Synthesis of N-Mannich Bases of some Substituted Carbazoles

Neetu Verma¹, Shruti Awasthi², Vikrant Jain¹

¹Department of Chemistry, Faculty of Science and IT, Madhyanchal Professional University,

Ratibad - 462044, Bhopal - Madhya Pradesh, India.

²Department of Chemistry, Government College, Khurai - 470117, Madhya Pradesh.

*Corresponding Author E-mail: dr_vikrantjain@yahoo.in

Abstract:

Through reactions with numerous secondary amines and a series of aldehydes, including formaldehyde and acetaldehyde, novel carbazole derivative conjugates were created from carbazole. Corresponding analogues were identified through spectral studies, and they were tested for their ability to reduce pain and control seizures using the Eddy's Hot Plate method and the maximum electrical shock convinced convulsion method, respectively. Students created the statistical analysis using the "t" test, and the standards were stated as mean SEM.

KEYWORDS: Mannich bases, Carbazole, Anti-nociceptive, Anti-epileptic.

INTRODUCTION:

A mixture of an aldehyde, a secondary amine, and a compound with a combative hydrogen atom produced an overall reaction using the Mannich base^1-2. This reaction is useful for producing N-methyl conjugates and a variety of medicines. In order to have anti-convulsant³, anti-estrogenic⁴, anti-microbial⁵, anti-HIV⁶, and anti-tumor⁷ activities, the corresponding conjugates with carbazole moieties were developed. These interpretations, along with the critical role that carbazole conjugates are believed to play, motivated us to create a number of N-substituted carbazoles and test their anti-nociceptive and anti-epileptic effects.

EXPERIMENTAL:

The purity of the compounds was checked by TLC using silica gel as the stationary phase, and the spots were visually detected in the iodine chamber. Melting points were confirmed by open-ended capillary tube in the electrical melting point apparatus and are uncorrected. With the help of FT-IR (Shizamadu-8400 series) in KBr disc and FT-¹H NMR (Brucker 400 MHz) in DMSO-d⁶, the structures of the synthesized compounds were illuminated.

Preparation of N-Mannich bases of carbazoles:

Equimolar amounts of carbazole and secondary amine (0.01 moles each) were dissolved in 30 mL of methanol and continuously stirred under ideal ice-cold conditions. After that, 0.01 moles of the corresponding series of aldehydes (such as formaldehyde and acetaldehyde) were added, and the reaction was then gradually and intensely refluxed for three hours. The freezer was immediately reserved for the satisfied. Products that had been preserved were made by recrystallizing alcohol. Table 1 provided information on the percent yield, R_f value, melting point, and spectral data.

Table 1: Physical Data of Newly Synthesized Carbazole Derivatives

Compd. Code	Melting Point (°C)	Rf value	Log P	IR spectra (cm^-1)	^1H NMR spectra
1a	198-203	0.822	4.131	750, 1205, 1394, 1450, 1492, 1602, 1624	6.86 – 7.84(m, Ar-H),2.32 (s, CH3), 6.02(s,CH2), 5.12(S, OH)
1b	201-205	0.786	7.791	778, 1328, 1378, 1450, 1509, 1650	6.661– 7.951(m, Ar-H),5.8(s, OH), 2.02(s, CH3)
1c	209-211	0.904	3.443	723, 1315, 1452, 1482, 2938	7.12 – 7.42 (m, Ar-H),2.32 (s, CH3), 2.48(s,CH2), 4.98(s, CH2)
1d	175-182	0.914	4.869	726, 751, 1335, 1449, 1492, 1694	6.78 – 7.66 (m, Ar-H),3.52 (s, CH2), 5.64(s,CH2), 10.8(d, OH)
2a	216-218	0.618	4.494	750, 1205, 1335, 1450, 1492, 1697	6.562 – 7.888(m, Ar-H)2.499(s, CH3),2.096(s, CH3)
2b	190-195	0.762	8.154	777, 1335, 1450, 1785, 2360, 3054	6.653 – 7.341(m, Ar-H),1.973(s, CH3), 3.312(s,CH3)
2c	221-223	0.784	3.806	749, 1335, 1450, 3049	7.08 – 7.46(m, Ar-H),2.22 (s, CH3), 2.46(s,CH2), 5.02(d, CH),1.68(d, CH3)
2d	268-271	0.622	5.232	666, 752, 1330, 1454, 1648, 2975	7.4 – 8.6(m, Ar-H),6.11(s, CH), 2.506(d,CH2)

Anti-nociceptive activity:

Eddy's hot plate techniques were used to test the anti-nociceptive activity of all newly synthesized Mannich bases of carbazole. Adult albino mice of either sex weighing 20–30 g were used in this study. The animals were divided into ten groups’ total, with six animals in each group. Pentazocine (5 mg/kg, ip) and a novel series of synthesized carbazoles derivatives (20 mg/kg, ip) were administered to mice as treatments. On Eddy's hot plate, the percentage increase in the basal response period before and after the actions of synthetic and standard drugs at 15, 30, 60, and 120 minutes became well-known. By using the students "t" test⁹, all the data were statistically analyzed, expressed as mean SEM, and tabulated in Table 2.

Anti-epileptic activity (MES method):

Utilizing convulsions caused by a maximal electrical shock (MES), anti-epileptic effectiveness was assessed10. For the revision, adult albino mice of either sex weighing 20–30 g were used. Both phenobarbitone (20 mg/kg, ip) and newly synthesized carbazoles (20 mg/kg, ip) were used to preserve mice. After 30 minutes, the animals were shocked with 150 mA of electricity delivered through ear electrodes for 0.2 seconds by an electro convulsiometer. The occurrence and lack of an extensor response was evident, and the duration of the shock was evaluated statistically using a students "t" test⁹ and presented in mean SEM in Table 3.

Table 2. Anti-nociceptive evaluation of newly synthesized compounds

Treatment	Basel reaction time (sec) before treatment (Mean ±SEM)	Reaction time (in sec) after administration Mean ± SEM
		15 min	30 min	60 min	120 min
Control	4.1232 ± 0.2342	4.0228 ± 0.2322	4.1244 ± 0.2478	4.3244 ± 0.2286	4.3646 ± 0.2672
Pentazocine(standard)	4.5120 ± 0.9012	8.800 ± 0.9031**	10.22 ± 0.2642**	11.48 ± 0.3476**	13.22 ± 0.2974**
1a	4.9400 ± 0.6274	5.560 ± 0.6325*	6.48 ± 0.2224*	8.66 ± 0.2462**	10.34 ± 0.2874**
1b	4.8819 ± 0.4654	5.042 ± 0.4761*	6.58 ± 0.2978 *	8.44 ± 0.2536**	10.48 ± 0.3576**
1c	4.5276 ± 0.4123	4.686 ± 0.3055	5.66 ± 0.2732*	6.78 ± 0.2626*	7.88 ± 0.2674**
1d	4.7258 ± 0.4839	5.702 ± 0.4830*	7.46 ± 0.2564**	9.26 ± 0.2978**	11.22 ± 0.6428**
2a	4.5276 ± 0.5432	5.226 ± 0.5428**	7.62 ± 0.2464 **	8.70 ± 0.3260**	9.86 ± 0.2642**
2b	4.5276 ± 0.5324	5.406 ± 0.5428*	7.44 ± 0.4242**	9.66 ± 0.2484**	10.26 ± 0.2564**
2c	4.0332 ± 0.7654	4.715 ± 0.3332	5.26 ± 0.3678*	5.42 ± 0.2564*	6.38 ± 0.5478**
2d	4.6863 ± 0.4912	5.863 ± 0.3726*	7.54 ± 0.4264**	9.02 ± 0.2478 **	10.68 ± 0.2346**

** p< 0.001 vs. control indicates highly significant.

* p< 0.01 vs. control indicates significant

Table 3. Anti-epileptic evaluation of newly synthesized carbazole derivatives

Treatment	Duration (sec)(Mean ± SEM)			Recovery/Death
	Extensor	Clonus	Stupor
Control	31.50 ± 0.9220	22.66 ±1.7638	69.33 ±3.2830	Recovery
Phenytoin (Standard)	16.667 ±1.0541**	9.50 ±0.9574**	24.66 ±2.1551**	Recovery
1a	29.66 ±0.8819	20.33 ±0.9819	42.83 ±1.9221	Recovery
1b	22.66 ±1.1738*	15.33 ±1.1293*	28.00 ±2.7203*	Recovery
1c	26.83 ±0.8724*	15.00 ±0.7746*	34.66 ±2.5517*	Recovery
1d	37.00 ±1.2383	21.33 ±0.8028	38.00 ±2.4631	Recovery
2a	31.50 ±0.7188	22.83 ±1.4701	41.33 ±2.8597	Recovery
2b	17.00 ±2.4766**	17.16 ±1.1377**	35.00 ±2.3523**	Recovery
2c	25.00 ±2.3094*	12.00 ±1.0646*	23.50 ±2.9183*	Recovery
2d	29.83 ±0.8333	21.83 ±1.7208	63.16 ±1.4926	Recovery

RESULTS AND DISCUSSION:

In this reaction, a total of 8 novel carbazoles conjugates were obtained, their anti-nociceptive and anti-epileptic activities were assessed using spectral data, and they were analysed. With the exception of 1c and 2c, all of these compounds exhibit extremely notable analgesic activity. Compounds 1c and 2c exhibit weak anti-nociceptive activity when n-methyl piperazine is substituted. All of the compounds exhibit anti-nociceptive evaluation at the beginning of their effects, which last for up to 120 minutes. Due to the substitution of 2-(2, 3-dimethylphenylamino)benzoic acid, compound 2b exhibits extremely notable anti-epileptic activity. Compounds 1a, 1d, 2a, and 2d have been evaluated as anti-epileptic but are empty. The animals treated with 20 mg/kg body weight of the synthetic compounds as well as those animals treated with conventional pentazocine (5 mg/kg) and phenytoin (20 mg/kg), respectively, experienced the greatest anti-nociceptive and anti-epileptic effects.

Scheme: Synthesis of Carbazole Derivatives

Compounds Code	R	R^1& R^2
1a	H
1b	H
1c	H
1d	H
2a	CH3
2b	CH3
2c	CH3
2d	CH3

REFERENCES:

1. A. J. Waring, Comprehensive Organic Chemistry, Vol. 1, Pergamon Press, Oxford, (1997), p.1041.

2. C. Mannich and W. Krosche, Arch. Pharm., 250, 647 (1912).

3. K. J. Rajendra Prasad and C. Kavitha, Ind. J. Heterocyclic Chem., 12, (2003).

4. C. Biberger, T. Golob, G. Walter and E. Von Angerer, Arch. Pharm., 333 (9), 305-311, (2000).

5. V. V. Mulwad, M. B. Dalvi and B. S. Mahaddalkar, Ind. J. Chem., 7, 1477-1479, (2002).

6. Hua Yan, Tomoko Chiba, Yashihiro Kitamura Hideka Miura and Masayuki Fujino,Antivir. Chem. Chemother., 16 (6), 363-373, (2005).

7. Christina Aschea, Walter Frankb and Antje Albertb, Bio. Org. Med. Chem., 13 (3),817-837, (2005).

8. S. K. Kulkarni, Handbook of Experimental Pharmacology, 3^rd Edn, Vallabh Prakashan, (1987) p. 125.

9. S. K. Kulkarni, Handbook of Experimental Pharmacology, 3^rdEdn, Vallabh Prakashan, (1987) p. 175.

10. S. K. Kulkarni, Handbook of Experimental Pharmacology, 3rd Edn, Vallabh Prakashan, (1987) p. 131.

Received on 21.07.2022            Modified on 10.08.2022

Accepted on 28.08.2022           ©A&V Publications All right reserved

Research J. Science and Tech. 2022; 14(4):208-212.

DOI: 10.52711/2349-2988.2022.00034