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Synthesis and biological evaluation of newer 1,3,4-oxadiazoles incorporated with benzothiazepine and benzodiazepine moieties

  • Patel Navin EMAIL logo , Patel Sarvil , Purohit Amit , Patel Divyesh , Rajani Dhansukh , Rosa Moo-Puc and Gildardo Rivera
Published/Copyright: February 9, 2017
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Zeitschrift für Naturforschung C
From the journal Zeitschrift für Naturforschung C Volume 72 Issue 3-4

Abstract

A series of thiazepines and diazepines having 1,3,4-oxadiazole moiety were synthesized, and they were analyzed for their in vitro antimicrobial activity against several bacteria (Staphylococcus aureus, Staphylococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger, and Aspergillus Clavatus) and protozoa (Entamoeba histolytica, Giardia lamblia, Trypanosoma cruzi and Leishmania mexicana). Few of the selected compounds were tested for their antitubercular activity. However, it was noticed that the potency of final analogs against each strain placed reliance on the type of substituent present on aryl ring of oxadiazole as well as presence of thiophene, pyridine, and furan at benzothiazepines and benzodiazepines. The biological screening identified that some of the compounds were found to possess good antimicrobial and antitubercular (62.5–100 μg/mL of MIC) activity.

Keywords: antimicrobial activity; antituberculosis activity; benzodiazepines; benzothiazepines; 1,3,4-Oxadiazole

1 Introduction

The worldwide prevalence of multi-drug-resistant bacteria strains in care stations, hospitals, and general community demands new compounds with novel mechanisms to combat these pathogens. In recent years, much attention has been focused on the multi-drug-resistant bacteria and fungi resulting from the widespread use and misuse of classical antimicrobial drugs. Developing novel antimicrobial agents with different mode of action than that of existing drugs is one of the main challenges to overcome antimicrobial resistance. In view of these facts, it is important to develop more effective antimicrobial agents. Thus, the synthesis and discovery of more efficient antimicrobial agents have been intensively considered during the last decade. Different heterocyclic compounds containing nitrogen, sulphur, and oxygen as hetero atoms have been explored for the development of new antimicrobial agents as well as for other bioactivities [1], [2], [3], [4].

Among several heterocyclic compounds, 1,3,4-oxadiazole has become an important construction motif for the development of new drugs. Compounds containing 1,3,4-oxadiazole cores have a broad biological activity spectrum including antibacterial, antifungal [5], anti-HIV [6], antitumor [7], anti-inflammatory [8], antitubercular [9], anticancer [10], anticonvulsant, and anti-diabetic [11] properties. On the other hand, benzothiazepine derivatives have attracted considerable interest owing to their wide spectrum of biological activity [12], [13], including anticonvulsant [14], [15], antipsychotic [16], antitumor [17], anti-HIV [18], and antimicrobial [19] properties, while benzodiazepine analogs were found to show anti-inflammatory, anti-pyretic [20], anticancer [21], antidepressant [22], and anti-anxiety activity [23]. The 1,3,4-oxadiazole, benzothiazepine, and benzodiazepine nucleus has emerged as one of the potential pharmacophores responsible for diverse pharmacological properties. In a view of above bioactivity results found in literature survey aspired us to derive a system in which 1,3,4-oxadiazole incorporated with thiazepine and diazepines (Figure 1).

Figure 1: General structure and numeration for 6a–o, 7a–o.
Figure 1:

General structure and numeration for 6a–o, 7a–o.

2 Results and discussion

2.1 Chemistry

The reaction arrangements adapted to furnish intermediates 3a–o (thiazepines), 4a–o (diazepines), and final derivatives 6a–o and 7a–o (1,3,4-oxadiazoles) are outlined in Scheme 1. Solvents and reagents were used as received or were dried prior to use as needed. In this work, as shown in Scheme 1, 2-amino thiophenol/o-phenylenediamine 1 on reaction with 1-(4-hydroxy-phenyl)-3-thiophene/pyridine/furan-2-yl-propenone 2 yielded the intermediate compounds 3a–c and 4a–c having thiazepine and diazepine moiety, respectively, clubbed with thiophene, pyridine, and furan ring.

Scheme 1: Synthesis of thiazepine and diazepine derivatives. (i) Ethanol, TFA, refluxed 15–17 h; (ii) methanol, KOH, refluxed 12–15 h.
Scheme 1:

Synthesis of thiazepine and diazepine derivatives. (i) Ethanol, TFA, refluxed 15–17 h; (ii) methanol, KOH, refluxed 12–15 h.

In our previous work, we have already reported the synthesis of 2-chloromethyl-5-(substituted phenyl)-1,3,4-oxadiazoles [24]. Further on, the reaction of compounds 3a–c and 4a–c with 2-chloromethyl-5-(substituted phenyl)-1,3,4-oxadiazoles 5a–e yielded the corresponding 1,3,4-oxadiazoles with thiazepine 6a–o and diazepine 7a–o final analogs.

The structures of the synthesized compounds were confirmed by spectral data and elemental analysis, and they were in full agreement with the proposed structures. As we have provided, the spectral data from that IR spectrum (see supplementary material data) of compound 3b having thiazepine moiety showed band at 3290 cm−1 for O-H group, 2963 cm−1 and 2840 cm−1 for C-H asym and sym band, and 1616 cm−1 for >C=N-, while compound 4a having diazepine moiety displayed band at 3341 cm−1 (N-H), 3258 cm−1 (O-H), and 1592 cm−1 (>C=N-). From 1H NMR data, the structure of thiophene ring containing compound 3a was confirmed by the presence of one proton of -OH as singlet at δ 8.35 ppm. Protons corresponding to the -CH2 resonated at δ 3.06–3.74 ppm, and their peaks appeared as doublet of doublet (dd) and one dd peak was observed at δ 5.52–5.56 ppm, while aromatic protons appeared as multiplate at δ 6.91–8.03 ppm. In 1H NMR of compound 4c having furan ring, the presence of -NH was confirmed by singlet peak at δ 8.35 ppm. The appearance of two dd peaks for CH2 at δ 3.07–3.75 ppm, one dd at δ 5.50–5.55 ppm, and aromatic hydrogen as multiplate at 7.15–8.10 ppm also gave confirmation for formation of compound 4c. Therefore, in a similar way, structures of other compounds of 3a–o and 4a–o were confirmed.

In the case of final thiazepine analogs 6a–o, the IR spectrum of final analog 6f containing -Cl group on aryl ring of oxadiazole showed characteristic band at 743 cm−1 and 1618 cm−1 for >C=N. Compound 6m having -NO2 group on aryl ring showed asym and sym band at 1529 and 1349 cm−1, respectively. In 1H NMR of compound 6b, the proton corresponding to -OCH3 was observed at δ 3.85 ppm as singlet and other singlet peak at δ 5.28 ppm for protons of -CH2O was observed. The mass spectrum of compound 6o (mw=493.58) showed the m/z value as 493.1 (M+), 494.1 (M++1), and 495.1 (M++2).

In the case of diazepine analogs 7a–o, compound 7a having -Cl and 7I having 3-NO2 at aryl ring showed band at 747 cm−1 and 1545, 1360 cm−1 (asym, sym), respectively. The presence of -NH was confirmed by band at 3355 cm−1 (for 7a) and 3360 cm−1 (for 7I). In 1H NMR data of compound 7l, the singlet peak for one proton of NH appeared at δ 8.38 ppm. The presence of -OCH3 was supported by singlet peak for three protons at δ 3.85 ppm. The singlet signal at δ 5.26 ppm for -CH2O also gave correction to the formation of 7l. The mass spectrum of compound 7k (mw=496.94) showed the m/z value as 497.3 (M+), 498.3 (M++1), 499.1 (M++2), and 500.1 (M++3). Therefore, in a similar way, the structure confirmations of other final analogs were also confirmed by their spectral and elemental analysis, which is shown in the characterization data.

2.2 Biological activities

The synthesized compounds 3a–c, 4a–c, 6a–o, and 7a–o were evaluated for in vitro antibacterial, antifungal, and antiprotozoal activities against various Gram-positive and Gram-negative bacteria, fungal, and protozoal species. The results are shown in Tables 1–6 .

Table 1:

In vitro antimicrobial activity of newly synthesized compounds 3a–c and 4a–c.

Compd. no.RMinimum inhibitory concentration (MIC) in (μg/mL)
Gram negative bacteriaGram positive bacteriaFungal species
E. coliP. aeruginosaS. aureusS. pyogenesC. albicansA. nigerA. Clavatus
3aThiophen-2-yl125200250250100010001000
3bPyridine-2-yl200250125200500>1000>1000
3cFuran-2-yl1001002002001000>1000>1000
4aThiophen-2-yl125100250250500>1000>1000
4bPyridine-2-yl200250250200500>1000>1000
4cFuran-2-yl2502505001000>1000500500
Ampicillin100100250100–––
Chloramphenicol50505050–––
Griseofulvin––––500100100
Table 2:

In vitro antimicrobial activity of thiazepine compounds 6a–o.

Compd. no.RMinimum inhibitory concentration (MIC) in (μg/mL)
Gram negative bacteriaGram positive bacteriaFungal species
E. coliP. aeruginosaS. aureusS. pyogenesC. albicansA. nigerA. Clavatus
6a4-Cl1251002002001000250500
6b4-OCH3100125250250500500500
6c4-NO212520062.510025010001000
6d3-NO225025010012550010001000
6e4-CH3200200250125500>1000>1000
6f4-Cl2502502002501000500500
6g4-OCH3250250125250>10002501000
6h4-NO2500100062.5100>10005001000
6i3-NO2250125125200>1000500500
6j4-CH312562.5250250>1000>1000>1000
6k4-Cl125250125100250500500
6l4- OCH320025062.5125250500500
6m4-NO2100200100200100010001000
6n3-NO22502502502505001000>1000
6o4-CH32001002002501000500500
Ampicillin100100250100–––
Chloramphenicol50505050–––
Griseofulvin––––500100100
Table 3:

In vitro antimicrobial activity of newly diazepine compounds 7a–o.

Compd. no.RMinimum inhibitory concentration (MIC) in (μg/mL)
Gram negative bacteriaGram positive bacteriaFungal species
E. coliP. aeruginosaS. aureusS. pyogenesC. albicansA. nigerA. Clavatus
7a4-Cl200250100100500>1000>1000
7b4-OCH320025062.5200500>1000>1000
7c4-NO2200125200250250>1000>1000
7d3-NO21251002002505005001000
7e4-CH32002502502001000500500
7f4-Cl250200250250100010001000
7g4-OCH3125125500500100010001000
7h4-NO220062.5250500>1000>1000>1000
7i3-NO2250125200250>1000>1000>1000
7j4-CH320020010010001000500500
7k4-Cl125100100200100010001000
7l4-OCH3250200100250500>1000>1000
7m4-NO2250250200250>1000>1000>1000
7n3-NO2100100125250>1000>1000>1000
7o4-CH3200250200250250>1000>1000
Ampicillin100100250100–––
Chloramphenicol50505050–––
Griseofulvin––––500100100
Table 4:

Antitubercular activity of some selected compounds (MICs, μg/mL).

CompoundMIC (μg/mL)CompoundMIC (μg/mL)R
6a21.07a21.54-Cl
6b>1007b21.54-OCH3
6c>1007c10.34-NO2
6d11.07d47.53-NO2
6e11.97e>1004-CH3
6f>1007f40.54-Cl
6g28.57g45.74-OCH3
6h>1007h95.34-NO2
6i11.67i>1003-NO2
6j29.67j23.04-CH3
6k44.87k14.94-Cl
6l44.67l8.84-OCH3
6m43.77m6.24-NO2
6n>1007n24.33-NO2
6o>1007o49.44-CH3
Rifampicin0.05
Isoniazid0.23
Streptomycin0.46
PA-8240.14
TMC0.12
Table 5:

Antiprotozoal activity of compounds 6a–o.

CompoundRIC50 (μg/mL)
T. vaginalisG. lambliaT. cruziL. mexicana
6a4-Cl>203.89>50>50
6b4-OCH3>2019.86>50>50
6c4-NO2>202.01>500.65
6d3-NO2>205.95>504.06
6e4-CH3>208.64>502.69
6f4-Cl>20>20>50>50
6g4-OCH3>204.86>50>50
6h4-NO2>20>10>50>50
6i3-NO2>202.74>503.02
6j4-CH3>20>20>50>50
6k4-Cl5.94>20>50>50
6l4-OCH3>2016.21>50>50
6m4-NO2>20>20>504.06
6n3-NO2>20>20>504.73
6o4-CH3>20>20>50>50
Albendazole0.0161.083––
Metronidazole0.220.119––
Nitazoxanide0.0070.308––
Benznidazole––2.90–
Miltefosine–––0.55
Table 6:

Antiprotozoal activity of compounds 7a–o.

CompoundRIC50 (μg/mL)
T. vaginalisG. lambliaT. cruziL. mexicana
7a4-Cl>20>20>50>50
7b4-OCH3>2013.44>50>50
7c4-NO2>20>200.910.19
7d3-NO2>20>20>502.78
7e4-CH3>2010.80>50>50
7f4-Cl>20>20>50>50
7g4-OCH3>208.63>500.33
7h4-NO2>2012.795.140.92
7i3-NO2>20>20>502.20
7j4-CH3>205.29>50>50
7k4-Cl>203.164.022.51
7l4-OCH3>201.851.030.82
7m4-NO2>2015.38>505.90
7n3-NO216.12>20>50>50
7o4-CH3>20>20>50>50
Albendazole0.0161.083––
Metronidazole0.220.119––
Nitazoxanide0.0070.308––
Benznidazole––2.90–
Miltefosine–––0.55

From the antibacterial and antifungal activity of compounds 3a–c and 4a–c (Table 1), it was found that benzothiazepine compound 3c having furan ring showed excellent activity (MIC=100 μg/mL) against both Gram-negative bacteria and it is comparable to the standard drug ampicillin, while compound 3b having pyridine ring showed a minimum value of MIC=125 μg/mL against Staphylococcus aureus compared to other compounds. Compounds 3b, 3c, and 4b inhibited Streptococcus pyogenes at similar MIC=200 μg/mL.

The antibacterial and antifungal activity of compound 6a–o (Table 2) showed that pyridin ring containing compound 6j having 4-CH3 group at aryl ring showed the best MIC=62.5 μg/mL against Pseudomonas aeruginosa compared to other compounds. Compounds 6c (4-NO2), 6h (4-NO2), and 6l (4-OCH3) having thiophene, pyridine, and furan rings, respectively, showed significant MIC=62.5 μg/mL against S. aureus, which is better than the MIC of ampicillin against the same bacteria. For antifungal activity, the activity of compounds 6c, 6k, and 6l against Candida albicans is better than that of the standard drug griseofulvin.

In case of antibacterial and antifungal activity of compound 7a–o (Table 3), bacterium S. aureus was inhibited at the lowest MIC=62.5 μg/mL by 7b (4-OCH3) having thiophene ring. Compound 7a having -Cl group at aryl ring and thiophene moiety showed equipotent activity with standard drug ampicillin (MIC=100 μg/mL) against S. pyogenes. Benzodiazepines 7c and 7o inhibited to C. albicans at MIC=250 μg/mL, while others in the range of MICs=500 to >1000 μg/mL, against all fungi.

The antitubercular activity (Table 4) revealed that compounds 6a (Cl), 6d (3-NO2), and 6e (4-CH3) showed MICs in the range of 11.0–21.0 μg/mL. In pyridine derivatives, 6g and 6i showed MIC values of 28.5 and 11.6 μg/mL, respectively. From the screening, it was found that compound 7m with NO2 group at 4-position on benzene and furan groups on benzodiazepine ring showed better MIC=6.2 μg/mL.

In the case of antiprotozoal activity of 6a–o (Table 5), biological activity on G. lamblia showed interesting results. Compound 6i with a 4-NO2 group showed the best IC50 with a value of 2.74 μg/mL, and compounds 6a, 6c, and 6g showed values of IC50<5.0 μg/mL. These compounds have a thiophene and pyridine ring on benzothiazepine moiety. Compounds 6d, 6e, 6i, 6m, and 6n demonstrated a good leishmanicidal activity with values of IC50 between 2.69 and 4.73 μg/mL against L. mexicana but with IC50 values above the control positive. Only compound 6c with a NO2 group at para position on benzene and thiophene ring on benzothiazepine moiety showed a significant IC50 of 0.65 μg/mL, a similar value with that of the standard drug miltefosine.

The antiprotozoal activity of 7a–o (Table 6) displays that compounds 7k (4-Cl) and 7l (4-OCH3) with a furan ring on benzodiazepine moiety showed the better biological activity on Giardia lamblia with MIC values of 3.16 and 1.85 μg/mL, respectively. In case of trypanocidal activity, compounds 7c and 7l, with NO2 and OCH3 groups at para position on benzene ring, respectively, showed better values of IC50 than the reference drug benznidazole. Also, 7c and 7g showed better values of IC50 on Leishmania mexicana than miltefosine. Interestingly, compound 7c with an electron-withdrawing (NO2) group at para position on benzene ring and thiophene on benzodiazepine moiety had a better biological activity against both parasites than that of the reference drugs.

3 Experimental

The solvents and reagents were used as received or were dried prior to use as needed. Melting points were determined in open capillaries on a Veego electronic apparatus VMP-D and are uncorrected. IR spectra (4000–400 cm−1) of synthesized compounds were recorded on a Shimadzu 8400-S FT-IR spectrophotometer using KBr pellets. Thin layer chromatography was performed on object glass slides (2 cm×7.5 cm) coated with silica gel-G, and spots were visualized under UV irradiation. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance II 400 MHz model spectrometer using CDCl3 as a solvent and TMS as internal standard with 1H resonant frequency of 400 MHz and 13C resonant frequency of 100 MHz. The 1H NMR and 13C NMR chemical shifts were reported as parts per million (ppm) downfield from TMS (Me4Si). Splitting patterns are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; q, quartet; and m, multiplet. The mass spectra were recorded on an JEOL SX-102 (EI) model. Elemental analyses (C, H, and N) CDCl3 were performed using a Heraeus Carlo Erba 1180 CHN analyzer. All chemicals and reagents were purchased from Sigma Aldrich, India.

3.1 Synthesis

3.1.1 Synthesis of 4-(2-thiophen-2-yl-2,3,5a,9a-tetrahydro-benzo[b][1,4]thiazepin-4-yl)-phenol (3a) and 4-[2-(1H-pyrrol-2-yl)-2,3,5a,9a-tetrahydro-benzo[b][1,4]thiazepin-4-yl]-phenol (4a)

A solution of 1-(4-hydroxy-phenyl)-3-thiophen-2-yl-propenone 2a (0.01 mol) and 2-amino thiophenol (for 3a)/o-phenylenediamine (for 4a) (0.015 mol) in 60 mL ethanol was refluxed for 30 min; afterwards, 3 mL trifluoroacetic acid was added and refluxed for another 15–17 h. Progress of the reaction was checked by TLC using toluene:methanol (80:20) as mobile phase. Reaction mixture was diluted with 50 mL 10% NaOH solution and extracted with 20×3 mL methylene dichloride. The aqueous solution was acidified with dilute HCl. The solid obtained was filtered and washed with water. Purification by column chromatography:mobile phase toluene:ethylacetate (7.5:2.5) has been selected after putting TLC in different solvent systems. In particular, system impurity and product were well separated with Rf value of 0.84 (impurity) and 0.59 (product). Pecked silica column was saturated with mobile phase, and solution of compound was added; 10–15 fractions were collected separately. Pure compound was obtained by putting the TLC of every fraction.

By similar process, pyridine (3b, 4b) and furan (3c, 4c) compounds were synthesized.

3.1.1.1 Characterization of 3a–c and 4a–c 4-(2-thiophen-2-yl-2,3,5a,9a-tetrahydro-benzo[b][1,4]thiazepin-4-yl)-phenol (3a)

Yield: 68%; m.p. 103–106°C; IR (KBr, cm−1): 3287 (O-H), 2955, 2838 (C-H asym, sym), 1610 (>C=N-); 1H NMR (CDCl3): 3.06–3.12 (dd, 1H, JBA =17.56, JBX =4.52), 3.66–3.74 (dd, 1H, JAB =17.56, JAX =11.76), 5.52–5.56 (d, 1H, JXB =4.52, JXA =11.76), 6.91–8.03 (m, 14H, Ar-H), 8.35 (s, 1H, OH). MS (EI) m/z: 340.1 (M+1); Anal. Calcd for C19H17NOS2: C, 67.22; H, 5.05; N, 4.13%. Found: C, 67.16; H, 3.97; N, 7.82%.

3.1.1.2 4-(2-Pyridin-2-yl-2,3,5a,9a-tetrahydro-benzo[b][1,4]thiazepin-4-yl)-phenol (3b)

Yield: 71%; m.p. 121–125°C; IR (KBr, cm−1): 3290 (O-H), 2963, 2840 (C-H asym, sym), 1616 (>C=N-); 1H NMR (CDCl3): 3.11–3.15 (dd, 1H, JBA =17.34, JBX =4.43), 3.62–3.71 (dd, 1H, JAB =17.51, JAX =11.65), 5.61–5.68 (d, 1H, JXB =4.47, JXA =11.68), 6.82–8.01 (m, 14H, Ar-H), 8.31(s, 1H, OH). MS (EI) m/z: 335.3 (M+1); Anal. Calcd for C20H18N2OS: C, 71.83; H, 5.42; N, 8.38%. Found: C, 71.75; H, 5.33; N, 8.43%.

3.1.1.3 4-(2-Furan-2-yl-2,3,5a,9a-tetrahydro-benzo[b][1,4]thiazepin-4-yl)-phenol (3c)

Yield: 69%; m.p. 133–135°C; IR (KBr, cm−1): 3282 (O-H), 2968, 2847 (C-H asym, sym), 1627 (>C=N-); 1H NMR (CDCl3): 3.14–3.18 (dd, 1H, JBA =17.45, JBX =4.41), 3.55–3.61 (dd, 1H, JAB =17.49, JAX =11.61), 5.58–5.63 (d, 1H, JXB =4.36, JXA =11.58), 6.69–8.11 (m, 14H, Ar-H), 8.42 (s, 1H, OH); MS (EI) m/z: 324.5 (M+1); Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33%. Found: C, 70.51; H, 5.37; N, 4.33%.

3.1.1.4 4-(4-Thiophen-2-yl-4,5,5a,9a-tetrahydro-3H-benzo[b][1,4]diazepin-2-yl)-phenol (4a)

Yield: 77%; m.p. 119–122°C; IR (KBr, cm−1): 3341 (N-H), 3258 (O-H), 2916, 2830 (C-H asym, sym), 1592 (>C=N-); 1H NMR (CDCl3): δ 3.21–3.30 (dd, 1H, JBA =17.42, JBX =3.81), 3.60–3.73 (dd, 1H, JAB =17.45, JAX =11.32), 5.81–5.88 (dd, 1H, JXA =3.77, JXB =11.27), 6.83–7.66 (m, 13H, Ar-H), 8.25(s, 1H, >NH), 8.47 (s, 1H, OH); MS (EI) m/z: 323.4 (M+1); Anal. Calcd for C19H18N2OS: C, 70.78; H, 5.63; N, 8.69%. Found: C, 70.86; H, 5.58; N, 8.62%.

3.1.1.5 4-(4-Pyridin-2-yl-4,5,5a,9a-tetrahydro-3H-benzo[b][1,4]diazepin-2-yl)-phenol (4b)

Yield: 75%; m.p. 144–146°C; IR (KBr, cm−1): 3337 (N-H), 3265 (O-H), 2931, 2843 (C-H asym, sym), 1583 (>C=N-); 1H NMR (CDCl3): δ 3.28–3.34 (dd, 1H, JBA =17.34, JBX =3.87), 3.67–3.75 (dd, 1H, JAB =17.27, JAX =11.43), 5.77–5.83 (dd, 1H, JXA =3.60, JXB =11.45), 6.92–7.89 (m, 14H, Ar-H), 8.20 (s, 1H, >NH), 8.53 (s, 1H, OH); MS (EI) m/z: 318.1 (M+1); Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24%. Found: C, 75.61; H, 6.15; N, 13.17%.

3.1.1.6 4-(4-Furan-2-yl-4,5,5a,9a-tetrahydro-3H-benzo[b][1,4]diazepin-2-yl)-phenol (4c)

Yield: 80%; m.p. 134–136°C; IR (KBr, cm−1): 3345 (N-H), 3271 (O-H), 2953, 2840 (C-H asym, sym), 1612 (>C=N-); 1H NMR (CDCl3): δ 3.07–3.12 (dd, 1H, JBA =17.41, JBX =4.11), 3.68–3.75 (dd, 1H, JAB =17.67, JAX =11.71), 5.50–5.55 (dd, 1H, JXA =4.32, JXB =11.50), 7.15–8.10 (m, 13H, Ar-H), 8.35 (s, 1H, >NH), 8.68 (s, 1H, OH); MS (EI) m/z: 307.8 (M+1); Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14%. Found: C, 74.42; H, 5.88; N, 9.22%.

3.1.2 Synthesis of 4-{4-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6a) and 4-{4-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7a)

Solution of 2-chloromethyl-5-(4-chlorophenyl)-1,3,4-oxadiazole 5a (0.01 mol) in 15 mL methanol was added part wise in 15 mL methanolic solution of 3a/4a (0.01 mol) and potassium hydroxide (0.15 mol). After addition, reaction mixture was refluxed on water bath for 12–15 h. Progress of the reaction was checked by TLC using toluene:methanol (75:25) as mobile phase. The reaction mixture was cooled and poured into crushed ice with continuous stirring. The resulting solid thus obtained was collected by filtration, washed well with cold water, dried, and recrystallized from absolute ethanol and yielded the compound 6a/7a. Other 1,3,4-oxadiazolyl-benzothiazepines and 1,3,4-oxadiazolyl-benzodiazepines have been prepared by the same method with thiophene-2-aldehyde (for synthesis of 6b–e and 7b–e), pyridine-2-aldehyde (for synthesis of 6f–j and 7f–j), and furan-2-aldehyde (for synthesis of 6k–o and 7k–o).

3.2 Characterization data of compound 6a–o

3.2.1 4-{4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6a)

Yield: 57%; m.p. 141–143°C; IR (KBr, cm−1): 2958, 2862 (C-H asym, sym), 1612 (>C=N-), 758 (C-Cl); 1H NMR (CDCl3): δ 3.26–3.32 (dd, 1H, JBA =17.45, JBX =3.89), 3.67–3.75 (dd, 1H, JAB =17.45, JAX =11.32), 5.31 (s, 2H, -CH2O-), 5.89–5.94 (dd, 1H, JXA =3.86, JXB =11.37), 6.86–8.25 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.46 (C-18), 44.21 (C-19), 72.76 (C-10), 116.97 (C-22), 119.11 (C-14), 121.19 (C-29), 121.56 (C-27), 122.76 (C-23), 124.23 (C-28), 125.15 (C-24), 126.52 (C-12, C-16), 127.46 (C-3, C-7), 128.33 (C-25), 129.14 (C-4, C-6), 129.67 (C-13, C-15), 133.66 (C-5), 135.33 (C-2), 140.22 (C-20), 140.65 (C-26), 142.56 (C-21), 144.47 (C-17), 144.78 (C-11), 162.33 (C-8), 164.13 (C-9); MS (EI) m/z: 531.1 (M+1); Anal. Calcd for C28H20N3O2ClS2: C, 63.45; H, 3.80; N, 7.93%. Found: C, 63.41; H, 3.87; N, 7.87%.

3.2.2 4-{4-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6b)

Yield: 62%; m.p. 161–163°C; IR (KBr, cm−1): 2953, 2860 (C-H asym, sym), 1616 (>C=N-), 1289 (-OCH3); 1H NMR (CDCl3): δ 3.29–3.34 (dd, 1H, JBA =17.48, JBX =3.84), 3.65–3.72 (dd, 1H, JAB =17.48, JAX =11.36), 3.85 (s, 3H, -OCH3), 5.28 (s, 2H, -CH2O-), 5.87–5.91 (dd, 1H, JXA =3.80, JXB =11.32), 6.90–8.30 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.28 (C-18), 44.52 (C-19), 59.29 (C-1), 72.68 (C-10), 117.15 (C-22), 119.18 (C-14), 121.14 (C-29), 121.21 (C-27), 123.45 (C-23), 124.51 (C-28), 125.48 (C-24), 126.59 (C-12, C-16), 127.15 (C-3, C-7), 128.45 (C-25), 129.05 (C-4, C-6), 129.53 (C-13, C-15), 133.37 (C-5), 140.50 (C-20), 140.86 (C-26), 142.22 (C-21), 144.16 (C-17), 145.58 (C-11), 153.88 (C-2), 162.78 (C-8), 164.82 (C-9); MS (EI) m/z: 526.0 (M+1); Anal. Calcd for C29H23N3O3S2: C, 66.26; H, 4.41; N, 7.99%. Found: C, 66.23; H, 4.48; N, 7.91%.

3.2.3 4-{4-[5-(4-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6c)

Yield: 58%; m.p. 193–195°C; IR (KBr, cm−1): 2962, 2859 (C-H asym, sym), 1615 (>C=N-), 1531, 1347 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.34–3.39 (dd, 1H, JBA =17.45, JBX =3.91), 3.60–3.66 (dd, 1H, JAB =17.40, JAX =11.28), 5.32 (s, 2H, -CH2O-), 5.83–5.90 (dd, 1H, JXA =3.82, JXB =11.30), 6.92–8.32 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.33 (C-18), 43.68 (C-19), 71.96 (C-10), 116.91 (C-22), 119.56 (C-14), 121.22 (C-29), 121.32 (C-27), 122.71 (C-23), 124.39 (C-28), 125.19 (C-24), 126.47 (C-12, C-16), 127.97 (C-3, C-7), 128.56 (C-25), 128.95 (C-4, C-6), 129.55 (C-13, C-15), 134.12 (C-5), 140.35 (C-20), 140.77 (C-26), 142.13 (C-21), 144.54 (C-17), 144.89 (C-11), 148.31 (C-2), 161.90 (C-8), 164.27 (C-9); MS (EI) m/z: 541.2 (M+1); Anal. Calcd for C28H20N4O4S2: C, 62.21; H, 3.73; N, 10.36%. Found: C, 62.28; H, 3.76; N, 10.30%.

3.2.4 4-{4-[5-(3-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6d)

Yield: 60%; m.p. 174–175°C; IR (KBr, cm−1): 2959, 2863 (C-H asym, sym), 1621 (>C=N-), 1535, 1351 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.32–3.38 (dd, 1H, JBA =17.43, JBX =3.93), 3.65–3.71 (dd, 1H, JAB =17.36, JAX =11.35), 5.37 (s, 2H, -CH2O-), 5.81–5.88 (dd, 1H, JXA =3.76, JXB =11.37), 6.87–8.25 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.69 (C-18), 44.15 (C-19), 72.37 (C-10), 117.54 (C-22), 119.32 (C-14), 121.33 (C-29), 121.52 (C-27), 122.64 (C-23), 124.20 (C-28), 125.36 (C-24), 126.55 (C-12, C-16), 128.25 (C-3, C-7), 128.59 (C-25), 129.21(C-4, C-6), 129.44 (C-13, C-15), 134.10 (C-5), 140.39 (C-20), 140.89 (C-26), 142.25 (C-21), 144.77 (C-17), 145.11 (C-11), 147.52 (C-2), 162.23 (C-8), 164.49 (C-9); MS (EI) m/z: 541.1 (M+1); Anal. Calcd for C28H20N4O4S2: C, 62.21; H, 3.73; N, 10.36%. Found: C, 62.24; H, 3.71; N, 10.40%.

3.2.5 2-Thiophen-2-yl-4-[4-(5-p-tolyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-2,3-dihydro-benzo[b][1,4]thiazepine (6e)

Yield: 68%; m.p. 152–154°C; IR (KBr, cm−1): 2958, 2864 (C-H asym, sym), 1611 (>C=N-), 1446 (-CH3); 1H NMR (CDCl3): δ 2.29 (s, 3H, -CH3), 3.31–3.36 (dd, 1H, JBA =17.41, JBX =3.87), 3.61–3.68 (dd, 1H, JAB =17.43, JAX =11.32), 5.32 (s, 2H, -CH2O-), 5.85–5.89 (dd, 1H, JXA =3.77, JXB =11.26), 6.92–8.32 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.21 (C-18), 44.63 (C-19), 21.27 (C-1), 72.76 (C-10), 117.11 (C-22), 119.12 (C-14), 120.94 (C-29), 121.52 (C-27), 123.63 (C-23), 124.11 (C-28), 125.40 (C-24), 126.35 (C-12, C-16), 127.10 (C-3, C-7), 128.32 (C-25), 129.18 (C-4, C-6), 129.67 (C-13, C-15), 133.29 (C-5), 138.17 (C-2), 140.66 (C-20), 140.81 (C-26), 142.10 (C-21), 144.23 (C-17), 145.63 (C-11), 162.64 (C-8), 164.22 (C-9); MS (EI) m/z: 510.1 (M+1); Anal. Calcd for C29H23N3O2S2: C, 68.34; H, 4.55; N, 8.25%. Found: C, 68.39; H, 4.50; N, 8.17%.

3.2.6 4-{4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6f)

Yield: 61%; m.p. 169–171°C; IR (KBr, cm−1): 2969, 2865 (C-H asym, sym), 1618 (>C=N-), 743 (C-Cl); 1H NMR (CDCl3): δ 3.35–3.41 (dd, 1H, JBA =17.34, JBX =3.87), 3.61–3.72 (dd, 1H, JAB =17.32, JAX =11.37), 5.22 (s, 2H, -CH2O-), 5.88–5.93 (dd, 1H, JXA =3.87, JXB =11.33), 6.90–8.30 (m, 16H, Ar-H); 13C NMR (CDCl3): 42.17 (C-18), 44.75 (C-19), 72.68 (C-10), 117.11 (C-22), 119.56 (C-14), 121.32 (C-29), 122.56 (C-27), 122.62 (C-23), 125.11 (C-24), 126.82 (C-12, C-16), 127.30 (C-3, C-7), 128.12 (C-25), 129.25 (C-4, C-6), 129.79 (C-13, C-15), 133.52 (C-5), 134.91 (C-28), 135.10 (C-2), 140.49 (C-20), 142.22 (C-21), 144.69 (C-17), 144.86 (C-11), 151.53 (C-30), 161.31 (C-26), 162.88 (C-8), 164.45 (C-9); MS (EI) m/z: 526.0 (M+1); Anal. Calcd for C29H21N4O2ClS: C, 66.34; H, 4.03; N, 10.67%. Found: C, 66.24; H, 4.10; N, 10.71%.

3.2.7 4-{4-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6g)

Yield: 72%; m.p. 178–180°C; IR (KBr, cm−1): 2959, 2855 (C-H asym, sym), 1610 (>C=N-), 1285 (-OCH3); 1H NMR (CDCl3): δ 3.33–3.38 (dd, 1H, JBA =17.32, JBX =3.81), 3.63–3.70 (dd, 1H, JAB =17.38, JAX =11.32), 3.79 (s, 3H, -OCH3), 5.27 (s, 2H, -CH2O-), 5.91–5.96 (dd, 1H, JXA =3.83, JXB =11.36), 6.95–8.35 (m, 16H, Ar-H); 13C NMR (CDCl3): 42.54 (C-18), 43.95 (C-19), 59.56 (C-1), 72.12 (C-10), 117.95 (C-22), 119.23 (C-14), 121.45 (C-29), 122.76 (C-27), 122.88 (C-23), 125.24 (C-24), 126.37 (C-12, C-16), 127.29 (C-3, C-7), 128.05 (C-25), 129.34 (C-4, C-6), 130.11 (C-13, C-15), 133.43 (C-5), 135.12 (C-28), 135.10 (C-2), 140.49 (C-20), 142.22 (C-21), 144.69 (C-17), 144.86 (C-11), 151.53 (C-30), 161.46 (C-26), 162.92 (C-8), 164.66 (C-9); MS (EI) m/z: 521.3 (M+1); Anal. Calcd for C30H24N4O3S: C, 69.21; H, 4.65; N, 10.76%. Found: C, 69.26; H, 4.61; N, 10.85%.

3.2.8 4-{4-[5-(4-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6h)

Yield: 78%; m.p. 187–189°C; IR (KBr, cm−1): 2961, 2868 (C-H asym, sym), 1623 (>C=N-), 1532, 1347 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.25–3.31 (dd, 1H, JBA=17.26, JBX=3.85), 3.70–3.77 (dd, 1H, JAB=17.35, JAX=11.32), 5.30 (s, 2H, -CH2O-), 5.91–5.96 (dd, 1H, JXA=3.84, JXB=11.42), 6.83–8.22 (m, 16H, Ar-H); 13C NMR (CDCl3): 42.35 (C-18), 44.65 (C-19), 72.21 (C-10), 117.49 (C-22), 119.44 (C-14), 121.67 (C-29), 122.23 (C-27), 122.53 (C-23), 125.74 (C-24), 126.41 (C-12, C-16), 127.22 (C-3, C-7), 128.29 (C-25), 129.38 (C-4, C-6), 129.90 (C-13, C-15), 133.41 (C-5), 134.88 (C-28), 140.41 (C-20), 142.06 (C-21), 144.32 (C-17), 145.17 (C-11), 148.29 (C-2), 151.66 (C-30), 161.39 (C-26), 163.12 (C-8), 164.65 (C-9); MS (EI) m/z: 536.1 (M+1); Anal. Calcd for C29H21N5O4S: C, 65.04; H, 3.95; N, 13.08%. Found: C, 65.09; H, 3.91; N, 13.02%.

3.2.9 4-{4-[5-(3-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6i)

Yield: 65%; m.p. 156–158°C; IR (KBr, cm−1): 2965, 2865 (C-H asym, sym), 1619 (>C=N-), 1539, 1341 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.28–3.34 (dd, 1H, JBA =17.22, JBX =3.89), 3.73–3.81 (dd, 1H, JAB =17.32, JAX =11.37), 5.33 (s, 2H, -CH2O-), 5.88–5.93 (dd, 1H, JXA =3.88, JXB =11.49), 6.80–8.18 (m, 16H, Ar-H); 13C NMR (CDCl3): 21.24 (C-1), 42.11 (C-18), 43.22 (C-19), 72.19 (C-10), 118.22 (C-22), 119.21 (C-14), 121.65 (C-29), 122.69 (C-27), 122.90 (C-23), 125.20 (C-24), 126.21 (C-12, C-16), 127.49 (C-3, C-7), 128.23 (C-25), 129.31 (C-4, C-6), 130.27 (C-13, C-15), 133.58 (C-5), 135.27 (C-28), 138.62 (C-2), 140.53 (C-20), 142.34 (C-21), 144.30 (C-17), 144.39 (C-11), 151.77 (C-30), 161.11 (C-26), 163.42 (C-8), 164.79 (C-9); MS (EI) m/z: 536.2 (M+1); Anal. Calcd for C29H21N5O4S: C, 65.04; H, 3.95; N, 13.08%. Found: C, 65.08; H, 3.88; N, 13.13%.

3.2.10 2-Pyridin-2-yl-4-[4-(5-p-tolyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-2,3-dihydro-benzo[b][1,4]thiazepine (6j)

Yield: 68%; m.p. 146–148°C; IR (KBr, cm−1): 2952, 2858 (C-H asym, sym), 1621 (>C=N-), 1449 (-CH3); 1H NMR (CDCl3): δ 2.27 (s, 3H, -CH3), 3.28–3.33 (dd, 1H, JBA =17.29, JBX =3.83), 3.67–3.74 (dd, 1H, JAB =17.32, JAX =11.35), 5.30 (s, 2H, -CH2O-), 5.90–5.94 (dd, 1H, JXA =3.81, JXB =11.36), 6.85–8.25 (m, 16H, Ar-H); 13C NMR (CDCl3): 21.53 (C-1), 42.33 (C-18), 43.21(C-19), 72.11 (C-10), 117.64 (C-22), 119.20 (C-14), 121.22 (C-29), 122.34 (C-27), 122.92 (C-23), 125.21 (C-24), 126.76 (C-12, C-16), 127.47 (C-3, C-7), 128.11 (C-25), 129.27 (C-4, C-6), 130.56 (C-13, C-15), 133.21 (C-5), 135.39 (C-28), 138.90 (C-2), 141.41 (C-20), 142.36 (C-21), 144.32 (C-17), 144.70 (C-11), 151.31 (C-30), 161.77 (C-26), 162.88 (C-8), 164.89 (C-9); MS (EI) m/z: 505.0 (M+1); Anal. Calcd for C30H24N4O2S: C, 71.41; H, 4.79; N, 11.10%. Found: C, 71.47; H, 4.82; N, 11.03%.

3.2.11 4-{4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-furan-2-yl-2,3-dihydro-benzo[b][1,4]thiazepine (6k)

Yield: 59%; m.p. 196–197°C; IR (KBr, cm−1): 2955, 2861 (C-H asym, sym), 1608 (>C=N-), 769 (C-Cl); 1H NMR (CDCl3): δ 3.24–3.31 (dd, 1H, JBA =17.19, JBX =4.27), 3.56–3.62 (dd, 1H, JAB =17.66, JAX =11.41), 5.25 (s, 2H, -CH2O-), 5.92–5.97 (dd, 1H, JXA =4.51, JXB =11.77), 6.83–8.22 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.38 (C-18), 55.15 (C-19), 71.91 (C-10), 117.49 (C-22), 119.58 (C-14), 102.33 (C-27), 104.20 (C-28), 122.47 (C-20), 124.32 (C-23), 125.58 (C-24), 126.29 (C-12, C-16), 127.46 (C-3, C-7), 128.49 (C-25), 129.77 (C-4, C-6), 129.64 (C-13, C-15), 133.47 (C-5), 135.78 (C-2), 137.16 (C-26), 137.28 (C-29), 142.40 (C-21), 143.92 (C-17), 145.25 (C-11), 163.15 (C-8), 165.10 (C-9); MS (EI) m/z: 514.4 (M+1); Anal. Calcd for C28H20N3O3ClS: C, 65.43; H, 3.92; N, 8.18%. Found: C, 65.49; H, 3.96; N, 8.1%.

3.2.12 2-Furan-2-yl-4-{4-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2,3-dihydro-benzo[b][1,4]thiazepine (6l)

Yield: 63%; m.p. 182–184°C; IR (KBr, cm−1): 2965, 2851 (C-H asym, sym), 1614 (>C=N-), 1281 (-OCH3); 1H NMR (CDCl3): δ 3.26–3.31 (dd, 1H, JBA =17.11, JBX =4.22), 3.59–3.66 (dd, 1H, JAB =17.61, JAX =11.43), 3.85 (s, 3H, -OCH3), 5.29 (s, 2H, -CH2O-), 5.92–5.96 (dd, 1H, JXA =4.51, JXB =11.77), 6.87–8.27 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.28 (C-18), 55.23 (C-19), 59.67 (C-1), 72.61 (C-10), 117.43 (C-22), 119.27 (C-14), 102.28 (C-27), 104.41 (C-28), 122.13 (C-20), 123.41 (C-23), 125.40 (C-24), 126.32 (C-12, C-16), 127.11 (C-3, C-7), 128.35 (C-25), 129.11 (C-4, C-6), 129.59 (C-13, C-15), 133.31 (C-5), 137.10 (C-26), 137.13 (C-29), 142.65 (C-21), 144.11 (C-17), 145.42 (C-11), 153.43 (C-2), 162.89 (C-8), 164.92 (C-9); MS (EI) m/z: 510.1 (M+1); Anal. Calcd for C29H23N3O4S: C, 68.35; H, 4.55; N, 8.25%. Found: C, 68.30; H, 4.51; N, 8.28%.

3.2.13 2-Furan-2-yl-4-{4-[5-(4-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2,3-dihydro-benzo[b][1,4]thiazepine (6m)

Yield: 60%; m.p. 136–137°C; IR (KBr, cm−1): 2959, 2865 (C-H asym, sym), 1608 (>C=N-), 1529, 1349 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.33–3.39 (dd, 1H, JBA =17.26, JBX =4.22), 3.63–3.69 (dd, 1H, JAB =17.49, JAX =11.55), 5.37 (s, 2H, -CH2O-), 5.87–5.92 (dd, 1H, JXA =4.48, JXB =11.65), 6.79–8.36 (m, 15H, Ar-H); 13C NMR (CDCl3): 42.12 (C-18), 55.11 (C-19), 72.11 (C-10), 117.42 (C-22), 119.67 (C-14), 102.39 (C-27), 104.35 (C-28), 122.31 (C-20), 124.28 (C-23), 125.33 (C-24), 126.40 (C-12, C-16), 127.56 (C-3, C-7), 128.67 (C-25), 129.23 (C-4, C-6), 129.78 (C-13, C-15), 133.62 (C-5), 137.46 (C-26), 137.87 (C-29), 142.33 (C-21), 143.85 (C-17), 145.11 (C-11), 148.67 (C-2), 163.10 (C-8), 165.19 (C-9); MS (EI) m/z: 525.2 (M+1); Anal. Calcd for C28H20N4O5S: C, 64.11; H, 3.84; N, 10.68%. Found: C, 64.14; H, 3.81; N, 10.73%.

3.2.14 2-Furan-2-yl-4-{4-[5-(3-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2,3-dihydro-benzo[b][1,4]thiazepine (6n)

Yield: 59%; m.p. 165–166°C; IR (KBr, cm−1): 2963, 2855 (C-H asym, sym), 1610 (>C=N-), 1535, 1345 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.30–3.35 (dd, 1H, JBA =17.22, JBX =4.17), 3.60–3.66 (dd, 1H, JAB =17.42, JAX =11.46), 5.30 (s, 2H, -CH2O-), 5.84–5.92 (dd, 1H, JXA =4.42, JXB =11.70), 6.82–8.32 (m, 15H, Ar-H); 13C NMR (CDCl3): 41.90 (C-18), 55.48 (C-19), 72.67 (C-10), 116.82 (C-22), 119.54 (C-14), 102.77 (C-27), 104.31 (C-28), 122.56 (C-20), 124.33 (C-23), 125.21 (C-24), 126.76 (C-12, C-16), 127.44 (C-3, C-7), 128.45 (C-25), 128.79 (C-4, C-6), 129.11 (C-13, C-15), 133.15 (C-5), 137.76 (C-26), 137.81 (C-29), 142.20 (C-21), 143.49 (C-17), 145.55 (C-11), 148.77 (C-2), 163.17 (C-8), 164.10 (C-9); MS (EI) m/z: 525.1 (M+1); Anal. Calcd for C28H20N4O5S: C, 64.11; H, 3.84; N, 10.68%. Found: C, 64.19; H, 3.80; N, 10.72%.

3.2.15 2-Furan-2-yl-4-[4-(5-p-tolyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-2,3-dihydro-benzo[b][1,4]thiazepine (6o)

Yield: 69%; m.p. 199–201°C; IR (KBr, cm−1): 2953, 2859 (C-H asym, sym), 1613 (>C=N-), 1451 (-CH3); 1H NMR (CDCl3): δ 2.23 (s, 3H, -CH3), 3.29–3.34 (dd, 1H, JBA =17.19, JBX =4.27), 3.64–3.71 (dd, 1H, JAB =17.58, JAX =11.48), 5.31 (s, 2H, -CH2O-), 5.88–5.92 (dd, 1H, JXA =4.56, JXB =11.72), 6.91–8.31 (m, 15H, Ar-H); 13C NMR (CDCl3): 21.67 (C-1), 42.56 (C-18), 55.67 (C-19), 72.13 (C-10), 117.40 (C-22), 119.34 (C-14), 102.69 (C-27), 104.13 (C-28), 122.11 (C-20), 123.43 (C-23), 125.54 (C-24), 126.36 (C-12, C-16), 127.64 (C-3, C-7), 128.64 (C-25), 129.32 (C-4, C-6), 129.41 (C-13, C-15), 133.67 (C-5), 137.69 (C-26), 137.88 (C-29), 138.43 (C-2), 142.22 (C-21), 144.78 (C-17), 145.68 (C-11), 162.35 (C-8), 164.67 (C-9); MS (EI) m/z: 494.1 (M+1); Anal. Calcd for C29H23N3O3S: C, 70.57; H, 4.70; N, 8.51%. Found: C, 70.62; H, 4.66; N, 8.43%.

3.2.16 4-{4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7a)

Yield: 57%; m.p. 131–133°C; IR (KBr, cm−1): 3355 (N-H), 2960, 2867 (C-H asym, sym), 1616 (>C=N-), 747 (C-Cl); 1H NMR (CDCl3): δ 3.29–3.37 (dd, 1H, JBA =17.42, JBX =3.81), 3.62–3.71 (dd, 1H, JAB =17.44, JAX =11.41), 5.31 (s, 2H, -CH2O-), 5.82–5.87 (dd, 1H, JXA =3.87, JXB =11.25), 6.77–7.53 (m, 15H, Ar-H), 8.39 (s, 1H, >NH); 13C NMR (CDCl3): 42.21 (C-18), 44.56 (C-19), 72.12 (C-10), 110.64 (C-25), 112.43 (C-5), 115.12 (C-12, C-16), 115.66 (C-3, C-7), 119.23 (C-23), 121.21 (C-29), 121.40 (C-27), 122.15 (C-22), 124.64 (C-28), 127.18 (C-14), 128.11 (C-24), 129.11 (C-4, C-6), 129.65 (C-13, C-15), 129.68 (C-20, C-21), 134.97 (C-2), 140.62 (C-26), 140.76 (C-20), 154.32 (C-11), 160.45 (C-17), 163.31 (C-9), 166.63 (C-8); MS (EI) m/z: 514.0 (M+1); Anal. Calcd for C28H21N4O2ClS: C, 65.55; H, 4.13; N, 10.92%. Found: C, 65.59; H, 4.11; N, 10.97%.

3.2.17 4-{4-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7b)

Yield: 62%; m.p. 165–167°C; IR (KBr, cm−1): 3364 (N-H), 2951, 2853 (C-H asym, sym), 1610 (>C=N-), 1283 (-OCH3); 1H NMR (CDCl3): δ 3.27–3.33 (dd, 1H, JBA =17.48, JBX =3.84), 3.66–3.71 (dd, 1H, JAB =17.48, JAX =11.36), 3.81 (s, 3H, -OCH3), 5.36 (s, 2H, -CH2O-), 5.85–5.89 (dd, 1H, JXA =3.80, JXB =11.32), 6.80–7.56 (m, 15H, Ar-H), 8.33 (s, 1H, >NH); 13C NMR (CDCl3): 42.57 (C-18), 44.22 (C-19), 59.38 (C-1), 71.83 (C-10), 110.67 (C-25), 112.11 (C-5), 114.98 (C-12, C-16), 115.72 (C-3, C-7), 119.77 (C-23), 121.25 (C-29), 121.46 (C-27), 122.09 (C-22), 124.55 (C-28), 127.30 (C-14), 128.13 (C-24), 128.69 (C-4, C-6), 129.32 (C-13, C-15), 129.52 (C-20, C-21), 140.76 (C-26), 140.89 (C-20), 153.20 (C-2), 154.47 (C-11), 160.63 (C-17), 163.25 (C-9), 166.47 (C-8); MS (EI) m/z: 509.1 (M+1); Anal. Calcd for C29H24N4O3S: C, 68.49; H, 4.76; N, 11.02%. Found: C, 68.43; H, 4.72; N, 11.07%.

3.2.18 4-{4-[5-(4-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7c)

Yield: 58%; m.p. 189–191°C; IR (KBr, cm−1): 3353 (N-H), 2947, 2859 (C-H asym, sym), 1618 (>C=N-), 1535, 1348 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.28–3.35 (dd, 1H, JBA =17.37, JBX =3.82), 3.66–33.72 (dd, 1H, JAB =17.36, JAX =11.40), 5.35 (s, 2H, -CH2O-), 5.84–5.90 (dd, 1H, JXA =3.73, JXB =11.29), 6.85–7.61 (m, 15H, Ar-H), 8.42 (s, 1H, >NH); 13C NMR (CDCl3): 42.49 (C-18), 43.96 (C-19), 72.89 (C-10), 110.50 (C-25), 112.21 (C-5), 115.47 (C-12, C-16), 116.11 (C-3, C-7), 119.44 (C-23), 121.26 (C-29), 121.56 (C-27), 121.98 (C-22), 124.60 (C-28), 126.89 (C-14), 128.15 (C-24), 129.21 (C-4, C-6), 129.77 (C-13, C-15), 129.85 (C-20, C-21), 140.43 (C-26), 140.82 (C-20), 148.06 (C-2), 154.67 (C-11), 160.31 (C-17), 164.55 (C-9), 166.22 (C-8); MS (EI) m/z: 524.2 (M+1); Anal. Calcd for C28H21N5O4S: C, 64.23; H, 4.04; N, 13.38%. Found: C, 64.21; H, 4.11; N, 13.33%.

3.2.19 4-{4-[5-(3-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7d)

Yield: 60%; m.p. 152–154°C; IR (KBr, cm−1):3363 (N-H), 2935, 2856 (C-H asym, sym), 1622 (>C=N-), 1541, 1364 (-NO2 asym, sym);1H NMR (CDCl3): δ 3.34–3.41 (dd, 1H, JBA =17.39, JBX =3.87), 3.62–33.68 (dd, 1H, JAB =17.33, JAX =11.46), 5.32 (s, 2H, -CH2O-), 5.88–5.94 (dd, 1H, JXA =3.79, JXB =11.26), 6.89–7.68 (m, 15H, Ar-H), 8.38 (s, 1H, >NH); 13C NMR (CDCl3): 42.11 (C-18), 43.36 (C-19), 71.29 (C-10), 110.57 (C-25), 112.43 (C-5), 115.22 (C-12, C-16), 116.48 (C-3, C-7), 119.32 (C-23), 121.52 (C-29), 121.67 (C-27), 122.12 (C-22), 124.87 (C-28), 127.21 (C-14), 128.22 (C-24), 129.19 (C-4, C-6), 129.46 (C-13, C-15), 129.93 (C-20, C-21), 140.67 (C-26), 140.80 (C-20), 148.17 (C-2), 154.61 (C-11), 161.37 (C-17), 163.21 (C-9), 166.77 (C-8); MS (EI) m/z: 524.1 (M+1); Anal. Calcd for C28H21N5O4S: C, 64.23; H, 4.04; N, 13.38%. Found: C, 64.27; H, 4.01; N, 13.42%.

3.2.20 2-Thiophen-2-yl-4-[4-(5-p-tolyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-2,3-dihydro-1H-benzo[b][1,4]diazepine (7e)

Yield: 68%; m.p. 161–163°C; IR (KBr, cm−1): 3356 (N-H), 2951, 2859 (C-H asym, sym), 1623 (>C=N-), 1452 (-CH3); 1H NMR (CDCl3): δ 2.41 (s, 3H, -CH3), 3.25–3.31 (dd, 1H, JBA =17.42, JBX =3.88), 3.62–3.69 (dd, 1H, JAB =17.41, JAX =11.43), 5.39 (s, 2H, -CH2O-), 5.89–5.93 (dd, 1H, JXA =3.76, JXB =11.27), 6.82–7.58 (m, 15H, Ar-H), 8.37 (s, 1H, >NH); 13C NMR (CDCl3): 21.77 (C-1), 42.44 (C-18), 44.19 (C-19), 72.12 (C-10), 110.63 (C-25), 112.24 (C-5), 115.11 (C-12, C-16), 115.69 (C-3, C-7), 119.31 (C-23), 121.56 (C-29), 121.68 (C-27), 122.25 (C-22), 124.48 (C-28), 127.20 (C-14), 128.06 (C-24), 128.70 (C-4, C-6), 129.21 (C-13, C-15), 129.69 (C-20, C-21), 138.29 (C-2), 140.89 (C-26), 140.92 (C-20), 154.65 (C-11), 160.22 (C-17), 163.29 (C-9), 166.69 (C-8); MS (EI) m/z: 493.0 (M+1); Anal. Calcd for C29H24N4O2S: C, 70.71; H, 4.91; N, 11.37%. Found: C, 70.76; H, 4.86; N, 11.32%.

3.2.21 4-{4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7f)

Yield: 61%; m.p. 183–185°C; IR (KBr, cm−1): 3358 (N-H), 2943, 2861 (C-H asym, sym), 1621 (>C=N-), 767 (C-Cl); 1H NMR (CDCl3): δ 3.34–3.39 (dd, 1H, JBA =17.37, JBX =3.91), 3.62–3.70 (dd, 1H, JAB =17.38, JAX =11.27), 5.33 (s, 2H, -CH2O-), 5.82–5.88 (dd, 1H, JXA =3.84, JXB =11.31), 6.89–7.60 (m, 16H, Ar-H), 8.30 (s, 1H, >NH); 13C NMR (CDCl3): 41.93 (C-18), 55.44 (C-19), 72.11 (C-10), 110.43 (C-25), 112.54 (C-5), 115.10 (C-12, C-16), 115.43 (C-3, C-7), 120.56 (C-23), 121.62 (C-29), 122.65 (C-22), 122.78 (C-27), 127.35 (C-14), 128.21 (C-24), 128.27 (C-4, C-6), 128.49 (C-13, C-15), 129.67 (C-20, C-21), 134.31 (C-28), 135.11 (C-2), 151.76 (C-30), 154.24 (C-11), 161.13 (C-17), 161.78 (C-26), 163.11 (C-9), 166.22 (C-8); MS (EI) m/z: 508.1 (M+1); Anal. Calcd for C29H22N5O2Cl: C, 68.57; H, 4.37; N, 13.79%. Found: C, 68.53; H, 4.41; N, 13.75%.

3.2.22 4-{4-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7g)

Yield: 72%; m.p. 142–143°C; IR (KBr, cm−1): 3368 (N-H), 2939, 2850 (C-H asym, sym), 1621 (>C=N-), 1287 (-OCH3); 1H NMR (CDCl3): δ 3.31–3.37 (dd, 1H, JBA =17.31, JBX =3.85), 3.68–3.75 (dd, 1H, JAB =17.32, JAX =11.32), 3.78 (s, 3H, -OCH3), 5.42 (s, 2H, -CH2O-), 5.86–5.90 (dd, 1H, JXA =3.80, JXB =11.36), 6.92–7.68 (m, 16H, Ar-H), 8.34 (s, 1H, >NH); 13C NMR (CDCl3): 42.31 (C-18), 55.16 (C-19), 59.20 (C-1), 71.89 (C-10), 110.79 (C-25), 112.11 (C-5), 114.90 (C-12, C-16), 115.80 (C-3, C-7), 120.13 (C-23), 121.33 (C-29), 122.15 (C-22), 122.46 (C-27), 127.41 (C-14), 128.33 (C-24), 128.51 (C-4, C-6), 128.33 (C-13, C-15), 129.42 (C-20, C-21), 134.11 (C-28), 140.22 (C-2), 151.22 (C-30), 154.19 (C-11), 160.98 (C-17), 161.67 (C-26), 163.24 (C-9), 166.66 (C-8); MS (EI) m/z: 504.0 (M+1); Anal. Calcd for C30H25N5O3: C, 71.56; H, 5.00; N, 13.91%. Found: C, 71.58; H, 5.06; N, 13.87%.

3.2.23 4-{4-[5-(4-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7h)

Yield: 78%; m.p. 157–159°C; IR (KBr, cm−1): 3357 (N-H), 2942, 2858 (C-H asym, sym), 1614 (>C=N-), 1549, 1355 (-NO2asym, sym); 1H NMR (CDCl3): δ 3.25–3.31 (dd, 1H, JBA =17.36, JBX =3.77), 3.62–3.74(dd, 1H, JAB =17.33, JAX =11.31), 5.33 (s, 2H, -CH2O-), 5.82–5.86 (dd, 1H, JXA =3.92, JXB =11.45), 6.82–7.60 (m, 16H, Ar-H), 8.27 (s, 1H, >NH); 13C NMR (CDCl3): 42.14 (C-18), 55.32 (C-19), 72.56 (C-10), 110.37 (C-25), 112.64 (C-5), 115.22 (C-12, C-16), 115.68 (C-3, C-7), 120.63 (C-23), 121.22 (C-29), 122.34 (C-22), 122.65 (C-27), 127.21 (C-14), 128.22 (C-24), 128.55 (C-4, C-6), 128.48 (C-13, C-15), 129.61 (C-20, C-21), 134.39 (C-28), 148.23 (C-2), 151.33 (C-30), 154.74 (C-11), 161.26 (C-17), 161.71 (C-26), 163.39 (C-9), 166.54 (C-8); MS (EI) m/z: 519.1 (M+1); Anal. Calcd for C29H22N6O4: C, 67.17; H, 4.28; N, 16.21%. Found: C, 67.11; H, 4.22; N, 16.28%.

3.2.24 4-{4-[5-(3-Nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-pyridin-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7i)

Yield: 65%; m.p. 147–149°C; IR (KBr, cm−1): 3360 (N-H), 2926, 2850 (C-H asym, sym), 1619 (>C=N-), 1545, 1360 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.28–3.34 (dd, 1H, JBA =17.39, JBX =3.79), 3.60–3.68 (dd, 1H, JAB =17.37, JAX =11.36), 5.31 (s, 2H, -CH2O-), 5.86–5.91 (dd, 1H, JXA =3.92, JXB =11.45), 6.87–7.69 (m, 16H, Ar-H), 8.23 (s, 1H, >NH); 13C NMR (CDCl3): 42.27 (C-18), 55.45 (C-19), 72.69 (C-10), 111.15 (C-25), 112.35 (C-5), 115.46 (C-12, C-16), 115.87 (C-3, C-7), 120.67 (C-23), 121.34 (C-29), 122.67 (C-22), 122.77 (C-27), 127.35 (C-14), 128.10 (C-24), 128.67 (C-4, C-6), 128.85 (C-13, C-15), 129.12 (C-20, C-21), 134.62 (C-28), 148.10 (C-2), 151.46 (C-30), 154.33 (C-11), 161.20 (C-17), 161.89 (C-26), 163.47 (C-9), 165.11 (C-8); MS (EI) m/z: 519.1 (M+1); Anal. Calcd for C29H22N6O4: C, 67.17; H, 4.28; N, 16.21%. Found: C, 67.13; H, 4.20; N, 16.24%.

3.2.25 2-Pyridin-2-yl-4-[4-(5-p-tolyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-2,3-dihydro-1H-benzo[b][1,4]diazepine (7j)

Yield: 68%; m.p. 136–138°C; IR (KBr, cm−1): 3360 (N-H), 2955, 2862 (C-H asym, sym), 1624 (>C=N-), 1441 (-CH3); 1H NMR (CDCl3): δ 2.37 (s, 3H, -CH3), 3.28–3.34 (dd, 1H, JBA =17.33, JBX =3.80), 3.64–3.71 (dd, 1H, JAB =17.31, JAX =11.37), 5.38 (s, 2H, -CH2O-), 5.84–5.88 (dd, 1H, JXA =3.86, JXB =11.41), 6.87–7.63 (m, 16H, Ar-H), 8.36 (s, 1H, >NH); 13C NMR (CDCl3): 21.37 (C-1), 42.52 (C-18), 55.11 (C-19), 72.14 (C-10), 110.55 (C-25), 112.65 (C-5), 114.32 (C-12, C-16), 115.11 (C-3, C-7), 120.28 (C-23), 121.54 (C-29), 122.68 (C-22), 122.76 (C-27), 127.64 (C-14), 128.21 (C-24), 128.59 (C-4, C-6), 128.66 (C-13, C-15), 129.41 (C-20, C-21), 134.43 (C-28), 138.69 (C-2), 151.56 (C-30), 154.25 (C-11), 160.91 (C-17), 161.33 (C-26), 163.16 (C-9), 166.31 (C-8); MS (EI) m/z: 488.2 (M+1); Anal. Calcd for C30H25N5O2: C, 73.90; H, 5.17; N, 14.36%. Found: C, 73.95; H, 5.14; N, 14.30%.

3.2.26 4-{4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2-furan-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (7k)

Yield: 59%; m.p. 176–178°C; IR (KBr, cm−1): 3361 (N-H), 2955, 2856 (C-H asym, sym), 1613 (>C=N-), 761 (C-Cl); 1H NMR (CDCl3): δ 3.11–3.15 (dd, 1H, JBA =17.52, JBX =4.36), 3.62–3.71 (dd, 1H, JAB =17.56, JAX =11.83), 5.32 (s, 2H, -CH2O-), 5.47–5.53 (dd, 1H, JXA =4.50, JXB =11.82), 6.68–8.10 (m, 15H, Ar-H), 8.34 (s, 1H, >NH); 13C NMR (CDCl3): 42.13 (C-18), 55.45 (C-19), 72.13 (C-10), 102.11 (C-27), 104.37 (C-28), 110.76 (C-25), 112.50 (C-5), 114.88 (C-12, C-16), 115.90 (C-3, C-7), 120.12 (C-23), 122.17 (C-22), 127.31 (C-14), 128.44 (C-24), 128.67 (C-4, C-6), 129.63 (C-13, C-15), 129.73 (C-20, C-21), 135.87 (C-2), 137.11 (C-29), 137.55 (C-26), 154.14 (C-11), 160.89 (C-17), 163.42 (C-9), 166.33 (C-8); MS (EI) m/z: 497.3 (M+1); Anal. Calcd for C28H21N4O3Cl: C, 67.67; H, 4.26; N, 11.27%. Found: C, 67.62; H, 4.29; N, 11.20%.

3.2.27 2-Furan-2-yl-4-{4-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2,3-dihydro-1H-benzo[b][1,4]diazepine (7l)

Yield: 63%; m.p. 126–128°C; IR (KBr, cm−1): 3360 (N-H), 2956, 2859 (C-H asym, sym), 1620 (>C=N-), 1280 (-OCH3); 1H NMR (CDCl3): δ 3.06–3.11 (dd, 1H, JBA =17.56, JBX =4.56), 3.68–3.75 (dd, 1H, JAB =17.64, JAX =11.80), 3.85 (s, 3H, -OCH3), 5.26 (s, 2H, -CH2O-), 5.51–5.55 (dd, 1H, JXA =4.56, JXB =11.80), 6.71–8.12 (m, 15H, Ar-H), 8.38 (s, 1H, >NH); 13C NMR (CDCl3): 42.36 (C-18), 55.26 (C-19), 59.23 (C-1), 71.94 (C-10), 102.05 (C-27), 104.45 (C-28), 110.92 (C-25), 112.18 (C-5), 114.94 (C-12, C-16), 115.84 (C-3, C-7), 119.93 (C-23), 122.02 (C-22), 126.60 (C-14), 127.39 (C-24), 128.27 (C-4, C-6), 128.52 (C-13, C-15), 129.52 (C-20, C-21), 136.96 (C-29), 137.86 (C-26), 140.83 (C-2), 154.08 (C-11), 160.91 (C-17), 163.35 (C-9), 166.52 (C-8); MS (EI) m/z: 493.2 (M+1); Anal. Calcd for C29H24N4O4: C, 70.72; H, 4.91; N, 11.38%. Found: C, 70.76; H, 4.87; N, 11.32%.

3.2.28 2-Furan-2-yl-4-{4-[5-(4-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2,3-dihydro-1H-benzo[b][1,4]diazepine (7m)

Yield: 60%; m.p. 171–173°C; IR (KBr, cm−1): 3356 (N-H), 2954, 2859 (C-H asym, sym), 1612 (>C=N-), 1539, 1345 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.27–3.34 (dd, 1H, JBA =17.49, JBX =4.52), 3.56–3.62 (dd, 1H, JAB =17.61, JAX =11.75), 5.37 (s, 2H, -CH2O-), 5.87–5.91 (dd, 1H, JXA =4.52, JXB =11.83), 6.95–7.74 (m, 15H, Ar-H), 8.39 (s, 1H, >NH); 13C NMR (CDCl3): 42.44 (C-18), 55.32 (C-19), 72.27 (C-10), 102.29 (C-27), 104.31 (C-28), 110.34 (C-25), 112.47 (C-5), 114.91 (C-12, C-16), 115.69 (C-3, C-7), 120.19 (C-23), 122.26 (C-22), 127.55 (C-14), 128.38 (C-24), 128.51 (C-4, C-6), 129.47 (C-13, C-15), 129.66 (C-20, C-21), 137.43 (C-29), 137.65 (C-26), 148.22 (C-2), 154.33 (C-11), 160.44 (C-17), 163.77 (C-9), 166.48 (C-8); MS (EI) m/z: 508.2 (M+1); Anal. Calcd for C28H21N5O5: C, 66.27; H, 4.17; N, 13.80%. Found: C, 66.22; H, 4.13; N, 13.86%.

3.2.29 2-Furan-2-yl-4-{4-[5-(3-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethoxy]-phenyl}-2,3-dihydro-1H-benzo[b][1,4]diazepine (7n)

Yield: 59%; m.p. 191–193°C; IR (KBr, cm−1): 3362 (N-H), 2920, 2843 (C-H asym, sym), 1622 (>C=N-), 1542, 1367 (-NO2 asym, sym); 1H NMR (CDCl3): δ 3.30–3.37 (dd, 1H, JBA =17.42, JBX =4.58), 3.60–3.66 (dd, 1H, JAB =17.67, JAX =11.71), 5.30 (s, 2H, -CH2O-), 5.85–5.90 (dd, 1H, JXA =4.44, JXB =11.81), 6.93–7.72 (m, 15H, Ar-H), 8.35 (s, 1H, >NH); 13C NMR (CDCl3): 42.67 (C-18), 55.21 (C-19), 72.68 (C-10), 102.33 (C-27), 104.66 (C-28), 110.15 (C-25), 112.33 (C-5), 115.22 (C-12, C-16), 115.61 (C-3, C-7), 120.44 (C-23), 122.56 (C-22), 127.20 (C-14), 128.56 (C-24), 128.64 (C-4, C-6), 129.11(C-13, C-15), 129.29 (C-20, C-21), 137.56 (C-29), 137.59 (C-26), 148.67 (C-2), 154.39 (C-11), 160.20 (C-17), 164.11 (C-9), 166.69 (C-8); MS (EI) m/z: 508.1 (M+1); Anal. Calcd for C28H21N5O5: C, 66.27; H, 4.17; N, 13.80%. Found: C, 66.21; H, 4.19; N, 13.82%.

3.2.30 2-Furan-2-yl-4-[4-(5-p-tolyl-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-2,3-dihydro-1H-benzo[b][1,4]diazepine (7o)

Yield: 69%; m.p. 179–181°C; IR (KBr, cm−1): 3362 (N-H), 2952, 2852 (C-H asym, sym), 1611 (>C=N-), 1449 (-CH3); 1H NMR (CDCl3): δ 2.36 (s, 3H, -CH3), 3.32–3.38 (dd, 1H, JBA =17.56, JBX =4.56), 3.61–3.68 (dd, 1H, JAB =17.64, JAX =11.80), 5.40 (s, 2H, -CH2O-), 5.90–5.94 (dd, 1H, JXA =4.56, JXB =11.80), 6.90–7.66 (m, 15H, Ar-H), 8.41 (s, 1H, >NH); 13C NMR (CDCl3): 21.79 (C-1), 42.10 (C-18), 55.34 (C-19), 71.89 (C-10), 102.29 (C-27), 104.31 (C-28), 111.12 (C-25), 112.28 (C-5), 115.13 (C-12, C-16), 115.81 (C-3, C-7), 119.65 (C-23), 122.16 (C-22), 126.44 (C-14), 127.59 (C-24), 128.37 (C-4, C-6), 128.66 (C-13, C-15), 129.40 (C-20, C-21), 136.92 (C-29), 137.73 (C-26), 138.20 (C-2), 154.11 (C-11), 160.54 (C-17), 163.19 (C-9), 166.69 (C-8); MS (EI) m/z: 477.1 (M+1); Anal. Calcd for C29H24N4O3: C, 73.09; H, 5.08; N, 11.76%. Found: C, 73.12; H, 5.11; N, 11.72%.

3.3 Biological activities

The MICs of synthesized compounds were carried out by broth micro dilution method as described by Rattan [25]. The antitubercular activity (MICs values) was assessed in vitro against Mycobacterium tuberculosis H37Rv ATCC 27294 according to a modified Microplate Alamar Blue Assay [26]. For antiprotozoal activity, in vitro susceptibility assays and the growth inhibition test were performed on promastigotes of L. mexicana and epimastigotes of Trypanosoma cruzi were performed using a method previously described [27], [28].

4 Conclusion

Thirty newer 1,3,4-oxadiazolyl-benzodiazepines and benzothiazepines analogues were synthesized and examined for biological activity. From the study of structure activity relationship (SAR) and the results of biological screening, it is clearly indicated that the pharmacological properties of synthesized compounds depend on electron withdrawing/donating groups present on aryl ring at 1,3,4-oxadiazole moiety. The presence of thiophene, pyridine, and furan at benzothiazepine and benzodiazepine ring also plays a major role in bioactivity profile. In case of antibacterial and antifungal activity, few of the compounds showed equipotent activity when compared to standard drugs.

Acknowledgments

The authors are thankful to the Department of Chemistry, VNSGU, Surat, for providing necessary research facilities and NCI, Bethesda, MD, USA, for performing the antitumor screening. We also thank CDRI Lucknow for elemental analysis and SAIF Chandigarh for spectral analysis of the compounds.

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Supplemental Material:

The online version of this article (DOI: https://doi.org/10.1515/znc-2016-0129) offers supplementary material, available to authorized users.

Received: 2016-06-22
Revised: 2016-12-04
Accepted: 2016-12-28
Published Online: 2017-02-09
Published in Print: 2017-03-01

©2017 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/znc-2016-0129
Keywords for this article
antimicrobial activity; antituberculosis activity; benzodiazepines; benzothiazepines; 1,3,4-Oxadiazole

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