Synthesis and Anticonvulsant Activity of 2, 4-Dinitrophenyl Hydrazones and Hydrazide-Hydrazones

 

Rajesh Vishnoi1, Mohammad Sabir2, Mahesh Kumar Gupta3 , M. P. Gupta4

1District Tuberculosis Centre, Kanpur, U.P., India-208001

2District Tuberculosis Centre, Kanpur  Dehat, U.P., India- Pin Code - 209111

3P.K.S.S. Mahavidyalaya, Kanpur Dehat, U.P., India-209111

4Naiminath Homoeopathic Medical College, Hospital and Research Centre, Nawalpur, Agra-283202 (U.P.) India

*Corresponding Author E-mail:

 

ABSTRACT:

A number of aldehydes and ketones were condensed with 2,4-dinitro phenyl hydrazine to give corresponding 2,4-dinitrophenyl hydrazones (Ia-Ic). Again aldehydes and ketones were reacted with 2-phenylacetohydrazide to give hydrazide-hydrazones (IIa-IIc). Structure of synthesized compounds were confirmed by elemental analysis and spectral data. The synthesized compounds were evaluated for anticonvulsant activity in maximial electroshock seizure (MES) test using phenytoin as standard drug. In which compound IIa was found most potent among the series.

 

KEYWORDS: Hydrazones, Hydrazide hydrazones, anticonvulsant activity, MES.

 

INTRODUCTION:

There has been considerable interest in the development of novel hydrazones containing –NH–N=CH– azometine moiety. Compounds containing this moiety show very broad spectrum of biological activities. Sah and Peoples1 synthesized isonicotinoyl hydrazones against M. tuberculosis in mice. Bukowski et al.2 synthesized is onicotinoyl hydrazone of 2-acetylimidazole, exhibited activity against M. tuberculosis, isolated from patients resistant against isoniazid, ethambutol, rifampicine. Epilepsy is a common neurological disorder that involves spontaneous, intermittent, abnormal electrical activity in the brain. For last twenty years new antiepileptic drugs have been introduced including hydrazones as novel anticonvulsant3-5.

 

Besides these activities, hydrazones are also found to possess antitumoral6-8, antiviral9, anti-inflammatory10,11, analgesic12 and antimalerial13,14 activities. In this regard potent molecules have been synthesized and evaluated for anticonvulsant activity by MES method using phenyltoin as standard drug.

 

EXPERIMENTAL:

(1) Chemical:

Melting points of synthesized compounds were recorded in liquid paraffin bath in open capillaries and are generally in agreement with the literature values. All the chemicals were purchased from Merck (India) and SD Fine Chemicals (India). Microanalysis for C, H, N were performed in Heraecus CHN rapid analyser and compounds gave satisfactory chemical analysis (± 0.3%). IR spectra were recorded in KBr on a Perkin-Elmer-983, while PMR spectra on Bruker 300 MHz spectrophotometer using TMS as standard scale and DMSO as solvent. Compounds (1a-1c) were synthesized by scheme-1.

 

Salicylaldehyde-2,4-dinitrophenyl hydrazone (1a) :

 

Compound was prepared according to the method18, salicylaldehyde (0.122g, 1.0 m mol) was added slowly to a clear solution of 2, 4-dinitrophenyl hydrazine (0.198 g, 1.0 m mol) and 1 mL of concentrated HCl acid in 15 mL of CH3OH. After few minutes precipitate was obtained which was filtered, washed with methanol and dried, Colour-orange yellow, Yield : 90%, m. p. 255oC, IR (KBr) : n =3600 (s, OH). 3450 (m, br, NH), 3105 (w, NH), 1574 (m, br, CH =N), n =1475 (m, NO2),  d = 1486 (m, NH), n = 1250 (s, C–N) 1175 (w, C–O),   d = 750 (vs, ArC-H, oop) cm-1. 1H PMR (DMSO-d6) :  d = 11.7 (s, 1H, NH), 8.0 (s, 1H, CH=N), 7.0 (s, 1H, OH), 6.7-8.5 (m, 7H, aromatic C–H). M.F. C13H10N4O5 : Calcd. C51.65, H3.30 N 18.54; found C 51.75,  H3.55, N18.40.

 

Pyridine-2-carbaldehyde-2,4-dinitrophenyl hydrazone (Ib) :

Pyridine-2-carbaldehyde (0.177g, 1.0 m mol) was added slowly to a clear solution of  2,4-dinitrophenyl hydrazine  (0.198 g, 1.0 m mol) and 1 mL of conc. HCl acid in 15 mL of CH3OH. The mixture was brought to boil to get precipitate which was filtered, washed with methanol and dried. Colour-yellow, Yield 92%, m. p. 239oC, IR (KBr), n =3424 (s, br, NH),  3109 (vs, NH), 1600 (m, br, CH =N), 1510 (m, NO2),  d = 1500 (m, NH), n = 1275 (s, C–N),  d = 760 (vs, ArC-H, oop) cm-1. 1H PMR (DMSO-d6):  d = 10.90 (s, 1H, NH), 8.0 (s, 1H, CH=N), 7.4 (s, 1H, OH), 6.5-7.0 (m, 7H, aromatic CH). M.F. C12H9N5O4 : Calcd. C50.17, H3.13,  N 24.40; found C 50.07,  H3.00, N24.65.

 

2-aminobenzophenone-2,4-dinitrophenyl hydrazone (Ic):

To the clear solution of 2,4-dinitrophenylhydrazine (0.198 g, 1.0 m mol),   mL of concentrated hydrochloric acid and 15 mL of methanol, 2-aminobenzo-phenone (0.197 g, 1.0 m mol) was added. The mixture was heated at reflux for    1 h, and allowed to stand overnight. The product precipitated was separated by filtration, washed with methanol, and air dried. Colour-red powder, Yield : 61%, m. p. 265oC, IR (KBr),  n = 3440 (s, br, NH), 3350 (s, NH2), 1635 ( vs, C= N) , 1500 (m, NO2), 1280 (s, C-N),  d = 750 (vs, ArC-H, oop) cm–1. 1H PMR (DMSO-d6):  d = 10.90 (s, 1H, NH), 7.5 - 8.5 (m, 12H, aromatic C–H), 6.60 (s, 2H, NH2),. M.F. C19H15N5O4 : Calcd. C60.47, H4.00,  N 18.56; found C 60.39,  H4.25, N18.50.

 

Compounds 2a-2c were synthesized by Scheme-2

 

 

Scheme-2-2-phenyl acetohydrazide hydrazone of 4-chlorobenzaldehyde (IIa)

An equimolar mixture of 4-chloro benzaldehyde and 2-phenyl acetohydrazide were dissolved in methanol, then two drops of conc. HCl were added as catalyst. The reaction mixture was heated below boiling temperature for some time with constant stirring and then poured into ice. The crude product was filtered and recrystallized from chloroform: methanol (8:2). Other compounds IIb-IIc were prepared by same method. Colour brown, yield 86%, m. p. 61oC, IR (KBr) :  n = 3430 (m, br, NH), 2930 (m, ArC–H), 1650 (vs, br, C = O), 1560 (m, br,  C = N), 1250 (s, C–N) cm-1. 1H NMR (DMSO-d6) : d 8.66 (s, 1H, NH), 7.5-8.0 (m, 9H, Ar-H), 6.7 (s, 2H, CH2), 1.25 (s, 1H, CH), M.F. C15H13N2OCl, Calcd. C66.05, H4.77, N10.27 found C66.25, H4.90, N 10.31.

 

2-Phenylacetohydrazide hydrazone of 4-hydroxyacetophenone (IIb):

Colour black, yield 90%, m. p. 52oC, IR (KBr) : n= 3590 (s, OH), 3400 (m, br, NH), 2840 (s, CH3), 1700 (Vs, C = O), 1530 (m, br, C=N),  = 740 (s, Ar-H, oop bent) cm-1, 1HNMR (DMSO-d6) : =8.50 (s, 1H, NH), 7.8 (s, 1H, OH), 6.8-7.5 (m, 9H, Ar-H), 6.7 (s, 2H, CH2), 5.30 (s, 3H, CH3), M.F. C16H16N2O2, Calcd. C71.64, H5.97, N 10.44, found C71.50, H6.03, N 10.70.

 

 

 

2-Phenylacetohydrazide hydrazone of acetophenone (IIc)

Colour brown, yield 85%, m.p. 61oC, IR (KBr) : n=3410 (m, br, NH), 2900 (s, CH3), 1720 (vs, C=O), 1520 (m, br, C=N), 730 (s, ArC-H oop bent)   cm-1, 1HNMR (DMSO-d6) : =8.2 (s, 1H, NH), 6.8-7.4 (m, 10H, Ar-H), 6.7 (s, 2H, CH2), 5.25 (s, 3H, CH3), M.F. C16H16N2O, Calcd. C76.19, H 6.34, N 11.11, Found C76.32, H 6.49, N 11.0

 

2. Biological Screening for anticonvulsant activity

Electroshock method19:

The albino rats of either sex, weighing 100-125 g were used. Food was withdrawn 12-15 h before commencing the experiment while water was withdrawn immediately before the experiment. Maximal seizures were induced through delivering current AC in a pulse of 6 Hz via corneal electrodes at 50 mA for 0.2 s. The animals which showed positive hind limb extensor response were used for testing. Maximal seizures were induced after 0.5 h, 4 h and 24 h of drug administration. Each testing compound is administered (i.p.) as solution in polyethylene glycol in logarithmic dose of 100 mg/kg to animals in groups of four and protections calculated. Thus each MES value is the average of three separate group protections. Pretreatment with effective anticonvulsant drug results the abolition of hind limb tonic extensor spasm. The data were compared by standard drug phenytoin and given in Table 1. The test has predictive value for drug of potential therapeutic value in the management of grandmal epilepsy20.

 

Table-1: Anticonvulsant activity data of compounds

Sl. No.

Compd.

R1

R2

Molecular formula

Dose mg/kg

Animals protected

0.5 H

4 H

24 H

1

Ia

o-C6H4OH

H

C13H10N4O5

100

1/4

0/4

0/4

2

Ib

o-C6H4N

H

C12H9N5O4

100

0/4

0/4

0/4

3

Ic

o-C6H4NH2

C6H5

C19H15N5O4

100

0/4

0/4

0/4

4

IIa

H

p-Cl

C15H13N2Cl

100

2/4

1/4

1/4

5

IIb

CH3

p-OH

C16H16N2O2

100

2/4

1/4

0/4

6

IIc

CH3

H

C16H16N2O

100

2/4

0/4

0/4

7

Standard drug phenytoin

100

4/4

3/4

0/4

 

 

RESULTS AND DISCUSSION:

In the MES test compounds Ia showed 25% anticonvulsant activity after 0.5 h of drug administration at a dose of 100 mg/kg but not found longer active more than 0.5 h. Compound IIa showed 50% anticonvulsant activity in the same test in same dose and also found 25% active in the extended durations after 4 hr and 24 h of drug administration. Compound IIb also showed 50% anticonvulsant activity in the MES test and also 25% active after 4 h of drug administration at a dose of 100 mg/kg. Compound IIc was found 50% active in the MES test of anticonvulsant activity at a dose of 100 mg/kg, it was no longer active after 0.5 h of drug administration. While compounds Ib and Ic are not active in the same test. The results were compared with standard drug phenytoin. All the compounds showed less anticonvulsant activity after 0.5 h and 4 h of the drug administration as compared with the standard drug phenytoin. One compound IIa was found more active than the standard drug and showed anticonvulsant activity after 24 h of drug administration, where standard drug was not so longer active.

 

ACKNOWLEDGEMENT:

The authors are thankful to the lab workers of Chemistry Department P.K.S.S. Mahavidyalaya for providing experimental facilities. Authors are also thankful for the co-workers of Tuberculosis Centre of Kanpur and Kanpur Dehat for active supports during the work.

 

REFERENCES:

1.        Sah, P.P.T.; Peoples, S.A. Isonicotinyl hydrazones as antitubercular agents and derivatives for idendification of aldehydes and ketones, J. Am. Pharm. Assoc. 1954, 43, 513-524.

2.        Bukowski, L.; Janowiec, M.; Zwolska-Kwiek, Z.; Andrzejczyk, Z. Synthesis and some reactions of 2-acetylimidazo[4,5-b]pyridine. Antituberculotic activity of the obtained  compounds. Pharmazie 1999, 54, 651-654.

3.        Dimmock, J.R.; Vashishtha, S.C.; Stables, J. P. Antconvulsant properties of various acetylhydrazones, oxamoylhydrazones and semicarbazones derived from aromatic and unsaturated carbonyl compounds. Eur. J. Med. Chem. 2000, 35, 241-248.

4.        Cakir, B.; Dag, O.; Yilirim, E.; Erol, K.; Sahin, M.F. Synthesis and anticonvulsant activity of some hydrazones of 2-[(3H)-oxobenzoxazolin-3-yl- aceto] hydrazide. J. Fac. Pharm. Gazi. 2001, 18, 99-106.

5.        Ragavendran, J.; Sriram, D.; Patel, S.; Reddy, I.; Bharathwajan, N.; Stables, J.; Yogeeshwari, P. Design and synthesis of anticonvulsants from combined phthalimide-GABA-anilide and hydrazone pharmacophone. Eur. J. Med. Chem. 2007, 42, 146-151.

6.        Zhang, H.; Drewe, J.; Tseng, B.; Kasibhatla, S.; Cai, S.X. Discovery and SAR of indole-2-carboxylic acid benzylidenehydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay. Bioorg. Med. Chem. 2004, 12, 3649-3655.

7.        Demirbas, N.; Karaoglu S.; Demirbas A.; Sancak K. Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl) methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl) methyl -5-oxo-[1,2,4]triazole derivatives. Eur. J. Med. Chem. 2004, 39, 793-804.

8.        Cocco, M.T.; Congiu, C.; Lilliu, V.; Onnis, V. Synthesis and in vitro antitumoral activity of new hydrazinopyrimidine-5-carbonitrile derivatives. Bioorg. Med. Chem. 2005, 14, 366-372.

9.        Abdel-Aal, M.T.; El-Sayed, W.A.; El-Ashry, E.H. Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives. Arch. Pharm. Chem. Life Sci. 2006, 339, 656-663.

10.     Todeschini, A.R.; Miranda, A. L.; Silva C.M.; Parrini, S.C.; Barreiro, E.J. Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives. Eur. J. Med. Chem. 1998, 33, 189-199.

11.     Lima, P.C.; Lima, L.M.; Silva, K.C.; Leda, P.H.; Miranda, A.L.P.; Fraga, C.A.M.; Barreiro, E. J.; Synthesis and analgesic activity of novel N-acyl hydrazones and isosters, derived from natural safrole. Eur. J. Med. Chem. 2000, 35, 187-203.

12.     Sham M. Shondhi Indian J. Chem. 48B, 2009, 1128-1136.

13.     Gemma, S.; Kukreja, G; Fattorusso, C.; Persico, M.; Romano, M.; Altarelli, M.; Savini, L.; Campiani, G.; Fattorusso, E.; Basilico, N. Synthesis of N1-arylidene-N2-quinolyl-and N2-acrydinyldydrazones as potent antimalarial agents active against CQ-resistant P. falciparum strains. Bioorg. Med. Chem. Lett. 2006, 16, 5384-5388.

14.     Bernardino, A.; Gomes, A.; Charret, K.; Freitas, A.; Machado, G.; Canto- Cavalheiro, M.; Leon, L.; Amaral, V. Synthesis and leishmanicidal activities of 1-(4-X-phenyl)-N'-[(4-Y-phenyl)methylene]-1H-pyrazole-4- carbohydrazides. Eur. J. Med. Chem. 2006, 41, 80-87.

15.     Katyal, M.; Dutt, Y., Talanta, 1975, 22, 151.

16.     Mohan, M.; Gupta, M.P.; Chandra, L.; Jhan, N. K. Inorg. Chem. Acta, 1988, 61, 151.

17.     Molodykh, Zh. V.; Buzykin, B.I.; Bystrykn, N. N.; Kitaev, Y. P. Khim Farm. 1978, 11, 37.

18.     Vogel, A. Vogel's Text book of Practical Organic Chemistry, 4th ed., Longman, New York, 1975, 1111.

19.     Toman, J.E.P., Swinyard, E.A.; Goodman, L.S. Neurophysiol, 1946, 9, 231.

20.     Pandeya, S. N., A textbook of Medical Chemistry, Vol. 1, Page 158, edn. 2003, S.G. Publisher, Varanasi, India.

 

 

 

 

Received on 23.07.2015         Modified on 03.08.2015

Accepted on 22.08.2015         © AJRC All right reserved

Asian J. Research Chem. 8(8): August 2015; Page 535-538

DOI: 10.5958/0974-4150.2015.00085.1