PHARMACEUTICAL POTENTIAL OF A RESOURCEFUL NITROGEN-CONTAINING HETEROCYCLE: PYRAZOLINE-A REVIEW

PHARMACEUTICAL POTENTIAL OF A RESOURCEFUL NITROGEN-CONTAINING HETEROCYCLE: PYRAZOLINE-A REVIEW

Alka Pradhan * and Pratibha Dwivedi

Department Chemistry, Government M. V. M. College, Bhopal, Madhya Pradesh, India.

ABSTRACT: Heterocyclic chemistry has grown very rapidly, particularly in evaluating synthetic methods and investigating synthesized materials' bioactive properties_. Heterocycle compounds are important in many facets of life's pharmacological activities. In their structure, many biologically active compounds such as amino acids, vitamins, hormones, nucleic acids, alkaloids, dyes, and drugs (natural and synthetic) possess heterocyclic ring molecules. Various pyrazole derivatives and their numerous physiological and pharmacological effects have been the subject of numerous investigations during the last decade. Part of the goal of these investigations was to uncover the vast spectrum of drug-like properties of pyrazole derivatives and their structure-activity connections to unlock the full potential of these molecules. This article focuses on the chemistry and pharmaceutic activity of the heterocycle pyrazoline, i.e., nitrogen-containing five-membered ring. An account of a different mode of synthesis from different starting materials is shown, along with the highlights of the therapeutic activity of pyrazoline.

Keywords: Pyrazoline, Therapeutic activity, Heterocycle

INTRODUCTION: Pyrazolines, which are one of the most studied classes of the azole family, are comprised of a five‐membered aromatic system ¹. Pyrazolines are fused heterocyclic deferential tested with anti-inflammatory action from an important family of compounds for the invention of novel drugs. When connected to various substituents such as alkyl, aromatic, heterocyclic rings, and several other groups at a different positions, the pyrazoline nucleus demonstrates significant anti-inflammatory activity to be more effectual ². The broad variety of bioactivities of pyrazolines leads many researchers to like to synthesize new pyrazoline derivatives ³.

Pyrazoline substituents are important target molecules for chemists because of their many potential applications, such as pharmaceuticals. Some pyrazoline derivatives have been shown to exhibit pharmacological effects such as antidepressant ⁴ antibacterial ⁵ antitumor ⁶ and anti‐inflammatory ⁷ activities. Pyrazolines have only one double bond within the nucleus and, depending on the position of the double bond, can exist in three separate forms: 1-pyrazoline, 2-pyrazoline, and 3-pyrazoline.

FIG. 1: THREE DIFFERENT FORMS OF PYRAZOLINE

Literature Survey:

Antimicrobial Activity: A central scaffold of antimicrobials, including antibacterial, antifungals, antivirals, and antiemetics, is the pyrazoline ring. However, antitubercular, could be considered a sub-class from antibacterial, we opted here to separate it under a specific subtitle because of its clinical importance.

Antibacterial and Antifungal Activity:  Narsinh. K. Desai et al_. ⁸ have reported antimicrobial activity inhibition of bacterial growth procedure by test compounds for a broad range of antimicrobial activity inhibiting growth of Gram-positive bacterial strains B. subtillis and S. aureus and Gram-negative bacterial strains E. coli and P. aeruginosa.

Several derivatives of 1-(4-aryl-2-thiazolyl)-3-(2 thienyl)-5-aryl-2-pyrazoline 2 were synthesized by Ozdemir et al. ⁹ and evaluated against Escherichia coli, Bacillus cereus, Salmonella typhimurium, Streptococcus faecalis, Staphylococcus aureus, Aeromonas hydrophila, Candida glabrata and Candida albicans for their antimicrobial activities. A substantial activity level was observed.

Udupi et al ¹⁰ have achieved the synthesis of naproxen pyrazoline derivatives, as represented by compound 3 (1-(1-acetyl-3-(4-aminophenyl)-4, 5-dihydro - 1H – pyrazol – 5 - yl)-2, 2-bis (6-methoxynaphthalen – 2 - yl) ethan-1-one). The biological assessment indicated that some of the series compounds had important dual antimicrobial and anti-inflammatory activities.

Anticancer Activity: Tutik Dwi Wahyuningsih et al. ¹¹ have reported the synthesized pyrazolines were evaluated as anticancer agents using MTT against breast cancer lines (MCF7 and T47D), the cervical cancer line (HeLa), and the normal cell line (Vero). The novel N-acetyl pyrazoline derivatives (5-chloro-2-(5-(3,4-dimethoxyphenyl)-1-(prop-1-en-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)phenol) containing methoxy groups obtained from veratraldehyde were successfully synthesized in excellent yield and purity by the cyclocondensation of chalcones and hydrazine hydrate in glacial acetic acid. Cytotoxicity evaluation revealed the presence of a halogen substituent such as Chloro on a pyrazoline derivative.

Havrylyuk et al. ¹² have been identified many novel thiazolone-based compounds containing 5-aryl-3-phenyl-4,5 dihydro-1H pyrazol-1-yl framework 5. The compound synthesized were tested for their cytotoxic activity in-vitro. Most of the compounds examined demonstrated promising anticancer activity compared to several forms of cancer, including leukaemia, melanoma, thyroid, colon, ovarian, renal, prosthetic, lung and breast cancer cell lines.

A series of replacements were prepared by Manna et al. ¹³ Pyrazolines structure 6 (1-(3-phenyl-5-(p-tolyl)-4, 5-dihydro-1H-pyrazol-1-yl) ethan-1-one) and tested for their anticancer role. Action and for their ability to inhibit multidrug resistance mediated through p-glycoprotein by direct binding to a purified an ATP- binding site and a protein domain-containing interacting region modulator compound discovery to bind to higher-affinity P-glycoprotein.

CNS Effects: The reported central nervous system (CNS) pharmacological role of pyrazoline derivatives includes antiepileptic and antidepressant effects and neurodegenerative disorders.

Antidepressant Activity: Some 1,3,5-triphenyl-2-pyrazolines having the general formula 7 and 3-(2- hydroxynapthalen-1-yl)-1,5-diphenyl-2 pyrazolines 8were synthesized by Prasad et al. ¹⁴ and their antidepressant activity was evaluated.

Antiepileptic Activity: Several 3-(3-acetoamino) phenyl-1,5-substituted phenyl-2 pyrazolines 9-11 have been synthesized and tested for their anticonvulsant activity by Singh et al. ¹⁵ The synthesized pyrazolines 9-11 displayed anticonvulsant activity, which was reflected by the safety observed by 60-80 percent versus seizures by PTZ. By inhibiting the oxidation of some nicotinamide-adenine-dinucleotide substrates, these compounds demonstrate their anticonvulsant ability.

Antiamoebic Activity: Compound 12 (1-(3-(4-aminophenyl)-5-(4-hydroxyphenyl)-4, 5-dihydro-1H-pyrazol-1-yl)-2-(naphthalen-1-yloxy) ethan-1-one) were synthesized by Hayat et al ¹⁶ and tested in-vitro for their anti-amoebic activity against Entamoeba histolytica strain HM1: IMSS.

The findings showed that the antiamoebic activity of these compounds was promising (IC₅₀ = 0.05, 0.31, 0.06 and 0.29 μM, respectively)

Some interesting bis-pyrazolines 13 prepared by cyclizing chalcones with N-4- substituted thiosemicarbazides under basic conditions by Bhat et al. ¹⁷.

Anti-amoebic activity research found that compounds with aromatic substituents were more active in the thiocorbamoyl group than in the cyclic groups.

Anti-inflammatory, Antipyretic and Analgesic Activities: Rathish et al. ¹⁸ Synthesized the new 1, 3, 5-trisubstituted pyrazolines bearing sulphonamides 14 of benzene and evaluated multiple compounds, their anti-inflammatory activity promising activity demonstrated.

Amir et al. ¹⁹ have published a series of 3-(4-biphenyl)-5-replacement phenyl-2-pyrazolines 15 and 1-benzoyl – 3 - (4-biphenyl) – 5 - replacement phenyl-2-pyrazolines 16 and have been screened for their anti-inflammatory and analgesic activity.

Khode et al. ²⁰ synthesized screened as sequence of 5-(substituted) aryl-3-(3-coumarinyl)-1-phenyl 2 pyrazolines 17 for in vivo anti-inflammatory analgesic activity.

Antiviral Activity: The frequency of viral infections has been gradually growing. Emerging on a global scale and re-emerging. Effectual there has been a much slower production of antiviral drugs than other forms of chemotherapy with anti-infective agents.

Some new 4,5-dihydropyrazoles derivatives of N-acetyl and N-thiocorbamoyl 18 have been synthesized by EI-Sabbagh et al ²¹ and tested against a wide variety of viruses in different cell cultures N-Acetyl 4,5-dihydropyrazole was the only active compound in HEL cell cultures with an EC₅₀ value of 7 μg/ml at subtoxic concentrations against vaccinia virus (Lederle strain).

Antisteroidal Activity: Zhang et al. ²² engineered several general formulas 19 pyrazolines and tested them as tissue-selective androgen receptor modulators by in-vivo screening (SARMs). As well as the core pyrazoline ring and the anilide linker, SARs were investigated at the R1 to R6 positions. Large electron-withdrawing groups at the positions of R1 and R2 and small groups at the positions of R5 and R6 were found to be optimal for androgen receptor agonist action.

Insecticidal Activity: Some insecticides related to pyrazolines (methyl 3-(4-chlorophenyl)-1-((4-chlorophenyl) carbamoyl)-4-methyl-4,5-dihydro-1H-pyrazole-4-carboxylate) 20 and 21 were synthesized by Silver and Soderlund et al. ²³ and their mode of action based on electrophysiological, pharmacological and toxicological information was examined. Eventually, these compounds were found to exert their insecticidal activity through neuronal targets.

Antioxidant Activity: A novel series of pyrazolines derivatives have been synthesized by Babu et al. ²⁴ and evaluated their antioxidant activity at various concentrations against standard ascorbic acid.

The pyrazoline 22 (2-(4-(3-(benzofuran – 2 - yl) – 1 - (2 - methylbenzoyl) - 4, 5-dihydro-1H-pyrazol-5-yl) phenoxy)acetic acid) among the series of the synthesized compounds showed excellent antioxidant activity as compared with ascorbic acid.

Antimycobacterial Activity: The synthesis of 1-(3, 5-diaryl-4, 5 – dihydro - 1H-pyrazole - 4 -yl)-1H-imidazole derivative 23 was reported by Zampieri et al. ²⁵ and tested against strains of C. A strain of albicans and M. H37Rv tuberculosis.

Antihepatotoxic Activity: Some novel 1,4-dioxane ring system pyrazoline derivatives were prepared by Habibullah Khalilullah et al ²⁶. Some of the synthesized compounds 24 (5-(2,3-dihydrobenzo[b] [1,4] dioxin-6-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazole) were tested against ccl_4-induced hepatotoxicity in rats for antihepatotoxicity activity. Important activity comparableto standard drug silymarin was demonstrated by compounds_.

Acetyl Cholinesterase Inhibitory Activity: The acetylcholinesterase inhibitory property of diaryl pyrazoline derivatives was investigated by Nibha Mishra et al ²⁷.

Raf Kinase Inhibition: The 3D QSAR analysis for amino-substituted N-acetyl and N-aroylpyrazolines 26 as B-Raf kinase inhibitors was performed by Omprakash Tanwar et al ²⁸, using a common five-point pharmacophore modal. The B-Raf inhibitory activity of selected compounds was investigated by Blackburn et al. ²⁹ from a large screening library of n an N-acetyl and N-aroylpyrazolines 27.

Nitric Oxide Synthaseinhibitors: In an attempt to find new compounds with neuroprotective activity, Camacho et al. ³⁰ have synthesized a new series of neural nitric oxide synthase (nNOS) inhibitors with 4, 5- di hydro-1h-pyrazole structure 28 pyrazolines 29 showed the highest activity with70 percent inhibition percentages.

Cholesterol Metabolism Modulators: A sequence of 3-(3,5 dialkyl-4-hydroxyphenyl)5-(multi substituted- 4-hydroxyphenyl)-2-pyrazolines have been prepared and evaluated for their inhibitory activity on acetyl coenzyme A cholesterol acetyltransferase which is responsible for the formation of the mevalonate pathway cholesterol precursor acetoacetyl CoA ³¹.

As an example of this series, pyrazoline 30 displayed in-vitro inhibitory activity on hACAT-1 and-2 ³².

Antimalarial: A new series of N-formyl-pyrazoline derivatives were prepared by Insuasty et al. ³⁵ and demonstrated their antimalarial activity. Compound 31 demonstrated excellent antimalarial activity. Wanare et al ³⁶ synthesized pyrazoline analogues 33 and evaluated for both chloroquine-sensitive strain (3D7) and chloroquine-resistant field isolate (RKL9) antimalarial activity of P. with falciparum. All of the compounds tested demonstrated promising antimalarial activity. B.N. synthesized a sequence of 1, 3, 5- trisubstituted pyrazolines. Acharya et al ³⁷ assessed in-vitro antimalarial efficacy against Plasmodium falciparum strains susceptible to chloroquine (MRC-02) and immune to chloroquine A (RKL9) and obtained encouraging results.

Antitrypanosomal Activity: Pyrazoline derivatives based on semi-carbazone described by compound 32 were designed as drug candidates for Chagas disease (American trypanosomiasis) ³⁸. As low as 80nm, compound 32 demonstrated inhibitory activity versus Trypanosoma cruzi.

Interestingly, compound 32 and its analogues demonstrated their antitrypanosomal behaviour by targeting cysteine protease cruzain with low cellular toxicity.

Seebacher et al. ³⁸ Along with a few others, I prepared compound 32 in 2003. Moderate activity against T cruzi ³⁹ was shown by compound 33.

Hypotensive Activity: Several 1-(4-arylthiazol-2-yl)-3,5-diaryl-2-pyrazolines 34 were synthesized by Turan-Zitouni et al ⁴⁰ and their hypotensive behaviour was examined by the tail-cuff process.

All of the pyrazolines synthesized demonstrated sub substantial hypotensive behaviour comparable to clonidine as a reference drug.

CONCLUSION: Substituted Pyrazoline has been synthesized successfully using a variety of methods. The screening results indicated the nature of substitution in newly synthesized compounds that affected biological activity. All of the synthesized compounds demonstrated improved biological activity against a variety of microorganisms. Pyrazoline is a biologically important compound that has attracted the attention of many medicinal chemists. This review looks at the pharmacological profiles of various pyrazoline derivatives. This article is a valuable resource for future research on bioactive pyrazoline rings and for better medicinal agent developments. This review aims to provide a forum to have all the scholars, academicians, chemists, and industrialists’ details about pyrazolines' therapeutic activity.

ACKNOWLEDGEMENT: We sincerely thank the department of chemistry, Govt. Motilal Vigyan Mahavidyalaya, Bhopal, India, for providing necessary facilities.

CONFLICTS OF INTEREST: There is no conflict of interest.

REFERENCE:

1. Sunita V, Kishor A and Mahesh M: Synthesis and antimicrobial evaluations of Bis – 3, 5- disubstituted isoxazoles based chalcones. Springer 2018; 88: 1904-1911.
2. 2 Miral V Lunagariya, Khyati P Thakor, Nikita J Patel: Synthesis, characterization and biological application of cyclometalated heteroleptic platinum (II) complexes. J App Organo. Chem 2017; 32(2): 4045.
3. Sever B Mehlika, Altıntop D, Mohamed O Radwan and Özdemir A: Design, synthesis and biological evaluation of a new series of thiazolyl pyrazolines as dual EGFR and HER2 inhibitors. Euro J Med Chem 2019; 182: 111648.
4. Rajendra Y Prasad, Lakshmana A Rao and Murali K: Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3- (2-hydroxy naphthalene-1-yl)-1,5 diphenyl-2 pyrazolines. Bioorg Med Chem 2005; 15(22): 1530.
5. Shubhalaxmi, Rachid Salghi and Hassane Lgaz: Pyrazoline derivatives as possible corrosion inhibitor for mild steel in acedic media: Acombined experimental and theoretical approach. Cog Engi 2018; 5(1): 1441585.
6. 6 Priyanka I Gaikwad, Priyanka S. Gandhi: Synthesis, characterization and in-vitro antimicrobial evaluation of pyrazolothiazol-4(5H)-one derivative. Ind J Pharm Sci 2013; 75(4): 496-500.
7. Eid NM and George RF: Facile synthesis of some pyrazoline-based compounds with promising anti-inflammatory activity. Future Med Chem 2017; 10(2): 183-199.
8. Narsinh K Desai: Synthesis and characterisation of Novel pyrazoline derivatives and their biological activity. Int J of Sci & Eng Res 2020; 11: 1225-1230.
9. Ozdemir A, Turan-Zitouni G and Kaplancikli: Synthesis and antifungal activity of new hydrazide derivatives. Enz Inhib J Med Chem 2013; 28(6): 1211-6.
10. Udupi RH, Kushnoor AS and Bhat AR: Synthesis and biological evaluation of some novel pyrazolines derivatives. Ind J Hetero Chem 2000; 9: 189-192.
11. Tutik Dwi Wahyuningsih and Stephanus Stria Wira: Evaluation of Furan-based Chalcone and Pyrazoline Derivatives as Antimalarial Scaffolds: Experimental and Molecular Docking Studies. J App Pharma Sci 2021; 9(03): 014-020.
12. Havrylyuk D, Zimenkovsky B and Vasylenko O: Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety. Eur J Med Chem 2010; 45(11): 5012-21.
13. Manna F, Chimenti F and Fioravanti R: Synthesis of some pyrazole derivatives and preliminary investigation of their affinity binding to P-glycoprotein. Bioorg Med Chem Lett 2005; 15(20): 4632- 4635.
14. Prasad YR, Rao AL and Prasoona L: Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2''-hydroxy naphthalen-1''-yl)-1,5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 2005; 15(22): 5030-4.
15. Singh SP, Chaudhari A, Barthwal JP and Parmar SS: Synthesis of 2‐(4‐arylthiosemicarbazidocarbonylthiob)e nzthiazoles and their monoamine oxidase inhibitory and anticonvulsant properties. J Pharm Sci 1975; 64(7): 1245-1247.
16. Hayat F, Salahuddin A, Umar S and Azam A: Recent advances in the therapeutic applications of pyrazolines. Bioorg Med Chem Lett 2012; 22(3): 253-291.
17. Akranth Marella, Md Rahmat Ali, Ritika Saha: Pyrazoline a biological review. Eur J Med Chem 2013; 13(6): 921-31.
18. Rathish IG, Javed K and Ahmad S: Synthesis and antiinflammatory activity of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulphonamide. Bioorg Med Chem Lett 2009; 19(1): 255-8.
19. Amir M, Kumar H and Khan SA: Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents. Bioorg Med Chem Lett 2008; 18(3): 918-22.
20. Khode S, Maddi V and Aragade P: Synthesis and pharmacological evaluation of a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents. Eur J Med Chem 2009; 44(4): 1682-8.
21. El-Sabbagh OI, Baraka MM and Ibrahim SM: Synthesis and antiviral activity of new pyrazole and thiazole derivatives. Eur J Med Chem 2009; 44(9): 3746-53.
22. Zhang XQ, Li XJ and Allan GF: Design, Synthesis, and in Vivo SAR of a Novel Series of Pyrazolines as Potent Selective Androgen Receptor Modulators. J Med Chem 2007; 50(16): 3857-3869.
23. Silver KS and Soderlund DM: Action of pyrazoline-type insecticides at neuronal target sites. Pest Biochem Physio 2005; 81(2): 136-143.
24. Sabrina B Ferreira and Carlos R Kaiser: Pyrazine derivatives: a patent review. Eur J Med Chem 2007; 22(9): 1033-51.
25. Zampieri D, Mamolo MG and Laurini E: Recent advances in the therapeutic applications of pyrazolines. Bioorg Med Chem 2012; 22(3): 253-291.
26. Khalilullah H, Khan S, Ahsan MJ and Ahmed B: Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives. Bioorg Med Chem Lett 2011; 21(24): 7251–7254.
27. Dalvi K, Deole S and Garud D: Review on synthesis of pyrazoline derivatives and its biological activities. IJCRT 2020; 5(5): 702–705.
28. Ravi K, Rubina B and Garima K: review on recent development of pyrazoline as a pharmocologically active molecule 2015; 6(10): 4113-4128.
29. Blackburn C, Duffey MO, Gould AE, Kulkarni B, Liu JX, Menon S, Nagayoshi M, Vos TJ and Williams J. Bioorg: Med. Chem. Lett. 2010; 20: 4795–4799.
30. Savita U, Avinash C Tripathi and Sarvesh P: 2-pyrazoline derivatives in neuropharmacology: Synthesis, ADME prediction, molecular docking and in vivo biological evaluation. J Med Chem 2017; 16: 628.
31. Ponwnall HJ: Recent advances in the therapeutic application of pyrazolines. J Med Chem 2012; 20: 2636-42.
32. Jin Hee Ahn and Mi Sik Shin: Synthesis, biological evaluation and structural determination of beta-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors. Bioorg Med Chem Lett 2007; 17(9): 2622-8.
33. Biswajit D, Sajidul K: Pyrazoline heterocyclic: a review.Int J Pharm Sci Res 2021; 12(5): 2570-2588.
34. Gajanan Wanare G, Aher R, Kawathekar N, Ranjan R, Kaushik NK and Sahal D: Synthesis of novel alpha-pyranochalcones and pyrazoline derivatives as Plasmodium falciparum growth inhibitors. Bioorg Med Chem Lett 2010; 20(15): 4675–4678.
35. Acharya BN, Saraswat D, Tiwari M, Shrivastava AK, Ghorpade R, Bapna S and Kaushik MP: Synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines. Eur J Med Chem 2010; 45(2): 430–438.
36. Du X, Guo C and Hansell E: 5-Nitroisatin-derived thiosemicarbazones: potential antileishmanial agents. Journal of E Inhibi and Med Chem 2014; 29(5): 628-632.
37. Mohamed R Shaaban Ahmad M Farag: Recent advances in the therapeutic applications of pyrazolines. J Med Chem 2012; 22(3): 253-291.
38. Turan-Zitouni G, Chevallet P, Kilic FS and Erol K: Synthesis and antifungal activity of new hydrazide derivatives. Eur J Med Chem 2013; 28(6): 1211-6.
    

    ---

    How to cite this article:

    Pradhan A and Dwivedi P: Pharmaceutical potential of a resourceful nitrogen-containing heterocycle: pyrazoline-a review. Int J Pharm Sci & Res 2022; 13(12): 4848-56. doi: 10.13040/IJPSR.0975-8232.13(12).4848-56.

    ---

    All © 2022 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.