INTRODUCTION:

Cyclic imides assume the role of important class of substrates for biological and chemical applications. They have been shown wide degree of biological activities such as antibacterial, antifungal. They have been also imputing them for medication and some of them are widely used as analgesic and anti-nociceptive agents [1].Cyclic imides like succinimides, male imides, phthalimides, glutarimides embracing the foremost part in the organic synthesis [2]. An imide nucleus can also constitute a structure of anticancer, anxiolytic and anti-inflammatory substances [3]. The molecular model methods of the substituted cyclic imides were prospectively inaugurates cytotoxic agents on DNA bindings and apoptosis induction of peripheral blood neutrophils [4]. It has been observed that few halo-substituted phenyl succinimide were retrieve the significant role in the mechanism of NDPS nephro -toxicity NDHS formation [5]. Succinimide acts as electro-convulsions [6]. Anti-muscarinic and nephrotoxic [7]. Along with succinimides most of the glutarimide drugs affected the uracil transport, thymine nucleosides in the biological membranes [8]. The influence of poly glutarimides PMMA thermal strength sonorously improves the imidization [9] by IRTF analysis [10]. Natural products like glutarimide alkaloids segregated from Croton pullei species which gives outstanding antibacterial and antifungal activities [11]. The buoyant effects of gluttarimides are actively found on spinal neurons [12] brain metabolism [13], mitochondrial respiration [14]. In spite of above discussion heterocyclic nitro [15] derivative pro vides the great fortune for the development of novel and compelling medicinal drugs. Heterocyclic imides such as succinimides [16], glutarimides [17] and their malononitriles [18] and chalcone [19]. Centredpyrazolies [20], pyrimidines [21] derivatives plays a very important key role in the synthesis of organic compounds.

MATERIALS AND METHODS:

Melting points were recorded in open glass capillaries and were uncorrected. The chemical structures of the obtained compounds were confirmed by spectral analyses. IR spectra in KBr pallets were obtained on Simadzu and ATR Brucker alpha FT-IR spectrophotometer. 1H NMR spectra were obtained on and 500.13 MHz by Brucker spectrophotometer. The chemical shifts were reported as parts per million (ppm) with (CH3)4Si (TMS) as an internal standard. Signal multiplicities are represented by: s (singlet), d (doublet), t (triplet), m (multiplet). The purity of compound was checked by thin layer chromatography which was performed by using pre-coated silica gel aluminum plates with mixture of diethyl ether and ethyl acetate 7:3 proportion. All the compounds (A, B, C, D, E and F) were synthesized from the corresponding commercial available aromatic amines, succinic anhydride, glutaric anhydride and water. Anti-microbial and Anti-fungal activities were carried out by Agar diffusion assay (Disk diffusion method, Disk size 6 mm) [22].

Heating in an oil bath with simultaneous distillation still the water is removed completely

Fig.1: Experimental Demonstration of N-Succinimide Derivative (Part-I) Synthesis – Green Method

GENERAL PROCEDURE OF SYNTHESIS:

Preparation of 1-(N-methylpyridin-2-yl) pyrrolidine-2, 5-dione (A, B and C)

1.01 Mole of the appropriately substituted 2- amino pyridine was dissolved in 20 mL of water and 0.01 mole of succinic anhydride was gradually added. The mixture was heated in an oil bath with simultaneous distillation of water. After the water was completely removed, the temperature of the reaction mixture was rose up to 180 ºC and was maintained for 1.5 h. The crude products were recrystallized from isopropanol [23]. (Scheme – I); Fig.1 and 2.

Preparation of 1-(N-methylpyridin-2-yl) piperidine-2, 6-dione (D, E and F)

1.01 mole of the appropriately substituted 2- amino pyridine was dissolved in 20 mL of water and 0.01 mole of glutaric anhydride was gradually added. The mixture was heated in an oil bath at 180 ºC and was maintained for 1.5 h. The crude products were recrystallized from isopropanol (Scheme – II); Fig.2.

Fig.2: Experimental Demonstration of N-Succinimide(Part-II)/N-Glutarimide Derivative Synthesis -Green Method

Physicochemical and analytical data for compounds A-F:1-(5-methylpyridin-2-yl)pyrrolidine-2, 5-dione (A)

Whitish solid, Yield (66.80%), M. P. 146-148 ºC, M.F. C₁₀H₁₀O ₂N_2, M.W.190.20, Composition: C (63.15%) H (5.30%) N (14.73%) O (16.82%); IR (KBr): 1709,2487,1334,1301, 3044, 2967,2924,1393,1490,1551,1598,2759 cm^-1. ¹H NMR (500.13 MHz, DMSO-d₆, δ ppm): 2.35 (s, 3H, CH₃-pyridine), 2.90 (s, 4H, imide), 7.85-8.47 (m, 2H, pyridine), 8.23 (d, 1H, pyridine).

1-(4-methylpyridin-2-yl) pyrrolidine-2, 5-dione (B)

Whitish solid, Yield (60.65%), M. P. 142-144 0C, M.F. C₁₀H₁₀ O₂N₂, M.W.190.20, Composition: C (63.15%) H (5.30%) N(14.73%) O (16.82%); IR (KBr): 1700,2447,1353,1301,3014,2969,2813,1444,1491,1551,1405,2764 cm^-1. ¹H NMR (500.13 MHz, DMSO-d₆, δ ppm): 2.41 (s, 3H, CH3-pyridine), 2.90 (s, 4H, imide), 7.16-7.19 (m, 2H, pyridine), 8.49 (d, 1H, pyridine).

Table I. Antimicrobial activities of cyclicimides

S. No	Sample	*E. coli*	*P. aeruginosa*	*S. aureus*	*B. subtilis*	*C. albicans*	*A. niger*
		Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD

1.	A	11.77±0.31	9.47±0.08	10.87±0.33	7.64± 0.21	---	---
2.	B	07.48±0.34	7.58±0.26	---	---	---	---
3.	C	12.05±0.06	12.51± 0.18	11.31±0.05	10.2± 0.07	---	---
4.	D	---	---	---	---	---	---
5.	E	---	---	---	---	---	---
6.	F	9.02±0.16	11.19±0.40	10.35±0.12	8.48± 0.07	---	---
	Chloramphenicol	24.09±0.10	14.39±0.07	23.92±0.17	28.43± 0.29	NA	NA
	Amphotericin B	NA	NA	NA	NA	15.21±0.15	11.8±0.08

Graph –I

1-(6-methylpyridin-2-yl)pyrrolidine-2, 5-dione (C)

Whitish solid, Yield (65.47%), M. P. 148-150 ºC, M.F. C₁₀H₁₀O ₂N_2, M.W.190.20, Composition: C (63.15%) H (5.30%) N (14.73%) O (16.82%); IR (KBr): 1689,2363,1261, 2967,2792,1640,1544,1403,1309,2559 cm^-1. ¹H NMR (500.13 MHz, DMSO-d₆, δ ppm): 2.59 (s, 3H, CH₃-pyridine), 2.90 (s, 4H, imide), 7.06(d, 1H, pyridine), 7.22 (d, 1H, pyridine), 7.74 (t, 1H, pyridine).

1-(5-methylpyridin-2-yl) piperidine-2, 6-dione (D)

Whitish solid, Yield (71.95%), M. P. 140-142 ºC, M.F. C₁₁H₁₂O ₂N_2, M.W. 204.225,Composition: C (64.69%) H (5.92%) N (13.72%) O (15.67%); IR (KBr): 1682, 1342,1310, 3272,1583,1455,1417, 1378,3083 cm^-1. ¹H NMR (500.13 MHz, DMSO-d₆, δ ppm): 2.35 (s, 3H, CH₃-piperidine), 2.16 (t, 4H, imide), 1.80 (m, 2H, imide), 7.82-8.47 (m, 2H, piperidine), 8.23 (d, 1H, piperidine).

1-(4-methylpyridin-2-yl)piperidine-2,6-dione (E)

Whitish solid, Yield (68.39%), M. P. 150-152 ºC, M.F. C₁₁H₁₂O ₂N_2, M.W. 204.225, Composition: C (64.69%) H (5.92%) N (13.72%) O (15.67%); IR (KBr): 1670, 1332,1295, 3262,1573,1445,1407,1368,3073 cm^-1_,¹H NMR (500.13 MHz,DMSO-d₆, δ ppm): 2.40 (s, 3H, CH₃-piperidine), 2.16 (t, 4H, imide), 1.80 (m, 2H, imide), 7.19-7.23 (m, 2H, piperidine), 8.52 (d, 1H, piperidine).

1-(6-methylpyridin-2-yl)piperidine-2,6-dione (F)

Whitish solid, Yield (69.75%), M. P. 154-156 ºC, M.F. C₁₁H₁₂O ₂N_2, M.W. 204.225, Composition: C (64.69%) H (5.92%) N (13.72%) O (15.67%); IR (KBr): 1692,1357,1305, 2966,1663,1636,1561,1484,3025 cm^-1. ¹H NMR (500.13 MHz, DMSO-d₆, δ ppm): 2.35 (s, 3H, CH₃-piperidine), 2.16 (t, 4H, imide), 1.80 (m, 2H, imide), 7.09(d, 1H, piperidine), 7.25 (d, 1H, piperidine), 7.77 (t, 1H, piperidine).

RESULTS AND DISCUSSION:

Chemistry:

The series of cyclicimides A, B and C were prepared by the reaction of succini can hydride and primary aromatic amines by distillation and reasonable yield is obtained. The formation of five membered cyclic imides was confirmed by IR,¹³CNMR and ¹HNMR and elemental analysis. The series of cyclicimides D, E and F were prepared by the reaction of glutaric anhydride and primary aromatic amines by distillation and reasonable yield is obtained. The formation of six membered cyclicimides was confirmed by IR, ¹³CNMRand¹ HNMR and elemental analysis.

Antimicrobial Activities:

All the synthesized compounds A, B, C, D, E and F were screened for their antibacterial activity against gram positive bacteria Staphylococcus aureus (NCIM 2079), Bacillus subtilis (NCIM 2250) and gram negative bacteria Escherichia coli (NCIM 2109), Pseudomonas aeruginosa (NCIM 2036) using DMSO solvent. Also, all these compounds were screened against Fungi (Yeast) Candida albicans (NCIM 3471) and Aspergillus niger (NCIM 545). The bacterial cultures were purchased from NCIM: National Collection of Industrial Microorganisms, National Chemical Laboratory (NCL), Pune 411008 (India). Some of the compound showed moderate to good activities against Bacillus subtilis and E- coli as shown in the Table–I and Graph –I.

CONCLUSION:

In conclusion, we have synthesized a series of five membered cyclic imides 1-(N-methylpyridin-2-yl) pyrrolidine-2,5-dione and a novel series of six membered cyclic imides 1-(N-methylpyridin-2-yl) piperidine-2, 6-dionefrom of 2-amino 5-methyl, 2-amino 4-methyl, 2-amino 6-methyl pyridine for the first time under convenient reaction conditions. These new series of compounds possess potent antimicrobial activities against some common pathogens like Bacillus Subtilis and E-coli. Further studies on structure activity relationships and on the scope of application of the compounds is going on.

REFERENCES:

1. Lin Z, Zhang W, Wang L, Yu H, Wu C. 2003. Mechanism of the synergistic toxicity of malononitrile and p– nitrobenzaldehyde with photobacterium phosphoreum. Toxicology mechanism and methods, 13(4): 241-245.

2. Kulveer Singh, Suman Kumari, Y.K. Gupta, “Synthesis and Antimicrobial Activity of New Pyrazoles and Chalcones Derived from Cyclic Imides.” Research Journal of Pharmacy and Technology (RJPT) Vol.10, Issue 12, pp 4479-4484, 2017. DOI: 10.5958/0974-360X.2017.00827.7

3. Arun Kumar, Vinita Gupta, Sanchita Singh, Y.K. Gupta, “Synthesis and Physico Chemical Studies of Some Chalcone and Their Derivatives as Potential Antimicrobial Agents.”Research Journal of Pharmacy and Technology (RJPT) Vol. 10, Issue 05, pp1155-1159, 2017. DOI: 10.5958/0974-360X.2017.00208.6

4. Alaa AM, Abdel-Aziz. 2007. Novel and versatile methodology for synthesis of cyclic imides and evaluation of their cytotoxic, DNA binding, apoptotic inducing activities and molecular modeling study, European Journal of Medicinal Chemistry, 42: 614-626.

5. Hong SK, Anestis DK, Hawco NM, Valentovic MA, Brown PI, Rankin GO. 1996. Nephrotoxicity of N-(3-bromophenyl)-2-hydroxyl succinimide: Role of halogen groups in the nephrotoxic potential of N-(halophenyl) succinimides. Elsevier, Toxicology, 110(1-3):17-25.

6. Luszczki JJ, Marzeda E, Kondrat-Wrobe MW, Wrobel J, Kocharov SL, Florek- Luszczki M. 2014. Effect of N-(p-ethoxy-carbonyl-phenyl-methyl)-p-isopropoxy phenyl succinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Journal of Preclinical and Clinical Research, 8(1): 34-37.

7. Hudkins RL, DeHaven-Hudkins DL, Doukas P. 1997. Design of dual acting anticonvulsant-ant muscarinicsuccinimides and hydantoin derivatives. Bioorganic and MedicinalChemistry Letters, 7(8): 979-984.

8. Michalska D, Morzyk B, Bienko DC, Wojciechowski W. 2000. Glutarimide: a carrier transporting drug through cell membranes. Medical Hypotheses, 54(3): 472–474.

9. Lee Y, Choi HW, Chin I, Won HY, Kim YS. 1995. Conversion of Poly (methyl methacrylate) to Polyglutarimide. Korea Polymer Journal, 3(2): 76-81.

10. Legay R, Roussel J, Boutevin B. 2000. Synthesis of polyglutarimides from PMMA and methylamine II, Influence of operating conditions on imidification reaction. European Polymer Journal, 36(7): 1365-1371.

11. Peixoto RNS, Guilhon GMPS, Zoghbi MGB, Araujo IS, Uetanabaro APT, Santos LS, Brasil DSB. 2013. Volatiles, A Glutarimide Alkaloid and Antimicrobial Effects of Croton pullei (Euphorbiaceae). Molecules, 18: 3195-3205.

12. Nicholson GM, Spence I, Johnston GAR. 1985. Effects of a depressant/ convulsant pair of glutarimides on neuronal activity in the isolated spinal cord of the immature rat. Elsevier, Neuropharmacology, 24(6): 461-464.

13. Nicholls PJ. 1962. The effects of certain glutarimides on brain metabolism. International Journal of Neuropharmacology, 1(1-3): 229.

14. Prado SRT, Cechinel-Filho V, Campos-Buzzi F, Correa R, Cadena SMS, 2004. Martinelli de Oliveira MB. Biological evaluation of some selected Cyclic Imides: Mitochondrial Effects and in vitro Cytotoxicity. Z. Naturforsch., 59c: 663-672.

15. Yogesh Kumar Gupta, Vinita Gupta, Sanchita Singh “Synthesis, Characterization and Antimicrobial activity of Pyrimidine based derivatives”. Journal of Pharmacy Research,(Elsevier)Vol. 07, No. 06, pp 491-495, 2013.

16. Gupta Vinita, Singh Sanchita and Gupta Y.K. “Synthesis and Antimicrobial Activity of some Salicylaldehyde Schiff bases of 2-aminopyridine”. Research Journal of Chemical Sciences, Vol. 03, Issue 09, pp 26-29, 2013

17. Kulveer Singh1, Suman Kumari2, Y.K. Gupta3* “Synthesis, Characterization and Antimicrobial Screening of New Cyclic Imides.” Research Journal of Science and Technology (RJST), Vol. 09, Issue 04, pp 691-694, 2017. DOI: 10.5958/2349-2988.2017.00117.6

18. [18] Arun Kumar, Vinita Gupta, Sanchita Singh, Y.K. Gupta. “Synthesis of Some Chalcone and Their Heterocyclic Derivatives as Potential Antimicrobial Agents: A Review”. Asian Journal of Research in Chemistry, Vol. 10, No 02, pp 225-239, 2017.DOI: 10.5958/0974-4150.2017.00038.4

19. Kulveer Singh, Suman Kumari, Y.K. Gupta. “ Synthesis and Antimicrobial Activity of Mono, Di and Tri Substituted Aromatic Amines and Napthyl Amine Cyclic Imides Derivatives. International Journal of Technology (IJT) Vol. 07, Issue 02, pp 85-89, 2017.

20. Arun Kumar, Vinita Gupta, Sanchita Singh, Y.K. Gupta. “Solubility of Some Pyrimidine Derivatives in Methyl- Alcohol at different Temperatures”. Asian Journal of Research in Chemistry, Vol. 10, No 02, pp186-190, 2017.DOI: 10.5958/0974-4150.2017.00031.1

21. Pal R, Sarkar T, Khasnobis S. 2012. Amberlyst-15 in organic synthesis. ARKIVOC, (i): 570-609.

22. Jorgensen JH, Murray PR, Baron EJ, Landry ML, Pfaller MA. 2007. Susceptibility Test methods: Dilution and Disk diffusion methods. In Manual of clinical Microbiology, II: 1152‐1173.

23. Kami-SkiK. and Obniska J. 2008. Synthesis and Anticonvulsant Properties of New 1-(2-Pyridinyl)-3-Substituted Pyrrolidine-2,5-Dione Derivatives. Acta Poloniae Pharmaceutica ñ Drug Research, 65 (4): 457-465.

Received on 05.12.2018 Modified on 30.12.2018

Research J. Science and Tech. 2019; 11(1):82-86.

DOI: 10.5958/2349-2988.2019.00013.5