Pyrazoline as a medicinal scaffold

Gurinderdeep Singh1*, Anju Goyal2, R S Bhatti3 & Sandeep Arora2. DOI. 10.21931/RB/2019.04.04.10 Abstract: Heterocyclic Chemistry is the backbone of medicinal compounds that exhibits numerous biological activities. Pyrazole and its derivatives possess nitrogen atom along with carbon atom as a substitution and show a diversity of biological activities such as antibacterial, antimicrobial, anti-inflammatory, antioxidant, antidiabetic, anticancer, antifungal, antidepressant, anticonvulsant, analgesic, and monoamine oxidases (MAOs)as shown by pyrazoline prepared from chalcone(Intermediate). The synthesized compounds are checked by the TLC and further analyzed by the IR, NMR, and UV spectroscopy.


Introduction
Pyrazole, well known heterocyclic compound with two adjacent nitrogen atoms within the ring and having a fivemembered ring carries one endocyclic double bonds and essential in nature 1 , represented by the molecular formula C 3 H 4 N 2 2 .Pyrazole melts at 700C, in spite of its low molecular weight. Clinically the substitution derivatives at 3 and five positions are indistinguishable from one another whereas the properties disappear the hydrogen atom on the nitrogen atom immediately is replaced by an alkyl group 3 .
heterocycle, as seen in pyrrole at position1 and pyridine at positions 2. Pyrazole subsists in three partially reduced forms. In 1883, Ludwig Knorr coined the term pyrazole, which is a weak base, acquires pKb 11.5(pKa value of the conjugated acid 2.49 at 25 0 C). Pyrazole having unique pharmacological effects on human beings and from watermelon seeds, 1-pyrazolylalanine was isolated and then classified as alkaloids on composition, first natural pyrazole in 1959 4 .

Chemistry and Synthetic approaches
In medicinal chemistry, heterocyclic rings such as Pyrazole containing active pharmacophore agents play an essential role in refined and efficient ways to make these heterocyclic heads. Pyrazole includes two nitrogen atoms also carry a π-excessive Pyrazole carries a boiling point of (186-188°C) due to its hydrogen bonding and exhibits two identical and non-separable tautomers owing to rapid interconversion of tautomers. In other words, In pyridine, nitrogen is prone to electrophilic attack, and the hydrogen atom bonded to the nitrogen at position 1 is more acidic than pyrrolic N-H, thus easily removed by nucleophiles. It can be synthesized via Claisen-Schmidt condensation followed by cyclizations with hydroxylamine HCl and hydrazine hydrate under the appropriate conditions. Pyrazole lower basicity with weak base (pKa= 2.52) because of extra destabilization of π-bonding after protonation and increases acidity with very weak acid (pKa=14.21) by the introduction of the electronwithdrawing group (-I & -M effect) 17 .
Synthetic approach to the pyrazole 1-(4,5-disubstitutedpyrazol-1-yl)-ethanone Synthesis: On the contrary, pyrazoles have been carried out by the reaction of β-formyl enamides with hydroxylamine hydrochloride catalyzed by potassium dihydrogen phosphate in acidic medium and become novel synthesis 18 .
Tri-and tetra-substituted pyrazoles Synthesis; For the facile synthesis of tri-and tetra-substituted pyrazoles using Dioxygen gas as the oxidant undergoing intramolecular oxidative CN coupling method catalyzed by A ruthenium (II) carried out the transformation, and the reaction demonstrates excellent reactivity, functional group tolerance, and high yields 20 .
General procedure for synthesizing pyrazoline A substituted Chalcone (0.01 mole) mixed with hydrazine hydrate (0.012 moles) and acetic acid(10ml) in methanol for five hours. The reaction mixture was poured in chilled water, and solid separated was filtered and recrystallized from ethanol. Again, the reaction completion was confirmed by the TLC and monitored.

Pharmacological activity
The usefulness and great therapeutic value of pyrazole nucleus have been recognized, and the most comprehensive range of activities of this nucleus evaluated for a long time. However, as the first synthetic organic compound carries pyrazoline-5-one nucleus to find use as an essential drug. Derivatives of the pyrazolopyrimidine ring system are known to possess potent biological properties 23 Out of these many natural and synthetic products having heterocyclic rings as Derivatives of the pyrazolopyrimidine ring system are known to possess potent biological properties 24 .Also condensed pyrazoles are biologically active and their chemistry has received considerable attention as pyrano [2,3-c]pyrazoles are reported to have useful biological effects, such as analgesic and anti-inflammatory activities 25 .In recent years significant progress has been made relating to oxidation in biological cells resulted from reactive oxygen species (ROS) and initiates lipid peroxidation in healthy cells leading to Alzheimer's disease, atherosclerosis, diabetes, Parkinson's disease, etc. Among plant kingdom and animal kingdom coumarins, Xanthones pyrazoles and acrylonitriles showed widespread use in medicine 26 .Synthetically, several methods have been published for the synthesis of 2-pyrazolines for the treatment of tumor, fungal and viral infection, Tuberculosis and depression, etc 27 .
Kendre M.M. and BASEER M.A. synthesized efficiently biologically active Pyrazoline derivatives with excellent yields via cyclization reaction of chalcones and hydrazine hydrate. The compounds 2a, 2b, and 2h showed significant activity in comparison with the standard drug. The presence of pyrazoline moiety, substituents, particularly having Bromo, Chloro, Hydroxyl, Iodo and Methyl groups in the ring may be responsible for antimicrobial activity of this class of compounds and screened that also reflects moderate to good activity against different strains of bacteria and fungi employed. All the synthesized compounds were confirmed by IR 1 ,HNMR and Mass spectral data 29 .  1-(1H-indol-3-yl)-3-aryl-2-propen-1-ones (1a-f) with p-methylphenylhydrazine hydrochloride in hot acetic acid. Pyrazoline derivatives, compound 2e exhibits 2,5-dichlorophenyl moiety identified the most promising agent against Klebsiella pneumoniae (ATCC 13883) and Candida glabrata (ATCC 36583) due to its inhibitory effects on K. pneumoniae and C. glabrata with a MIC value of 100 mg/mL as a nontoxic agent (LC50 > 1000 mg/mL). Structural elucidation of these compounds by IR, 1H NMR, and mass spectral data and elemental analysis and investigated toxicity by Brine-Shrimp lethality assay for their antimicrobial activity 30 . Dipankar et al. studied the reports of twelve 2-pyrazoline derivatives against S. aureus and A. niger thoroughly (Table1). Two varieties of acetophenones were condensed with three varieties of substituted benzimidazole derivatives to get six chalcone derivatives, which undergo condensation followed by cyclization with isoniazid and 1-(2-napthyloxy acetate) hydrazine two get the final 2-pyrazoline derivatives. Compound D7 exhibited the highest antibacterial activity, and compound D12 exhibited highest anti-fungal activity as well as comparable to the antibacterial activity and antifungal activity of the standard drugs at 200 µg/ml. These compounds were characterized by IR, 1H-NMR and Mass spectral studies. The synthesized compounds were found to have good antimicrobial activity in the range of 20-70 µg/ml 31 .
Sudhakarararao G et al., Synthesized compounds and then evaluated to suppress seizures and provide neuroprotection by minimizing the effects of the seizure attacks. To attain this some chalcone and chalcone based pyrazolines were Evaluated for their anticonvulsant activity and then structural elucidation was taken on the basis of the elemental analysis and spectroscopic studies (NMR, IR and Mass Spectroscopy) Among all compounds only compounds Ph1, Ph2, Py 3 and Py 4 shown to be good anticonvulsant activity with dose level of 4mg/kg b.w. 35 .
Abdel-Aziz et al., have described two synthetic paths for the formation of diacylhydrazines, 5amino-1-substiuted pyrazole-3,3,4-tricarbonitriles and oxadiazole, pyrazoline derivatives, Compounds 4a and 4b showed good activity in comparison to imipramine at a dose of 10 mg/kg dose level and showing antidepressant activity using tail suspension behavioural despair test and anticonvulsant activity against pentylenetetrazol induced seizures in mice 35 .

Antidepressant activity
B. K. Kaymakcıoğlu, S. Gumru, N. Beyhan, F. Aricioglu investigated a series of new 2-pyrazoline derivatives and activity was evaluated by using tail suspension test, Compounds 3d and 3e were effective and a significant reduction in immobility time was observed as compared to results of imipramine, as the reference standard drug. Compounds 3d and 3e remarked the potential for the treatment of depression 33 .   novelty. The newly synthesized compound proved to be more reversible, potent, and selective inhibitors of MAO-A than of MAO-Compounds 6 and 11 were found to be most potent 36 .

Anti-convulsant activity
activities against 14α-demethylase were investigated by molecular docking using the HEX docking software. These compounds docked into the active site of the receptor (PDB code, 1E9X) using Hex docking tools software, which showed good affinity for the enzyme when compared with the binding energies of standard drugs such as clotrimazole (-24.05) and griseofulvin (-36.57). Among all the designed compounds, compound 7 shows more binding energy values (-59.85) 38 .
Kumar R and Joshi Y. C. synthesized β-diketones/βketoesters, 4a-e on condensation with different β-diketones/ β-ketoesters, 3a-e in the presence of sodium hydroxide from the diazonium salt of 4-amino-1-methyl-3-propyl-1Hpyrazole-5-carboxamide. The β-diketones/β-ketoesters 4a-e were condensed with o-phenylenediamine (o-PDA) in the presence of p-toluene sulfonic acid/SiO 2 to give biologically active 3H-1,5-benzodiazepines, 5a-e. Crofloxin and ciclopirox olamine were used as reference standards for comparison of the antibacterial and antifungal activities, respectively. Compound 5c exhibited greater antimicrobial and antifungal activities than the standard drugs, whereas compounds 5d and 5e showed significant anthelmintic activity All the newly synthesized compounds were characterized by elemental analysis and spectral studies and screened for their antimicrobial, antifungal and anthelmintic activities 39 .
Deng et al., synthesized a series of 1,3,5-trisubstituted-2pyrazoline derivatives by introducing the furan rings. Among all compounds, compounds 4, 7, 9, 12, 18 and 19 displayed excellent antifungal activity against Rhizoctonia solani and tried to discover some more potent antifungal compounds. Additionally, at site 3 and site 5of the pyrazoline in the compounds 9 and 19 bearing two furan rings respectively and with the help of bioactivity results pyrazoline derivatives receives a template for the further structural optimization 40 .

Anticancer Activity
M. Shaharyar et al. synthesized series of benzimidazolewhich carries 2-pyrazolines and then tested as well as belonging to different panels these compounds against various cancer cell lines such as renal, breast, colon, melanoma, prostate, and so on. The most active compound of the series was found to be 2-[5-(3,4-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-1Hbenzimidazole. Based on close examination of the substituent it was concluded that the role of electron donating group on the phenyl ring at C5 of the phenyl ring had a great influence on anticancer activity 42 .
Eman M. Flefel et al. primarily synthesized a newly substituted pyrazole, thiazole, and 1, 2, 4-triazole derivatives and then reported. Among all the sugar hydrazones and their acetylated derivatives as yet derived acyclic C-nucleoside analogs, and the thioglycosides of the 1, 2, 4-traizole derivatives were also prepared. Compounds that were synthesized as well as studied and several compounds showed significant antitumor activities in the tested results 43 .

Conclusions
Pyrazoline, a heterocyclic compound that exhibits a two nitrogen in the ring nucleus which synthesized via cyclization of chalcone from the reaction of substituted aldehydes and ketones in the presence of basic conditions. Medicinally pyrazoline and its derivatives showed the diversity of biological activities such as antibacterial, antimicrobial, antiinflammatory, antioxidant, antidiabetic, anticancer, antifungal, antidepressant, anticonvulsant, analgesic, and monoamine oxidases (MAOs) and elucidated by spectral analysis and also characterized by elemental analysis.