INTRODUCTION:

Heterocyclic compounds are ring compounds containing one or more different atoms that replace one or more carbon atoms, these atoms are nitrogen, oxygen, and sulfur, the ring may consist of three or more atoms called heterocyclic ring compounds, these compounds are either saturated or unsaturated^1,4. There are many heterocyclic ring compounds of great importance as natural products in our lives such as some types of amino acids, hormones, and vitamins. Many non-natural products contain heterocyclic rings such as medicines, dyes, pesticides,… etc⁵.

From this wide range of heterocyclic compounds, pyrazole derivatives are used in the medical and pharmaceutical fields because of their extensive activities in the treatment of many infectious diseases such as anticonvulsant^6,7, antimicrobial^8,9, analgesic¹⁰, antitubercular^11,12, anti-inflammatory^13,14, anticancer^15,16, cardiovascular¹⁷... etc. Sulfadiazine is classified under the class of drugs known as sulfa antibiotics with typical sulfonamide structure which is widely used as a veterinary medicine¹⁸. It is used for the treatment of different infections such as prophylaxis of recurrent rheumatic fever, malaria, toxoplasmosis and certain types of brain infections and new antitumor agents can^{be designed by combining sulfadiazine and antitumor} ^{agents in one compound19 .}

MATERIALS AND METHODS:

All used chemicals were supplied by Merck, BDH, Fluke, and Sigma Aldrich Chemicals Company. Melting degrees were measured by using a Melting point measuring device, UK. Calculate absorption spectrum FT-IR values by using Fourier change infrared Bruker ALPHA FT-IR, college of Science, University of Kufa, Ira¹H NMR was recorded by Bruker spectrometer, operating at (500MHZ) with (DMSO-d6). Measurements were made at Faculty of Science, University of Tehran, Iran. The elemental analysis is recorded using E.A.G.E.R.-100, Carlo Erba, Italy. Measurements were made at the Department of Chemistry, University of Tehran, Iran. The progress of reactions for the preparation of compounds was monitored using thin-layer chromatography (TLC), compounds were detected by Iodine vapor.

METHODS:

Synthesis of 2-chloro-N-(4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl) acetamide) A(²⁰ : Solution of (0.01 mol, 2.5 g) of sulfadiazine in DMF was mixed with (1.5 ml) triethylamine and was added (0.01 mol, 0.8 ml) chloroacetyl chloride for to mixture drop by drop. Was stirred the mixture for (3-4 hrs.). The reaction was checked by TLC. Finally, isolation of the product is done by filtration and purification using recrystallization by absolute ethanol, yield pale yellow (79%), m.p. (228-230 ⁰C), and R_f (0.6) (benzene: methanol) (4:1).

Synthesis of 2-hydrazinyl-N-(4-(N-(pyrimidin-2 yl)sulfamoyl) phenyl) acetamide (B)²¹: Hydrazine hydrate (99%) (0.01mol , 0.5ml) in ice water bath was mixed with solution of 2-chloro-N-(4-(N-pyrimidin-2-ylsulfamoyl) phenyl) acetamide [A] (0.01mol, 2g ) in (20 ml) of absolute ethanol by used a magnetic stirrer for (30 min.), and at room temp. was stirred for (5 hrs.) . The reacted was monitored by TLC. The product was washed by solution of (0.1 M HCl) and distilled water. Finally, Isolation of the product is done by filtration and purification using recrystallization by absolute ethanol, yield white (70%), m.p. (95-97 ⁰C), and R_f (0.68) (benzene: methanol, 4:1).

General procedure for the synthesis of chalcones derivatives (C₁-C₅): 4-aminoacetophenone (0.01mol, 1.5g) was mixed with an aromatic aldehyde (0.01mol) dissolved in (20 ml) of absolute ethanol was stirred and for the mixture of NaOH (40%) was added drop by drop, and stirring was about (4 hours) at room temp. The reaction progress was followed by TLC (benzene: methanol) (4:1). Finally, isolation of the product was done by filtration and washed by (3% aqueous HCl) and distilled water, purification using recrystallization by absolute ethanol.

Some physical properties of compounds:

Compound (C₁): It was prepared as yellow powder; yield 84%; m. p.: 148-150 ºC; R_f: 0.65, Elemental Analysis of(C₁₅H₁₂ClNO): Calc.%: N, 5.44;H, 4.69; C, 69.91, Found: N, 6.08; H, 3.76;C, 70.43.

Compound (C₂): It was prepared as Orange powder; yield 85%; m. p.: 175-177 ºC; R_f: 0.61.

Compound (C₃): It was prepared as yellow powder; yield 84%; m. p.: 146-148 ºC; R_f: 0.62, Elemental Analysis of (C₁₅H₁₂N₂O₃): Calc.%: N, 10.44;H, 4.51; C, 67.16, Found: N, 10.23; H, 4.09;C, 66.79.

Compound (C₄): It was prepared as Pale yellow powder; yield 86%; m. p.: 120-122 ºC; R_f: 0.60, Elemental Analysis of (C₁₅H₁₂FNO): Calc.%: N, 5.81;H, 5.01; C, 74.68, Found: N, 6.56; H, 5.78;C, 73.61.

Compound (C₅): It was prepared as Dark brown powder; yield 83%; m. p.: 179-181 ºC; R_f: 0.63.

General Procedure for the synthesis of pyrazoline derivatives (BC₁-BC₅)²²: A mixture of (0.01 mol, 0.5g) compound [B] and (0.01 mol) of chalcone [C₁-C₅] was stirred in (15 mL) ethanol absolute and added KOH (0.01mol, 0.5 g in 2.5 mL of ethanol) refluxed was for (8 hrs.) at 50-60 C⁰.The reaction progress was followed by TLC (benzene: methanol)(4:1). Finally, isolation of the product is done by filtration and washed by ethanol absolute, purification using recrystallization by absolute ethanol.

Some physical properties of compounds:

Compound (BC₁): It was prepared as Red powder; yield 75%; m. p.: 143-145 ºC; R_f: 0.72, Elemental Analysis of(C₂₇H₂₄ClN₇O₃S) : Calc.%: S, 5.70; N, 17.45;H, 4.30; C, 57.70, Found: S, 5.12; N, 16.61; H, 4.88;C, 55.97.

Compound (BC₂): It was prepared as Black powder; yield 77%; m. p.: 138-140 ºC; R_f: 0.66.

Compound (BC₃): It was prepared as Pale brown powder; yield 73%; m. p.: 133-135 ºC; R_f: 0.73, Elemental Analysis of(C₂₇H₂₄N₈O₅S) : Calc.%: S, 5.60; N, 19.57;H, 4.22; C, 56.64, Found: S, 5.89; N, 20.43; H, 3.75;C, 57.77.

Compound (BC₄): It was prepared as Maroonowder; yield 72%; m. p.: 129-131 ºC; R_f: 0.72, Elemental Analysis of(C₂₇H₂₄FN₇O₃S) : Calc.%: S, 5.88; N, 17.97;H, 4.43; C, 59.44, Found: S, 6.23; N, 16.45; H, 5.36;C, 57.49.

Compound (BC₅): It was prepared as Red powder; yield 70%; m. p.: 135-137 ºC; R_f: 0.68.

General Procedure for the synthesis of pyrazole derivatives (IBC₁-IBC₅)²²: (0.01 mol, 0.5g) of the composite [B] was mixed with (0.01 mol) of the chalcon [C₁-C₅] in (10 ml) of acetic acid, and the solution was reflexed for (3 hrs.). Then, add (0.01mol,1g) Iodine, reflexed continued for (3-4 hrs.), follow the movement of the reaction by TLC (benzene: methanol) (4:1), and then pour the mixture on the crushed of ice and the mixture was treated by sodium hydrogen carbonate and filtered precipitate and washed with ethanol and recrystallized with ethanol absolute.

Some physical properties of compounds:

Compound (IBC₁): It was prepared as Dark brown powder; yield 72%; m. p.: 155-157 ºC; R_f: 0.74, Elemental Analysis of (C₂₇H₂₂ClN₇O₃S): Calc.%: S, 5.72; N, 17.51;H, 3.96; C, 57.91, Found: S, 4.65; N, 18.34; H, 4.86;C, 55.96.

Compound (IBC₂): It was prepared as Brown powder; yield 78%; m. p.: 146-148 ºC; R_f: 0.64.

Compound (IBC₃): It was prepared as Yellowish-brown powder; yield 74%; m. p.: 142-144 ºC; R_f: 0.70, Elemental Analysis of (C₂₇H₂₂N₈O₅S) : Calc.%: S, 5.62; N, 19.64;H, 3.89; C, 56.84, Found: S, 6.11; N17.89; H, 3.45;C, 59.13.

Compound (IBC₄): It was prepared as Black powder; yield 73%; m. p.: 138-140 ºC; R_f: 0.71, Elemental Analysis of (C₂₇H₂₂FN₇O₃S) : Calc.%: S, 5.90; N, 18.04;H, 4.08; C, 59.66, Found: S, 6.27; N, 17.31; H, 4.67;C, 60.52.

Compound (IBC₅): It was prepared as Dark brown powder; yield 75%; m. p.: 145-147 ºC; R_f: 0.67.

RESULTS AND DISCUSSION:

Synthesis and identification of 2-chloro-N-(4-(N-(pyrimidin-2- yl)sulfamoyl) phenyl) acetamide [A]: The main intermediate compound [A] was prepared by reacting sulfadiazine with chloroacetyl chloride in the presence of triethylene as a catalyst with (DMF) as solvent to form 2-chloro-N-(4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl) acetamide. The sodium fusion test indicates the presence of the chloride in the product. The compound [A] was characterized by (C.H.N.S) technique and by comparing the data of the calculated results with the theoretical results, there was a good agreement between the results and this is evidence of the composition of the compound. The data of analysis were listed in the table (4). FT-IR indicates on the disappearing of starching vibration of (-NH₂) group of sulphadiazine at (3416 cm^-1) and appearance of new absorption peak for (-NH) group of amide at (3243 cm^-1), also peak at (2970 cm-¹) to stretching vibration of (-CH₂) and absorption band at (1669 cm^-1) for the stretching of (-C=O). The final important peak at (731 cm^-1) for the bending bond of (-C-Cl). Elemental Analysis of compound (A): chemical formula (C₁₂H₁₁ClN₄O₃S) : Calc.%: S, 9.81; N, 17.15;H, 3.39; C, 44.11, Found: S, 9.17; N, 16.82; H, 3.04;C, 43.75. Whereas synthesis of the 2-hydrazinyl-N-(4-(N-(pyrimidin-2-yl)sulfamoyl) phenyl) acetamide compound [B] was an important step because it is of the compound necessary for the synthesis of last compounds, prepared from reaction 2-chloro-N-(4-(N-(pyrimidin-2-yl) sulfamoyl)phenyl) acetamide with hydrazine hydrate in absolute ethanol to form 2-hydrazinyl-N-(4-(N-(pyrimidin-2-yl)sulfamoyl) phenyl)acetamide. The compound [B] was characterized by (C.H.N.S) technique and by comparing the data of the calculated results with the theoretical results, there was a good agreement between the results and this is evidence of the composition of the compound. FT-IR indicates the disappearing of stretching shaking of (-C-Cl) group of compound [A] at (731 cm-¹), and appearance of new two absorption peaks for (-NH₂) group of compound [B] at ( 3409 cm-¹) and (3335 cm-¹). It shows spectroscopy of ¹H-NMR (δ ppm), Figure [1] of compound [B] using (DMSO-d6) as solvents , the following signals were obtained:[(2H) (COCH₂N)_methylene 3.71] , [(Ar-H) 7.3- 8.34] , [(1H) (-NH-NH₂)_{secondary
amine}4.9] , [(2H) (-NH-NH₂)_{primary amine} 3.44] , [(1H) (NH)_sulfonamide 11.30] , [(1H) (NH)_amide 10.19], Elemental Analysis of compound (B) chemical formula (C₁₂H₁₄N₆O₃S) : Calc.: S, 9.95; N, 26.01;H, 4.38; C, 44.71, Found: S, 9.22; N, 26.73; H, 4.12;C, 43.94.

Antibacterial activity^23,24

The antibacterial activity of synthesized compounds [BC₁, BC₂, BC₃, IBC₁, IBC_3,and IBC₄] was tested to inhibit the effectiveness of two types of bacteria Staphylococcus aureus (Gram-positive) and Klebsiella pneumonia (Gram-negative), Sulfadiazine was used as a standard compound because it is the first compound to prepare the compounds and to know the effect of bacteria on the prepared compounds, and the results of the test are listed in the table (12 ).

Table 01: Antibacterial activity of compounds [BC₁, BC₂, BC₃, IBC₁, IBC₃and IBC₄]

Comp. No.	Zone of inhibition (mm)
Comp. No.	*Staphylococcus aureus*	*Klebsiella Pneumoniae*
[BC₁]	17.3	16.5
[BC₃]	20.5	19.4
[BC₄]	28.3	26.3
[IBC₁]	22.7	21.6
[IBC₃]	28.5	27.8
[IBC₄]	18.2	19.4
Sulfadiazine	27.2	27.6

CONCLUSIONS:

All the synthesized compounds were stable by resonance and having high melting points relatively, this is evident on the extent of stability. Good evidence for the formation of the synthesized compounds was formed by ¹H NMR spectroscopy, FT-IR spectrum, and TLC data. Prepared compounds give a good antibacterial activity against Staphylococcus aureus (Gram-positive) and Klebsiella pneumonia (Gram-negative).

REFERENCES:

1. Abbass, A.F.; Zimam, E.H., Synthesis, characterization and study biological activity of some new pyrimidine and 1,2,3,4-tetrazole derivatives based on sulfadiazine, International Journal of ChemTech Research., 2016,9, 206-217.

2. Ali J. Radhi, Ezzat H. Zimam, Emad A. Jaffar, Synthesis of some novel barbital derivatives based on Carbohydrate as α-glucosidase inhibitors, Research J. Pharm. and Tech. 2019; 12(3): 1145-1154.

3. Ehab K. O., Hayder A. S., Najlaa, N. H., Ahmed K. H., Ali J. R., Synthesis and Design of New Gemcitabine Derivatives as in vitro α-Glucosidase Inhibitors, Journal of Global Pharma Technology, 2019,11(3):25-29.

4. Farked Wahoodi Salman, Ahmed Jasim Twayej, Hayder Ahmed Shaheed, Ali Jabbar Radhi, New Gemcitabine Derivatives as potent in vitro α-Glucosidase Inhibitors, Nano Biomed. Eng., 2019, 11(1): 84-90.

5. Khdur, R.A.; Zimam, E.H.; Synthesis and characterization of some new β-lactam derivatives from Azo sulphadiazine and its biological evaluation as anticancer. Oriental Journal of Chemistry, 2018, 34,371-380.

6. Abdel-Aziz M., Abuo-Rahma G. E. A., Hassan A. A., Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities, Eur. J. Med.Chem. 2009, 44, 3480-3487.

7. Kaushik D., Khan S. A., Chawla G., Kumar S., N’-[(5-chloro-3-methyl-1-phenyl-1Hpyrazol-4-yl)methylene]2/4-substituted hydrazides: synthesis and anticonvulsant activity, Eur.J. Med. Chem., 2010,45 3943-3949.

8. Malladi S., Isloor A. M., Peethambar S. K., Ganesh B. M., Goud P. S. K., SynthesisAnd antimicrobial activity of some new pyrazole containing cyanopyridone derivatives, Der. Pharm. Chem., 2012, 4 43-52.

9. B’Bhatt H., Sharma S., Synthesis and antimicrobial activity of pyrazole nucleus ontaining 2-thioxothiazolidin-4-one derivatives, Arabian J. Chem., 2013, doi:10.1016/j.arabjc.2013.05.029.

10. Vijesh A. M., Isloor A. M., Shetty P., Sundershan S., Fun H. K., New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents, Eur. J. Med. Chem.,2013,26, 410-415.

11. Khunt R. C., Khedkar V. M., Chawda R. S., Chauhan N. A., Parikh A. R., Coutinho E. C., Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazole derivatives, Bioorg. Med. Chem. Lett. ,2012, 22 666-678.

12. Pathak R.B., Chovatia P. T., Parekh H. H., Synthesis, antitubercular and antimicrobial evaluation of 3-(4-chlrophenyl)-4-substituted pyrazole derivatives, Bioorg. Med. Chem. Lett. 2012,22,5129-5133.

13. Daidone G., Maggio B., Raffa D., Plescia S., Bajardi M. L., Caruso A., Cutuli V. M. C., Amico-Roxas M., Synthesis and pharmacological study of ethyl 1-methyl-5- [2-substituted-4-oxo-3(4H)-quinazolinyl]-1H-pyrazole-4-acetates, Eur. J. Med. Chem., 1994, 29,707-711.

14. Gokhan-Kelekci N., Yabanoglu S., Kupeli E., Salgin U., Ozgen O., Ucar G., Yesilada E., Kendi E., Yesilada A., Bilgin A. A., A new therapeutic approach in Alzheimer disease: some novel pyrazole derivatives as dual MAO-B inhibitors and anti-inflammatory analgesics, Bioorg. Med. Chem. 2007,15, 5775-5786.

15. Koca I., Ozgur A., Coskun K.A., Tutar Y., Synthesis and anticancer activity of acylthioureas bearing pyrazole moiety, Bioorg. Med. Chem. 2013, 21, 3859-3865.

16. Dawood K. M., Eldebss T. M. A., El-Zahabi H.S.A., Yousef M.H., Metz P., Synthesis of some new pyrazole based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents, Eur. J.Med. Chem., 2013,70, 740-749.

17. Raffa D., Maggio B., Raimondi M.V., Cascioferro S., Plescia F., Cancemi G., Daidone G., Recent advanced in bioactive systems containing pyrazole fused with a five membered heterocycle, Eur. J. Med. Chem., 2015, 97,732-746.

18. Ehab k. O., Najlaa j. H., Farked w. S., Hayder A. S., Ali J. R., Synthesis, characterization and study biological activity of new Iron (III)complex with sulfadiazine derivative, International Journal of Pharmaceutical Research. 2019, 11(2):518-523.

19. Greenhalgh DG. Topical antimicrobial agents for burn wounds. Clin Plast Surg 2009;36 (4),597–606.

20. Mahmood M. F., Ezzat H. Z. and Majed J. M. A Series of Barbituric Acid Derivatives from Sulfa Drug: Synthesis and Antimicrobial Activity. Nano Biomed. Eng., 2019, 11(1), 67-83.

21. Sharma, R., Samadhiya, P., Srivastava, S.D. and S.K. Srivastava, Synthesis and biological significance of some 2-azetidinone derivatives, Journal of Science S, Islamic Republic of Iran , 2012, 23(2),139-146.

22. Mustafa K. Naeem, Ezzat H. Zimam, Synthesis and Identification of some New Sulphadiazine Derivatives, Journal of Applicable Chemistry. 2014, 3 (4): 1499-1509.

23. Ali Fattah Naser, Ammar Kareem Madlool, Dheyaa Hussein Mohsin, Ehab Kareem Obaid, Ali Jabbar Radhi,Synthesis of New Gemcitabine Derivatives Linked Tetrazole Ring as Antibacterial Activity, International Journal of Psychosocial Rehabilitation, 2020, 24, (05),1806-1813

24. Majed Jary Mohammed, Zeyad Kadhim Oleiwi, Muntadher Abdulabbas Hasan, Ahmed K. H. Mubarak, Ehab K.O.,Ali Jabbar Radhi^,Synthesis and Study Biological Activity of Gemcitabine Linked Heterocyclic Hybrids, Research J. Pharm. and Tech., 2020; 13(7): 3257-3261.

Received on 09.08.2020 Modified on 23.10.2020

Research J. Pharm. and Tech. 2021; 14(7):3905-3910.

DOI: 10.52711/0974-360X.2021.00678