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Synthesis of novel Indolyl benzo[b][1,4]diazepins as potent antimicrobial and antioxidant agents
⁎Corresponding author. Tel.: +91 8472 263292, mobile: +91 9449235534; fax: +91 8472 248632. jsbiradar@yahoo.com (Jaiprakash S. Biradar)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
A new series of novel indolyl benzo[b][1,4]diazepins bearing a 2,5-dichlorothiophene moiety are reported. Claisen–Schmidt condensation of 2,5-disubstituted indole-3-carboxaldehydes with 2,5-dichloro-3-acetylthiophene will produce (E)-3-(2,5-disubstituted-1H-indol-3-yl)-1-(2,5-dichlorothiophene-3-yl)prop-2-en-1-one. The acid catalysed cyclocondensation of preformed chalcones with substituted ortho-phenylenediamine has produced the titled compounds in good yields. All the newly synthesized compounds are characterised by IR, 1H NMR, 13C NMR, elemental analysis and mass spectroscopic data. Compounds 4b, 4c and 4f have emerged as most potent analogues in antimicrobial and antioxidant evaluations.
Keywords
2,5-Disubstituted indole-3-carboxaldehydes
2,5-Dichloro-3-acetylthiophene
Vilsmeier Haack formylation
Claisen–Schmidt condensation
Indolylbenzo[b][1,4]diazepins
Antimicrobial activity
Antioxidant activity
1 Introduction
Benzodiazepines have attracted greater attention as an important class of heterocyclic compounds in the field of drugs and pharmaceuticals. These compounds are widely used as anticonvulsants (Landquist, 1984), as antianxiety drugs (Schutz, 1982; Randall and Kapple, 1977), analgesics (Fryer, 1991), sedatives (Randall and Kapple, 1977), anti-depressives (Schutz, 1982), hypnotics (Randall and Kapple, 1977) and anti-inflammatory agents (De Baun et al., 1977). Since the discovery of flurazepam, flunitrazepam, quazepam, halazepam and triflubazepam the chemistry of [1,4] and [1,5] benzodiazepines and allied compounds have assumed considerable importance due to their use as drugs controlling mild to moderate CNS depression (Olkkola and Ahonen, 2008), mental tension depression (Olkkola and Ahonen, 2008), as hypnotics, anxyolitic agents and for controlling chronic insomnia (Stembach, 1971; Olkkola and Ahonen, 2008). In particular [1,4]benzodiazepines have been demonstrated to be non-nucleoside reverse transcriptase inhibitors, acquire a significant place in the treatment of the infections by the HIV (Darnag et al., 2010). The same analogues containing conjugated acrylyl C2-substituents possess significant cytotoxicity according to the NCI 60-cell line screen surpassing anthramycin in potency (Chen et al., 2004). Geigy, 1965, has described the [1,4]benzodiazepine analogues as anticonvulsants, muscle relaxants, blood pressure lowering and CNS depressant agents (Geigy, 1965).
Alongside, indoles and its biheterocycles are featured widely in a wide variety of biologically and pharmacologically active compounds (Sundberg, 1996). The indole derivatives are known to possess anticancer (Wu et al., 2009; Pojarova et al., 2007; Biradar and Sasidhar, 2011), antioxidant (Biradar et al., 2010a; Biradar et al., 2010b; Biradar and Sasidhar, 2011), antirheumatoidal and anti-HIV (Buyukbingol et al., 1994; Suzen and Buyukbingol, 1998) activities. Many indole derivatives are considered as the most potent scavenger of free radicals (Chyan et al., 1999). Indolyl[1,4]benzodiazepines are reported to possess inhibitory activity of central and motor nervous system, depression of blood pressure and dilation of pulmonary vessels (Reynolds and Carson, 1972). In our previous approach, we have reported the indolyl[1,4]benzodiazepine systems as antimicrobial, DNA cleavage (Biradar et al., 2010a; Biradar et al., 2010b), analgesic, CNS depressant and anti-inflammatory agents (Biradar and Manjunath, 2004).
In continuation of our enduring efforts on synthesis of ‘Drug-Like’ molecules (Biradar et al., 2008; Biradar and Sasidhar, 2011; Biradar and Manjunath, 2004a, 2004b), It was envisaged that the two pharmacophores if linked together (Scheme 1) would generate novel molecular templates which are likely to exhibit interesting biological properties.
Schematic representation for the synthesis of novel Indolylbenzodiazepins.
2 Results and discussion
2.1 Chemistry
Herein, we report the synthesis of novel indolyl benzo[b][1,4]diazepines bearing thiophenes via two step methodology utilising 2,5-disubstituted indole-3-carboxaldehydes. (E)-3-(2,5-disubstituted-1H-indol-3-yl)-1-(2,5-dichlorothiophen-3-yl)prop-2-en-1-one (3a–d) are obtained by the Claisen–Schmidt condensation of 2,5-dichloro-3-acetylthiophene (2) with various 2,5-disubstituted indole-3-carboxaldehydes (1a–d) (Scheme 1). The IR spectrum of (E)-1-(2,5-dichlorothiophen-3-yl)-3-(5-methyl-2-phenyl-1H-indol-3-yl)prop-2-en-1-one (3a) has shown a strong absorption at 3258 cm−1 corresponding to indole NH, absorptions at 2936 and 1717 cm−1 correspond to C–H (Aromatic) and C⚌O stretching, respectively. The 1H NMR spectrum of 3a has exhibited a singlet at δ 11.2 (S, 1H, indole NH) integrating for single proton due to deshielded indole NH which is D2O-exchangeable. A singlet at δ 2.0 (S, CH3, 3H,) for methyl protons and a multiplet between δ 6.9–8.0 (m, 9Ar-H, 2H, –CH⚌CH–) integrating for eleven protons in the molecule. This spectrum has also exhibited the absence of aldehydic proton confirming the formation of product. The 13C NMR spectrum of 3a has displayed highly deshielded signal at δ 180 for carbonyl carbon, up field signal at δ 30 for methyl carbon. In the mass spectrum of compound 3a, molecular ion peak is observed at m/z 412(100%) which is also the base peak, corresponding to the molecular weight of the compound. These spectral data support the formation of 3a.
The acid catalysed cyclocondensation of preformed chalcones (3a–d) and substituted ortho-phenylenediamine in ethanol has produced the titled compounds (4a–h) (Scheme 1). All the newly synthesized compounds were characterised by IR, 1H NMR, 13C NMR, elemental analysis and mass spectroscopic data.
The IR spectrum of (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-4-(5-methyl-2-phenyl-1H-indol-3-yl)-1H-benzo[b][1,4]diazepine (4a) has shown a strong absorption at 3131 cm−1 corresponding to indole NH and absorption at 3063 cm−1 is for diazepine NH. Absorptions at 2910 and 1626 cm−1 correspond to the C–H and C⚌N stretching respectively. The 1H NMR spectrum of 4a has exhibited a singlet at δ 11.80 due to deshielded indole NH, which is also D2O exchangeable. A singlet at δ 2.3 (s, 3H, CH3) for methyl protons and a multiplet between δ 6.8–7.6 ppm (m, 15H, 14Ar-H and Diazepine NH) integrating for fifteen protons. The 13C NMR spectrum of 4a has displayed a downfield signal at δ 165 integrated for the C⚌N of diazepine ring. Up field signal at δ 30 corresponds to the methyl carbon.
Mass spectrum of compound 4a has shown a peak at m/z 499 (90%), 501 (30) and 503 (10%) corresponding to the molecular weight and isotopic chlorine in the required ratio. Molecular ion has undergone into fragmentation by two routes. In the first route it has lost chlorine from thiophene ring to generate m1 at m/z 464(25%) and 466 (8%), fragment m1 has lost thiophene ring (C4HClS) to generate m2 at m/z 348 (55%), the radical cation m2 has lost C6H5N to generate the cation m3 at m/z 257 (35%). Cation m3 has lost azitidinyl fragment to generate m4 at m/z 206 (55%) and m4 has generated m5 at m/z 90 (27%) by loosing the fragment C8H6N. In another route, molecular ion on fragmentation looses C6H5N2 radical from the diazepine ring and displayed peaks at m6 m/z 394 (15%), 396 (5%) and 398 (1%) corresponding to the isotopic chlorine in the required ratio. M6 has lost the fragment C7H3Cl2S to generate m7 at m/z 206 (55%) and m7 has lost the fragment C8H6N to generate m8 at m/z 90 (27%). This fragmentation pattern supports the proposed structure of compound 4a. Spectral data of compounds 4b–h support their structures.
2.2 Biological evaluations
2.2.1 Antimicrobial activity
Results of antimicrobial activity are summarised in Table 1. Applying the agar plate diffusion technique (Verma and Imam, 1973) all of the newly synthesized compounds were screened in vitro for antibacterial activity against Escherichia coli (E. coli), (Gram-negative) and Bacillus subtilis (Gram-positive) at 25, 50, and 100 μg/ml concentrations, respectively. Under identical conditions, Streptomycin sulfate was used as the standard. The zone of inhibition was measured in mm for each concentration. All of the screened compounds were found to have moderate to significant antibacterial activity. Compound 4a and 4e have shown very interesting results against both the strains. Compound 4b against E. coli and 4f against B. subtilis have exhibited maximum inhibition. Std. 1, Streptomycin; Std. 2, Griseofulvin.
Compd
Antibacterial activity
Antifungal activity
E. coli
B. subtilis
A. niger
A. flavus
25
50
100
25
50
100
25
50
100
25
50
100
3a
8
9
11
10
10
11
8
9
11
9
10
12
3b
8
9
10
7
8
9
8
9
10
8
8
9
3c
6
6
7
4
5
7
5
6
6
6
6
7
3d
4
5
6
6
6
7
4
6
6
6
6
7
4a
11
12
13
10
12
14
10
11
13
9
11
14
4b
9
10
12
9
9
11
10
10
11
8
9
11
4c
7
7
9
8
8
9
8
8
9
7
8
8
4d
7
8
8
7
7
7
7
8
10
8
8
9
4e
10
12
14
14
15
17
11
12
14
11
12
14
4f
9
11
12
12
12
14
11
11
13
12
13
15
4g
6
8
10
8
8
9
7
7
8
9
9
10
4h
6
7
7
9
9
9
9
10
10
7
8
9
Std. 1
10
12
13
12
13
15
—
—
—
—
—
—
Std. 2
—
—
—
—
—
—
12
13
15
11
13
14
Similarly, the antifungal screening of the compounds was carried out in vitro against two fungi Aspergillus niger and Aspergillus flavus at 25, 50, and 100 μg/ml concentrations respectively, by using griseofulvin as the positive reference. Of all the tested indolylbenzodiazepine systems, majority of the compounds exhibited moderate to significant antifungal activity. Compounds 4a and 4e have shown very significant activity against both the strains and 4f against A. flavus has shown promising results by maximum inhibition than that of the standard Griseofulvin.
Hence, results clearly signify, the antimicrobial activity was increased with the methyl and chloro substitutions at the fifth position of the indole ring. Further, significant improvement in the activity was observed with the incorporation of methyl substituted benzodiazepine ring.
2.2.2 Antioxidant activity
2.2.2.1 Free radical scavenging activity
The newly synthesized compounds were screened for free radical scavenging activity by DPPH method (Singh et al., 2002). Samples were prepared at concentrations of 10, 50, and 100 μg/100 μl and Butylated hydroxy anisole (BHA) is taken as the standard. Among the tested compounds, 4b and 4f have shown promising scavenging activity. The increased activity may be due to the existence of ‘Cl’ substitution at the fifth position of the indole ring. Whereas, compounds 4c, 4g and 4h with ‘H' substitution at the fifth position of the indole ring have shown moderate activity. In contrast, ‘CH3’ substituted indolylbenzodiazepine derivatives 4a and 4e have shown least activity compared with the standard. Bar graph representation of percentage free radical scavenging activity is shown in Fig. 1.
Free radical scavenging activity of novel Indolylbenzodiazepins.
2.2.2.2 Total antioxidant capacity
In total antioxidant activity (Mruthunjaya and Hukkeri, 2008), antioxidant capacities are expressed as equivalents of ascorbic acid. Among the compounds tested, 4b and 4f which are ‘Cl’ substituted indolylbenzodiazepine analogues have shown strong antioxidant capacity and compounds 4e, 4g and 4h with CH3 and H substitution at the fifth position of the indole ring have shown moderate activity. It is also observed that, indolylbenzodiazepine system has improved the activity significantly than that of the chalcones Fig. 2.
Total antioxidant capacity of novel Indolylbenzodiazepins.
2.2.2.3 Ferric reducing antioxidant power activity
The compounds are also screened for ferric reducing antioxidant activity (Barreira et al., 2008). Butylated hydroxy anisole (BHA) was used as the standard. All the tested compounds have shown positive tendency toward the ferric reducing activity. As in the previous cases, indolylbenzodiazepine analogues (4a–h) have shown improved activity than the chalcones (3a–d). Further, compounds 4a, 4e and 4g with ‘CH3’ substitution have shown excellent ferric reducing antioxidant activity and other derivatives of indole have shown moderate to high activity. The presence of benzodiazepine ring in addition to the alkyl group may play an important role to act as a better electron donor which may enhance reducing power ability of 4a, 4e and 4g. The results are presented in Fig. 3.
Ferric reducing antioxidant activity of novel Indolylbenzodiazepins.
3 Experimental
3.1 Chemistry
3.1.1 General considerations
All the chemicals and reagents were purchased from MERCK, Himedia and SD fine chemical companies and are used without further purification. Melting points of the synthesized compounds are determined in open capillaries and are uncorrected. Reactions are monitored by thin-layer chromatography (TLC) on Silica Gel 60 F254 aluminium sheets (MERCK) and detection was made using UV light and iodine. IR spectra are recorded in KBr on Perkin–Elmer and FTIR Spectrophotometer (νmax in cm−1). 1H NMR and 13C NMR spectra on BRUKER AVENE II 400 MHz NMR Spectrometer (Chemical shift in δ ppm down field from TMS as an internal reference). The Mass spectra are recorded on LC-MSD-Trap-SL instruments. The elemental analysis was determined on FLASH EA 1112 SERIES instrument. All the compounds gave C, H and N analysis within ±0.5% of the theoretical values.
3.1.2 Typical experimental procedure for the synthesis of 2,5-disubstituted indole-3- carboxaldehydes (1a–d)
The precursors 2,5-disubstituted indole-3-carboxaldehydes (1a–d) were obtained from the Vilsmeier Haack formylation reaction of 2,5-disubstituted indoles (Biradar, 1982).
3.1.3 General procedure for the synthesis of (E)-3-(2,5-disubstituted-1H-indol-3-yl)-1-(2,5-dichlorothiophene-3-yl)prop-2-en-1-one (3a–d)
Claisen–Schmidt condensation of an equimolar mixture of 2,5-dicholro-3-acetylthiophene (2) (0.01 mol) and various 2,5-disubstituted indole-3-carboxaldehydes (1a–d) (0.01 mol) were refluxed (3–4 h) in ethanol (15–20 ml) with 1 ml of (20%) sodium hydroxide solution (Scheme 1). The completion of reaction was monitored by TLC in chloroform and benzene (1:1). After the completion of reaction, excess of solvent was removed under reduced pressure and kept at room temperature for few hours for the formation of crystals. The product obtained was filtered and purified with ethanol. All the newly synthesized compounds were characterised by IR, 1H NMR, 13C NMR and mass spectroscopic data. Yield 70–85%.
3.1.3.1 (E)-1-(2,5-dichlorothiophen-3-yl)-3-(5-methyl-2-phenyl-1H-indol-3-yl)prop-2-en-1-one (3a)
Yield 85% (ethanol); mp 244–245 °C; IR (KBr) (νmax in cm−1): 3258, 2936, 1717, 1545; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.20 (s, 1H, indole NH), 6.9–8.0 (m, 11H, 9Ar-H, CH⚌CH), 2.0 (s, 3H, CH3); 13C NMR(DMSO-d6 + CDCl3) δ (ppm): 185 (C⚌O), 30 (CH3) and 152, 150, 146, 144, 142, 141, 139, 137, 133, 129, 124, 105, 104, 100 and 30; MS: m/z = 413 [M+1]+. Anal. Calcd for C22H15Cl2NOS (412): C, 64.08; H, 3.67; N, 03.40. Found: C, 64.10; H, 3.62; N, 03.45.
3.1.3.2 (E)-3-(5-chloro-2-phenyl-1H-indol-3-yl)-1-(2,5-dichlorothiophen-3-yl)prop-2-en-1-One (3b)
Yield 80% (ethanol); mp 275–277 °C; IR (KBr) (νmax in cm−1): 3309, 2923, 1725, 1581; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.60 (s, 1H, indole NH), 7.1–8.2 (m, 11H, 9Ar-H, CH⚌CH); MS: m/z = 433 [M+1]+. Anal. Calcd for C21H12Cl3NOS (432): C, 58.28; H, 2.79; N, 3.24. Found: C, 58.30; H, 2.76; N, 03.28.
3.1.3.3 (E)-1-(2,5-dichlorothiophen-3-yl)-3-(2-phenyl-1H-indol-3-yl)prop-2-en-1-one (3c)
Yield 77% (ethanol); mp 236–237 °C; IR (KBr) (νmax in cm−1): 3228, 2946, 1730, 1550; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 10.60 (s, 1H, indole NH), 6.8–8.2 (m, 12H, 10Ar-H, CH⚌CH); MS: m/z = 400 [M+2]+. Anal. Calcd for C21H13Cl2NOS (398): C, 63.32; H, 3.29; N, 3.52. Found: C, 63.38; H, 3.26; N, 3.50.
3.1.3.4 (E)-1-(2,5-dichlorothiophen-3-yl)-3-(1H-indol-3-yl)prop-2-en-1-one (3d)
Yield 70% (ethanol); mp 220–221 °C; IR (KBr) (νmax in cm−1): 3211, 2930, 1717, 1595; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.00 (s, 1H, indole NH), 7.0–8.3 (m, 8H, 6Ar-H, CH⚌CH); MS: m/z = 323 [M+1]+. Anal. Calcd for C15H9Cl2NOS (322): C, 55.91; H, 2.82; N, 04.35. Found: C, 55.97; H, 3.85; N, 04.24.
3.1.4 General procedure for the synthesis of (2Z,4E)-8-substituted-2-(2,5-dichlorothiophen-3-yl)-4-(2,5-disubstituted-1H-indol-3-yl)-1H-benzo[b][1,4]diazepine (4a–h)
A mixture of appropriate (E)-3-(2,5-disubstituted-1H-indol-3-yl)-1-(2,5-dichloro thiophene-3-yl)prop-2-en-1-one (3a–d) (0.01 mol) and substituted orthophenylenediamine (0.01 mol) in ethanol (20 ml) were refluxed with catalytic amounts of acetic acid for 5–6 h. The completion of reaction was monitored by TLC in chloroform and ethylacetate (3:1). The excess of solvent was removed; reaction mixture was cooled and poured into crushed ice with constant stirring. The solid mass thus obtained was filtered and washed with water and recrystallized from ethanol to get the title compounds (4a–h) (Scheme 1). All the newly synthesized compounds were characterised by IR, 1H NMR, 13C NMR and mass spectroscopic data. Yield 67–75%.
3.1.4.1 (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-4-(5-methyl-2-phenyl-1H-indol-3-yl)-1H-benzo [b][1,4]diazepine (4a)
Yield 75% (ethanol); mp 180–181 °C; IR (KBr) (νmax in cm−1): 3131, 3063, 2910, 1626, 1573; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.80 (s, 1H, indole NH), 6.8–7.6 (m, 15H, 14Ar-H, diazepine NH), 2.3 (s, 3H, CH3); 13C NMR(DMSO-d6 + CDCl3) δ (ppm): 165 (C⚌N), 30 (CH3) and 148, 138, 134, 132, 131, 130, 129, 128, 127, 124, 120, 117, 115, 114, 113 and 108; MS: m/z = 499 [M−1]+. Anal. Calcd for C28H19Cl2N3S (500): C, 67.20; H, 3.83; N, 08.40. Found: C, 67.17; H, 3.88; N, 08.32.
3.1.4.2 (2Z,4E)-4-(5-chloro-2-phenyl-1H-indol-3-yl)-2-(2,5-dichlorothiophen-3-yl)-1H-benzo[b][1,4]diazepine (4b)
Yield 70% (ethanol); mp 260–261 °C; IR (KBr) (νmax in cm−1): 3156, 3003, 2947, 1635, 1581; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 12.09 (s, 1H, indole NH), 7.2–7.8 (m, 15H, 14Ar-H, diazepine NH); MS: m/z = 521 [M+1]+. Anal. Calcd for C27H16Cl3N3S (520): C, 62.26; H, 3.10; N, 08.07. Found: C, 62.22; H, 3.04; N, 08.05.
3.1.4.3 (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-4-(2-phenyl-1H-indol-3-yl)-1H-benzo[b][1,4]diazepine (4c)
Yield 67% (ethanol); mp 255–257 °C; IR (KBr) (νmax in cm−1): 3201, 3011, 2990, 1646, 1553; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.20 (s, 1H, indole NH), 6.6–7.3 (m, 16H, 15Ar-H, diazepine NH); MS: m/z = 488 [M+2]+. Anal. Calcd for C27H17 Cl2N3S (486): C, 66.67; H, 3.52; N, 8.64. Found: C, 66.58; H, 3.26; N, 8.50.
3.1.4.4 (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-4-(1H-indol-3-yl)-1H-benzo[b][1,4]diazepine (4d)
Yield 67% (ethanol); mp 225–227 °C; IR (KBr) (νmax in cm−1): 3109, 3070, 2923, 1630, 1581; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.40 (s, 1H, indole NH), 6.9–7.6 (m, 12H, 11Ar-H, diazepine NH); MS: m/z = 409 [M−1]+. Anal. Calcd for C21H13Cl2N3S (410): C, 61.47; H, 3.19; N, 10.24. Found: C, 61.42; H, 3.23; N, 10.21.
3.1.4.5 (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-8-methyl-4-(5-methyl-2-phenyl-1H-indol-3-yl)-1H-benzo[b][1,4]diazepine (4e)
Yield 71% (ethanol); mp 187–188 °C; IR (KBr) (νmax in cm−1): 3211, 3105, 2915, 1650, 1543; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 9.90 (s, 1H, indole NH), 7.4–7.8 (m, 14H, 13Ar-H, diazepine NH), 2.6 (s, 3H, CH3), 2.4 (s, 3H, CH3); MS: m/z = 515 [M+1]+. Anal. Calcd for C29H21Cl2N3S (514): C, 67.70; H, 4.11; N, 08.17. Found: C, 67.76; H, 4.14; N, 08.13.
3.1.4.6 (2Z,4E)-4-(5-chloro-2-phenyl-1H-indol-3-yl)-2-(2,5-dichlorothiophen-3-yl)-8-methyl-1H-benzo[b][1,4]diazepine (4f)
Yield 70% (ethanol); mp 220–221 °C; IR (KBr) (νmax in cm−1): 3305, 3150, 2918, 1641, 1601; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 11.70 (s, 1H, indole NH), 6.8–7.5 (m, 14H, 13Ar-H, diazepine NH), 2.2 (s, 3H, CH3); MS: m/z = 535 [M+1]+. Anal. Calcd for C28H18Cl3N3S (534): C, 62.87; H, 3.39; N, 07.86. Found: C, 62.58; H, 3.41; N, 07.83.
3.1.4.7 (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-8-methyl-4-(2-phenyl-1H-indol-3-yl)-1H-benzo[b][1,4]diazepine (4g)
Yield 68% (ethanol); mp 267–268 °C; IR (KBr) (νmax in cm−1): 3233, 3115, 2895, 1630, 1531; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 10.10 (s, 1H, indole NH), 7.1–7.7 (m, 15H, 14Ar-H, diazepine NH), 2.5 (s, 3H, CH3); MS: m/z = 347 [M+2]+. Anal. Calcd for C28H19Cl2N3S (345): C, 67.20; H, 3.83; N, 8.40. Found: C, 67.28; H, 3.76; N, 8.20.
3.1.4.8 (2Z,4E)-2-(2,5-dichlorothiophen-3-yl)-4-(1H-indol-3-yl)-8-methyl-1H-benzo[b][1,4]diazepine (4h)
Yield 67% (ethanol); mp 177–178 °C; IR (KBr) (νmax in cm−1): 3218, 3180, 2900, 1646, 1542; 1H NMR (DMSO-d6 + CDCl3) δ (ppm): 12.30 (s, 1H, indole NH), 7.3–8.0 (m, 11H, 10Ar-H, diazepine NH), 2.4 (s, 3H, CH3); MS: m/z = 425 [M+1]+. Anal. Calcd for C22H15Cl2N3S (424): C, 62.27; H, 3.56; N, 09.90. Found: C, 62.20; H, 3.52; N, 09.96.
4 Conclusions
In conclusion, a new series of novel indolylbenzo[b][1,4]diazepins are designed and synthesized in good yields. In biological evaluations; it was observed that, the antimicrobial activity was increased with the methyl (4a and 4e) and chloro (4b and 4f) substitutions at the fifth position of the indole ring. Compounds 4b and 4f have shown promising results for free radical scavenging and total antioxidant capacity activities. In ferric reducing antioxidant power, compounds 4a, 4e and 4g have shown maximum reducing power. Therefore, our findings will provide a great impact on chemists and biochemists for further investigations in the indole field in search of molecules possessing potent antioxidant and antimicrobial activities. Based on these results, selected novel compounds are being screened in vivo which will be reported in due course.
Acknowledgement
One of the Authors B.S.Sasidhar is thankful to CSIR-SRF (Senior Research Fellowship, Ref. No. 9/450(0032)2K10-EMR-I), New Delhi 110 012, the Indian Institute of Science, Bangalore and the Central University, Hyderabad for spectral analysis.
References
- Food Chem. Toxicol.. 2008;46:2230.
- Biradar, J.S., 1982. Ph.D thesis, Gulbarga University at Gulbarga.
- Indian J. Chem.. 2004;43B(2):389.
- Indian J. Chem.. 2004;43B(1):141.
- Indian J. Pharm. Sci.. 2004;66(2):177.
- Biradar, J.S., Sasidhar, B.S., 2011. Eur. J. Med. Chem. doi:10.1016/j.ejmech.2011.10.004
- Indian J. Heterocycl. Chem.. 2008;18:141.
- Indian J. Heterocycl. Chem.. 2010;20:181.
- Eur. J. Med. Chem.. 2010;45:4074.
- Il Farmaco.. 1994;49:443.
- Bioorg. Med. Chem. Lett.. 2004;14:1547.
- J. Biol. Chem.. 1999;274:21937.
- Eur. J. Med. Chem.. 2010;45:4.
- De Baun, J.R., Pallos, F.M., Baker, D.R., 1977. U. S. Patent 3, 978, 227, 1976; Chem. Abstr. 86, 5498.
- In Comprehensive Heterocyclic Chemistry. In: Taylor E.C., ed. Bicyclic Diazepines. Newyork: Wiley; 1991. Vol 50
- [Google Scholar]
- Geigy, J.R., 1965. French Patent, 1, 389, 529; Chem Abstr. 63, 620.
- Katrizky A.R., Rees C.W., eds. In Comprehensive Heterocyclic Chemistry. Pergamon: Oxford; 1984. Vol 1
- Phcog Mag.. 2008;13:42.
- In Handbook of Experimental Pharmacology: midazolam and other benzodiazepines. Springer; 2008. 182, 335
- Bioorg. Med. Chem.. 2007;15:7368.
- Garattini S., Musini E., Randall L.O., eds. In benzodiazepines. Newyork: Raven Press; 1977.
- Reynolds, B.E., Carson, J.R., 1972. US Patent, 3, 689, 503; Chem. Abstr. 77, 52241.
- Benzodiazepines. Heidelberg: Springer; 1982.
- J. Agri. Food Chem.. 2002;50:81.
- Angew. Chem. Internet. Edit.. 1971;10:34.
- The Chemistry of Indoles. Newyork: Academic Press; 1996.
- Il Farmaco.. 1998;53:525.
- Indian J. Microbiol.. 1973;13:45.
- J. Med. Chem.. 2009;52:4941.
