, 118.0, 116.9, 110.2, 27.0, 20.0; ESI MS m/z = 259.20 (M − 1)⁺; IR (KBr) (ν_max/cm^{− 1}): 3413 (NH), 3075, 2957, 1622, 1455, 1336, 1094, 1011, 737. Anal. Calcd for C₁₈H₁₆N₂: C, 83.05; H, 6.19; N, 10.76. Found: C, 83.40; H, 6.30; N, 10.62.

3,3′-Bis-indolyl propane (3u)

Semi solid; ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 10.00 (bs, 2H, NH), 7.46 (d, J = 7.81 Hz, 2H), 7.27 (d, J = 7.81 Hz, 2H), 6.92–7.06 (m, 4H), 6.86 (t, J = 7.03 Hz, 2H), 4.29 (t, J = 7.03 Hz, 1H), 2.20 (p, J = 7.03 Hz, 2H), 0.98 (t, J = 7.03 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃ + DMSO-d₆): δ 135.9, 127.4, 122.3, 120.6, 120.5, 116.0, 115.2, 109.3, 30.6, 24.8, 8.2; LC-MS m/z = 273.1 (M − 1)⁺; IR (KBr) (ν_max/cm^{− 1}): 3414 (NH), 3053, 2926, 2865, 1615, 1456, 1340, 1093, 1012, 744. Anal. Calcd for C₁₉H₁₈N₂: C, 83.18; H, 6.61; N, 10.21. Found: C, 83.01; H, 6.80; N, 10.33.

3,3′-Bis-indolyl pentane (3v)

Semi solid; ¹H NMR (200 MHz, CDCl₃ + DMSO-d₆): δ 7.60 (bs, 2H, NH), 7.52 (d, J = 7.55 Hz, 2H), 7.16–7.23 (m, 2H), 7.07 (dt, J = 6.79, 1.51 Hz, 2H), 6.97 (dt, J = 6.79, 1.51 Hz, 2H), 6.0 (dd, J = 2.66, 0.75 Hz, 2H), 4.40 (t, J = 7.55 Hz, 1H), 2.17 (q, J = 7.55 Hz, 2H), 1.20–1.40 (m, 4H), 0.87 (t, J = 6.79 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃ + DMSO-d₆): δ 136.8, 126.2, 123.1, 119.7, 119.8, 117.0, 116.0, 109.5, 34.2, 31.5, 26.7, 22.2, 12.2; LC-MS m/z = 301.1 (M − 1)⁺; IR (KBr) (ν_max/cm^{− 1}): 3413 (NH), 3054, 2927, 2858, 1617, 1456, 1339, 1094, 1011, 742. Anal. Calcd for C₂₁H₂₂N₂: C, 83.40; H, 7.33; N, 9.26. Found: C, 83.16; H, 7.42; N, 9.39.

Antibacterial assay

The antibacterial activity of the synthesized compounds was determined by the well diffusion method according to Linday [43]. Three to five identical colonies from each agar plate were lifted with a sterile wire loop and transferred into a tube containing 5 ml of nutrient agar. The turbidity of each bacterial suspension was adjusted to reach an optical comparison to that of a 0.5 McFarland standard; resulting in a suspension containing approximately 1–2 × 10⁸ CFU/ml. Nutrient agar plates were inoculated by streaking the swab over the entire sterile agar surface. This procedure was repeated by streaking two more times, rotating the plate approximately 60° each time to ensure uniform distribution of the inoculum. As a final step, the rim of the agar was also swabbed. After allowing the inoculum to dry at room temperature, 6 mm diameter wells were prepared in the agar with the help of sterilized cork borer. The different concentrations of the test compounds (100–150 μg/ml) were prepared by dissolving in dimethyl sulfoxide (DMSO) and introduced into duplicate wells. The plates were incubated at 37°C for 24 h. Subsequently, the plates were examined for bacterial growth inhibition and the inhibition zone diameter measured to the nearest millimeter. The standard antibiotic (streptomycin 50 μg/well) was used as positive control, whereas, the equivalent amount of solvent (DMSO) did not exhibit any activity in the assay.

Antifungal assay

The method followed for antifungal bioassay is similar to that followed for antibacterial assay, where the medium is PDA 39 g/l. All the test compounds were studied for their antifungal activity at concentration 100–150 μg/ml using DMSO as a solvent. The solvent did not exhibit any activity at the concentrations used. The treated and the controls were kept in an incubator at 28 ± 2°C for 48 h and inhibition zones were measured to the nearest millimeter. Three replicates were maintained for each treatment. Amphotericin-B (50 μg/ml) was used as positive control.

Results and discussion

Chemistry

BIMs were obtained by the condensation of indole (1) and various aldehydes (2a–v) in acetonitirle at room temperature in presence of 0.5 mol% Al(OTf)₃ in high yields in shorter reaction time (Scheme 1, Table I). Aromatic aldehydes with electron deficient substituents required longer reaction times to produce comparable yields than those of their simple and electron-rich counterparts. Electron rich aldehydes like anisaldehyde, reacted rapidly using indole within 12 min (compound 3i), whereas, aliphatic aldehydes gave good yields of their corresponding products in 25–40 min (compounds 3t–v). To best of our knowledge, this is the first report for the synthesis of BIMs using this catalyst which possess more advantages over earlier methods like mild reaction conditions, cleaner reactions, shorter reaction times, high yield of products and low catalytic amount.

Scheme 1.  Synthesis of BIMs.

Antibacterial activity

Amongst the synthesized compounds 3a, 3g, 3i and 3p–v were screened for their antibacterial activity against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Pseudomonas oleovorans (MTCC 617), Klebsiella pneumoniae (MTCC 618) as Gram-negative bacteria, Bacillus subtilis (MTCC 441), Staphylococcus aureus (MTCC 96), as Gram-positive bacteria and the antifungal activity was evaluated against yeast Candida albicans (MTCC 227) and filamentous fungi Rhizopus oryzae (MTCC-262), Aspergillus niger (MTCC 1344). The inhibitory zones (in mm) were determined by using agar well method (cup plate method). Antibiotics, streptomycin and amphotericin-B were used as positive controls against bacteria and fungi, respectively. In all determinations, tests were performed in duplicate and results were reported as mean of at least three determinations. Table II showed that all the tested compounds exhibited moderated to good antibacterial activity. Compounds 3q, 3t and 3u showed significant inhibition against all the bacteria tested and were not strain dependent. In compounds 3a, 3g and 3i, there was no effect of activating or deactivating substituents on the aryl ring in their inhibitory activity and found to be less potent than the other compounds tested. Moreover, these compounds were inactive against K. pneumoniae at all the concentrations used. The incorporation of 5-nitro furfuroyl group in BIM (3q) enhanced the activity in all the strains except P. aeruginosa than the corresponding furfuroyl derivative (3p) and activity reduced against S. aureus. Similarly, 5-nitrothiophenyl derivative (3s) was found to be more potent than the corresponding thiophenyl derivative (3r). The significant inhibition exhibited by the compounds 3q and 3s might be due to the presence of nitro group on the fifth position of their corresponding hetero aryl rings. Among the heteroaryl methyl(bisindoles) the activity is in the order 3q>3s>3p>3r. The replacement of aryl group with alkyl chain on the 3-methyl of bisindoles (3t–v) also enhanced the significant inhibitory activity. Compound 3u was found to be the most active from this series against all the bacterial strains tested.

Antifungal activity

The investigation of antifungal screening data from Table III revealed that all the tested compound showed moderate to good fungal inhibition. Compounds 3q and 3s–u were active against all the fungal species. The 5-nitro heteroaryl derivatives (3q and 3s) exhibited better inhibitory activity against all the three fungal strains than the corresponding heteroaryl derivatives, whereas, compound 3p was mild active only against R. oryzae and 3r active only against C. albicans. Compound 3t was found to be the most active against C. albicans and R. oryzae and 3u was the most active against A. niger.

Table III.  Antifungal activity of BIMs expressed in zone of inhibition in millimetres.

Compd	Yeast		Filamentous fungi
	C. albicans		R. oryzae		A. niger
	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml
3a	10	12	–	–	–	–
3g	10	14	–	–	–	–
3i	–	–	–	–	–	–
3p	–	–	10	12	–	–
3q	8	9	8	9	10	11
3r	10	12	–	–	–	–
3s	9	10	8	9	9	11
3t	12	14	18	20	12	14
3u	10	13	13	15	14	18
3v	–	–	10	12	–	–
Amph	23		23		22

–, No activity has shown; Amph, Amphotericin B (50 μg/ml).

Conclusions

In conclusion, we have developed an efficient synthetic protocol for the synthesis of BIMs from various aldehydes and indoles using 0.5 mol% Al(OTf)₃. Furthermore, the synthesized compounds using this method have been evaluated for their antibacterial and antifungal activities. Almost all the compounds showed moderate to good antibacterial and antifungal activities. 5-Nitro heteroaryl containing BIM (3q and 3s) have exhibited significant antibacterial activity. Compound 3u was found to be the most active from the tested compound in this series. Compounds 3s–u demonstrated significant antifungal activity. Further research in this area is in progress in our laboratory.

Acknowledgements

The authors (M.N.A.K., K.S.R. and S.K.A.) thank CSIR and the author (Y.V.V.S) thanks UGC, New Delhi, for the award of research fellowship.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.