Anxiolytic activity of some 2, 3-dihydrobenzo[b] [1, 4] oxazepine derivatives synthesized from Murrayanine-Chalcone

 

Debarshi Kar Mahapatra1*, Ruchi S. Shivhare2, Sayan Dutta Gupta3

1Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur 440037, Maharashtra, India

2Department of Pharmaceutical Chemistry, Kamla Nehru College of Pharmacy, Nagpur 441108, Maharashtra, India

3Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Hyderabad 500090, Telangana, India

*Corresponding Author E-mail: dkmbsp@gmail.com

 

ABSTRACT:

Due to the fact that, Murrayanine is one of the most active compounds of the present carbazole series with a simple chemistry which facilitate multiple sites for substituting varied active groups, and their pharmacological expression thereof. Several heterocycle based hybrids of the Murrayanine were fabricated rationally by our research group. Benzoxazepine is an exhaustively applied scaffold which finds application in diverse areas of pharmacotherapeutics. Hybridizing benzoxazepine with any components has often resulted in the discovery of prospective compounds. In the present research, we designed and synthesized certain seven-membered benzoxazepine molecules by cyclizing Murrayanine-Chalcone, the starting material previously reported by our research group and explored their anti-anxiety or hypnotic effects by evaluating locomotor inhibitory potentials in Swiss albino rat. The highest locomotor inhibition was exhibited by the compound 3d containing 4-iodo substituent which may be translated therapeutically as the anti-anxiety effect. However, none of the fabricated molecules presented higher pharmacological activity than the benzodiazepine (diazepam), the standard drug. A very clear SAR could not be established from this study. The murrayanine based benzoxazepine analogs (3a-h) produced hypnosis and anxiolysis by enhancing the effect of GABA neurotransmitter at GABAA receptor, a mechanism similar to that of the benzodiazepine (diazepam). The research will further explore more potential of the hybrid seven-member candidates and will motivate researchers in developing therapeutically active as well as safe analogs in upcoming time.

 

KEYWORDS Murraya koenigii, Murrayanine, Benzoxazepine, Chalcone, Locomotor, Heterocycle

 

 


INTRODUCTION:

Seven-membered heterocycles have the immense pharmacological potential to exhibit anti-convulsant, anti-anxiety, hypnotic, sedative, and miscellaneous CNS activities. Benzoxazepine is an exhaustively applied scaffold which finds application in diverse areas of pharmacotherapeutics like anti-ischemic1, anti-tumor2, anti-atherosclerotic3, neuroprotection4, anti-convulsant5, anti-microbial6, anti-hypertensive7, anti-emetic8, anti-psychotic9, anti-depressant10, anti-inflammatory11, anti-allergic12, anti-ulcer13, etc. Hybridizing benzoxazepine with any components has often resulted in the discovery of prospective compounds.14 Indian curry plant, Murraya koenigii L. (family: Rutaceae) is a plant of ethnopharmacological importance like bitter, acrid, carminative, astringent, purgative, strengthening of gums and teeth, stomachic, febrifuge, anti-helminthic, and anti-anemic.15 The polar and non-polar extracts of M. koenigii have been reported to have diverse potentials like anti-microbial, anti-oxidant, immunomodulatory, anti-ulcerogenic, etc,16 owing to the presence of large number of therapeutically active carbazole moieties like O-methylmurrayamine A, bismurrayafoline, mahaninebine, bismahanine, koenimbine, euchrestine B, bispyrayafoline, mahaninebicine, mahanine, O-methylmahanine, isomahanine, and murrayanine.17

 

Due to the fact that, Murrayanine is one of the most active compounds of the present carbazole series with a simple chemistry which facilitate multiple sites for substituting varied active groups, and their pharmacological expression thereof.18 Several heterocycle based hybrids of the Murrayanine were fabricated rationally by our research group.19-26 In the present research, we designed and synthesized certain seven-membered benzoxazepine molecules by cyclizing Murrayanine-Chalcone, the starting material previously reported by our research group and explored their anti-anxiety or hypnotic effects by evaluating locomotor inhibitory potentials in Swiss albino rat.

 

MATERIALS AND METHODS:

Chemical and Instrumentation:

The present synthesis commences with “Murrayanine-Chalcone”, a hybrid molecule reported previously by our research group. Solvents and chemical reagents used during the studies were of analytical grade and procured from Sigma-Aldrich, HiMedia, and Merck. The chemical reaction progress was monitored using Merck Pre-coated silica gel G TLC plates. The IR spectra were recorded on Shimadzu® IRAffinity-1 system using KBr method and the absorption frequency data were expressed in cm-1. The proton (1H)-NMR was taken on Bruker Avance-II instrument using tetramethylsilane (TMS) as the internal standard and the chemical shift data was expressed in ppm relative to the internal standard. The mass spectra were recorded using a MICROMASS Q-TOF instrument. The elemental CHN analyses were performed on PerkinElmer 2400 model Elemental Analyzer.

 

Animals:

The locomotor inhibitory potential of murrayanine-chalcone based benzoxazepine derivatives was screened on 5-6 weeks aged Swiss albino rat having the body weight of 150-250 g. For this experiment, all ethical issues were concerned from Department Ethical Committee and CPCSEA (1389/a/10/CPCSEA). The rats were kept in a controlled environment in the animal house under good hygienic conditions; i.e. 24–25ºC temperature, humidity 50–60%, 12 hr light and dark. The rats were given standard rodent pellets and were allowed free access to water.

 

Synthesis of target compounds:

The synthesis of 2,3-dihydrobenzo[b][1,4]oxazepine derivatives (3a-h) involved the conversion of corresponding murrayanine-chalcones (1a-h) by reacting with  2-amino phenol (2), where the carbonyl portion of the benzylideneacetophenone group was transformed into closed ring benzoxazepine form. The Scheme 1 demonstrates the outline for the synthesis of benzoxazepine derivatives.

 

 

Scheme 1. Benzoxazepine derivatives fabrication from the murrayanine-chalcones.

 

Synthetic protocol for 4-(1-methoxy-9H-carbazol-3-yl)-2-(substituted)-phenyl-2,3-dihydrobenzo[b][1,4]oxazepine (3a-h)

The ethanolic-methanolic solution of murrayanine-chalcone derivatives (1a-h) (0.1 M) was added to a solution of 2-amino phenol (2) in presence of 7-8 drops of glacial acetic acid and the content was refluxed for 8-10 hrs. After the termination of reflux process, the solvents were distilled off under reduced pressure and solid precipitate was obtained, which was re-crystallized using suitable solvents to obtain pure products (3a-h).

 

2-(2-fluorophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3a)

54% yield; FTIR (KBr) υ (cm-1): 3308 (-NH), 3062 (C-H, aromatic), 1650 (C=N, aromatic), 1631 (C=C, aromatic), 1542 (-NH, bending), 1344 (C-N), 1296 (C-O), 1203 (C-F); 1H NMR (δ, ppm, CDCl3): 10.12 (9, 1H), 6.9-8.4 (Aromatic, 14H), 5.19 (13, 1H), 3.86 (1, 3H), 2.24 (12, 1H); MS: M+ 436. Anal. Calcd. for C28H21FN2O2: C, 77.05; H, 4.85; N, 6.42. Found: C, 76.79; H, 4.52; N, 6.11

 

2-(4-fluorophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3b)

38% yield; FTIR (KBr) υ (cm-1): 3274 (-NH), 3157 (C-H, aromatic), 1641 (C=N, aromatic), 1614 (C=C, aromatic), 1568 (-NH, bending), 1320 (C-N), 1232 (C-O), 1185 (C-F); 1H NMR (δ, ppm, CDCl3): 10.19 (9, 1H), 7.1-8.6 (Aromatic, 14H), 5.13 (13, 1H), 3.91 (1, 3H), 2.21 (12, 1H); MS: M+ 436. Anal. Calcd. for C28H21FN2O2: C, 77.05; H, 4.85; N, 6.42. Found: C, 76.88; H, 4.69; N, 6.27

 

2-(2-iodophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3c)

59% yield; FTIR (KBr) υ (cm-1): 3255 (-NH), 3124 (C-H, aromatic), 1661 (C=N, aromatic), 1630 (C=C, aromatic), 1601 (-NH, bending), 1329 (C-N), 1266 (C-O), 618 (C-I); 1H NMR (δ, ppm, CDCl3): 10.11 (9, 1H), 7.0-8.5 (Aromatic, 14H), 5.16 (13, 1H), 3.83 (1, 3H), 2.18 (12, 1H); MS: M+ 544. Anal. Calcd. for C28H21IN2O2: C, 61.78; H, 3.89; N, 5.15. Found: C, 60.74; H, 3.59; N, 4.82

 

2-(4-iodophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3d)

46% yield; FTIR (KBr) υ (cm-1): 3289 (-NH), 3092 (C-H, aromatic), 1638 (C=N, aromatic), 1622 (C=C, aromatic), 1607 (-NH, bending), 1346 (C-N), 1212 (C-O), 622 (C-I); 1H NMR (δ, ppm, CDCl3): 10.18 (9, 1H), 7.1-8.6 (Aromatic, 14H), 5.04 (13, 1H), 3.79 (1, 3H), 2.25 (12, 1H); MS: M+ 544. Anal. Calcd. for C28H21IN2O2: C, 61.78; H, 3.89; N, 5.15. Found: C, 60.61; H, 3.53; N, 4.73

 

2-(4-bromophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3e)

62% yield; FTIR (KBr) υ (cm-1): 3261 (-NH), 3116 (C-H, aromatic), 1680 (C=N, aromatic), 1646 (C=C, aromatic), 1546 (-NH, bending), 1353 (C-N), 1234 (C-O), 607 (C-Br); 1H NMR (δ, ppm, CDCl3): 10.13 (9, 1H), 7.1-8.6 (Aromatic, 14H), 5.15 (13, 1H), 3.87 (1, 3H), 2.29 (12, 1H); MS: M+ 496, M+2 498. Anal. Calcd. for C28H21BrN2O2: C, 67.61; H, 4.26; N, 5.63. Found: C, 67.17; H, 3.98; N, 5.20

 

4-(1-methoxy-9H-carbazol-3-yl)-2-(2-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[b][1,4]oxazepine (3f)

51% yield; FTIR (KBr) υ (cm-1): 3246 (-NH), 3099 (C-H, aromatic), 1704 (C=N, aromatic), 1657 (C=C, aromatic), 1551 (-NH, bending), 1368 (C-N), 1240 (C-O), 1095 (C-F); 1H NMR (δ, ppm, CDCl3): 10.17 (9, 1H), 7.2-8.7 (Aromatic, 13H), 5.18 (14, 1H), 3.84 (1, 3H), 2.22 (12, 1H); MS: M+ 486. Anal. Calcd. for C29H21F3N2O2: C, 71.60; H, 4.35; N, 5.76. Found: C, 71.41; H, 4.18; N, 5.45

 

2-(3,5-bis(trifluoromethyl)phenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3g)

43% yield; FTIR (KBr) υ (cm-1): 3301 (-NH), 3127 (C-H, aromatic), 1676 (C=N, aromatic), 1635 (C=C, aromatic), 1539 (-NH, bending), 1381 (C-N), 1274 (C-O), 1134 (C-F); 1H NMR (δ, ppm, CDCl3): 10.21 (9, 1H), 7.0-8.5 (Aromatic, 13H), 5.09 (13, 1H), 3.80 (1, 3H), 2.06 (12, 1H); MS: M+ 554. Anal. Calcd. for C30H20F6N2O2: C, 64.98; H, 3.64; N, 5.05. Found: C, 64.33; H, 3.28; N, 4.76

 

2-(2,4-dichloro-5-fluorophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepine (3h)

35% yield; FTIR (KBr) υ (cm-1): 3268 (-NH), 3172 (C-H, aromatic), 1689 (C=N, aromatic), 1642 (C=C, aromatic), 1570 (-NH, bending), 1315 (C-N), 1261 (C-O), 1112 (C-F), 791 (C-Cl); 1H NMR (δ, ppm, CDCl3): 10.14 (9, 1H), 7.2-8.6 (Aromatic, 12H), 5.12 (13, 1H), 3.89 (1, 3H), 2.27 (12, 1H); MS: M+ 504, M+2 506. Anal. Calcd. for C28H19Cl2FN2O2: C, 66.55; H, 3.64; N, 5.05. Found: C, 64.33; H, 3.28; N, 4.76

 

Acute toxicity study:

The acute toxicity study is a parameter that establishes the dose which exerts utmost pharmacological activity with no visible toxic signs and symptoms. This study is imperative to estimate in vivo safety profile of the investigational molecules. The compounds were administered by progressively increasing dose of from 10 mg/kg to 100 mg/kg. The death of 50% animals at a certain quantity of administration was considered the lethal dose.

 

Accessing anti-anxiety effect by inhibition of locomotor activity:

The locomotor inhibitory potential of the benoxazepine derivatives was studied using an actophotometer with required modifications. Initially, individual animals were kept in the system frame and the basal activity score was determined for each animal after 10 and 20 min of drug administration. The activity on each rat was retested for 10 min. The dissimilarity in the locomotor activity was measured before and after the drug treatment, and the reduction in locomotor activity expressed in percentage.

 

Statistical treatment:

The acquired results were methodically applied with statistical parameters and analyzed using one-way ANOVA followed by Dunnett’s multiple comparisons test. The obtained results were compared with the vehicle control group and value of P< 0.01 was considered significant.

 

RESULTS AND DISCUSSION:

Chemistry:

The sophisticated techniques revealed the fabrication of the benzoxazepines. The formation of the seven-membered heterocycles was made certain by the disappearance of absorption frequency at 1670-1750 cm-1 in FT-IR spectra which is due to the conversion of the ketone group of murrayanine-chalcone, which earlier appeared at this range. The features of the three aromatic rings were chiefly detected by following features: C-H stretching in the range of 3062-3172 cm-1, C=C stretching in the range of 1614-1657 cm-1 in the FT-IR spectra, and aromatic ring protons were primarily determined in the 1H-NMR spectral range of 6.9-8.6 ppm. The evidence for carbazole moiety was supported by few characteristics like noticing the proton of carbazole nitrogen at 10 ppm; the C-N bond was observed in IR spectra particularly at the range of 1315-1381 cm-1, and methoxy group attached to 1-position was perceived in both IR and 1H-NMR where in the former part the C-O stretching was located in the distinctive range of 1212-1296 cm-1 whereas in the later half the three protons were determined in the range of 3.79-3.91 ppm, respectively.

 

The halogens were scrutinized predominantly in the range of 1095-1203 cm-1 for fluorine while iodine, bromine, and chlorine were seen at 622, 607, and 791 cm-1 at FT-IR spectra. The amide component at benzoxazepine was verified by stretching and bending aspects in the distinct ranges of 3246-3308 cm-1 and 1539-1607 cm-1, respectively. The mass spectra surely confirmed the development of the heterocycle based compounds from chalcones as indicated by the appearance of base peaks having exactly the molecular mass of the molecules. The presence of the isotope forms of halogen chlorine and bromine were viewed as peaks with molecular mass + 2 attributes. Fragment peaks of in the range of m/z 100-200 were found to appear in the mass spectra. The elemental analysis expressed the ratios of carbon, hydrogen, and nitrogen (CHN) composition of the fabricated compounds undoubtedly indicated the formation of proposed molecules.

 

Determination of LD50 value:

The acute toxicity study revealed the desired safety aspects of the produced novel benzoxazepine derivatives. There were no such signs and symptoms of toxicity observed in the range of 10-100 mg/kg b.w. For the exploration of locomotor inhibitory activity, a dose of 30 mg/kg b.w. was administered.

 

Locomotor inhibitory activity:

All the synthesized compounds demonstrated noteworthy locomotor inhibitory effect by producing adequate CNS depression which can be translated to its ability to induce the anti-anxiety effect. The expressed biological activity is a function of the position, number, and the type of substituent present in the molecule. The highest locomotor inhibition was exhibited by the compound 3d containing 4-iodo substituent. However, none of the fabricated molecules presented higher pharmacological activity than the benzodiazepine (diazepam), the standard drug. On studying the structure-activity-relationships (SARs), it was noticed that in fluorine substituents (3a and 3b), the ortho-position was found to be more prevalent for locomotion inhibitory effect. In contrast, the iodine substituents (3c and 3d), the para-position was found to be more privileged. The similar phenomenon was also detected in the case of benzodiazepine-based molecules in the previous study. In the case of bromo-substituent (3e) and single tri-fluoro compound (3f), the activity was seen to be handful better than the fluorinated analogs.

 

The analogs 3g and 3h represented moderate anxiolytic activity. The compound 3h containing two active electron-withdrawing groups resulted in rapid distribution in the adipose and privileged area and displayed low CNS activity. Here, lipophilicity may be considered as an imperative parameter which can better explain the performance of the treated molecules. It has been observed that the analogs with higher lipophilicity expressed low biological activity which resulted due to their large distribution in the pharmacokinetic components and not participated in the CNS interface to exert action.27 In another context, the formation of micelles of the fabricated benzoxazepine molecules or binding with the present amino acid residues produces hindrance in crossing the biological barrier.28 The murrayanine based benzoxazepine analogs (3a-h) produces hypnosis and anxiolysis by enhancing the effect of GABA neurotransmitter at GABAA receptor, a mechanism similar to that of the benzodiazepine (diazepam).29


 

Table 1. Locomotor inhibitory potential as anti-anxiety effect of some fabricated benzodiazepine derivatives.

Group

R

Photocell Count  in 10 min

% Inhibition

Photocell count in 20 min

% Inhibition

Control*

-

394.6±3.26

-

397.8±2.54

-

Standard#

-

115.8±1.77

70.66

108.2±1.84

72.81

3aand

2-F

235.8±2.94*

40.25

223.2±1.33**

43.90

3b

4-F

249.6±2.51*

36.75

241.2±3.38*

39.37

3c

2-I

199.8±1.69**

49.37

190.2±1.99**

52.19

3d

4-I

187.6±1.46**

52.46

182.2±1.86**

54.20

3e

4-Br

226.2±1.63*

42.68

219.2±1.73**

44.90

3f

2-CF3

238.4±1.82*

39.59

225.8±2.34*

43.24

3g

3,5-CF3

227.8±1.38*

42.28

216.4±1.52**

45.61

3h

2,4-Cl; 5-F

244.4±2.59**

38.61

238.6±2.47*

40.03

*0.9% saline; #Benzodiazepine – 3 mg/kg b.w.; andDose of 30 mg/kg b.w.; **P< 0.01, *P<0.05; Values expressed as mean ± SEM, from 6 rats.

 


CONCLUSION:

The present research represented the formation of seven-membered benzoxazepine derivatives from murrayanine-chalcones. The analytical tools revealed the formation of the desired compounds as indicated by the spectral results. The highest locomotor inhibition was exhibited by the compound 3d containing 4-iodo substituent which may be translated therapeutically as the anti-anxiety effect. However, none of the fabricated molecules presented higher pharmacological activity than the benzodiazepine (diazepam), the standard drug. A very clear SAR could not be established from this study. The murrayanine based benzoxazepine analogs (3a-h) produced hypnosis and anxiolysis by enhancing the effect of GABA neurotransmitter at GABAA receptor, a mechanism similar to that of the benzodiazepine (diazepam). The research will further explore more potential of the hybrid seven-member candidates and will motivate researchers in developing therapeutically active as well as safe analogs in upcoming time.

 

ACKNOWLEDGEMENT:

Authors are highly thankful to Savitribai Phule Pune University, Pune, Maharashtra, India for providing research grants (Grant No. 13PHM000126).

 

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Received on 17.02.2018                Modified on 26.02.2018

Accepted on 12.03.2018            © A&V Publications All right reserved

Asian J. Res. Pharm. Sci. 2018; 8(1):25-29.

DOI: 10.5958/2231-5659.2018.00006.1