INTRODUCTION:

The noun pyrazole was given for the first time by Ludwig Knorr in 1883¹. Pyrazoles are the important members of heterocyclic compounds with two adjacent nitrogen atoms in a five-membered ring system. Among the two nitrogen atoms, one is basic and the other is neutral in nature. The partially reduced forms of pyrazole are named as pyrazolines, while completely reduced form is referred to as pyrazolidine. Several pyrazoline substituted products are used in medicine. Pyrazoles and their derivatives, a class of well known nitrogen heterocycles, occupy a prime position in medicinal and pesticide chemistry for their diverse biological activities. Literature review concealed that many pyrazole derivatives have a broad spectrum of biological activities including antimicrobial^2,3, analgesic^4,5, anticancer^6,7, anti-tubercular⁸, anti-inflammatory⁹, antidepressant¹⁰, anticonvulsant¹⁰, antihyperglycemic¹¹, antipyretic¹², antihelmintic¹³, antioxidant¹⁴and herbicidal¹⁵ properties.

The pyrazole ring is present as the core in a variety of leading drugs such as Celebrex, Sildenafil (Viagra), Ionazlac, antipyrine, phenylbutazone, Rimonabant, Difenamizole, dipyrone etc. Pyrazole analogues have found use as building blocks in organic synthesis for designing pharmaceutical and agrochemicals and as bifunctional ligands for metal catalysis. These scaffolds are classified as alkaloids, although they are rare in nature. In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons by Noe et Fowden¹⁶. Against this background, to extend our research work on synthesis of biologically active molecules, we have designed and synthesized a series of 1-[2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl] derivatives (2a-e) via one-pot multicomponent reaction using 2-chloro-1-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-ethanone (1), Ethanol/ Benzen. All the target molecules were screened for their Anti-bacterial, Anthelimintic and Haemostatic activity.

MATERIALS AND METHODS:

Chemistry:

Melting points were determined by open capillary method and are uncorrected. The IR spectra (in KBr pellets) were recorded on a Techno search Instrument, M-15 FT-IR spectrophotometer. The Ultraviolet visible spectroscopy analysis has been carried out in UV–Pharma Spec 2060+ Anlytical UV-visible spectrophotometer using the concentration of 0.01% of the synthesized substituted pyrazole compounds in Chloroform as solvent. ¹H FT-NMR analysis spectra were recorded (DMSO-d6) on a Brukur (400 MHz) spectrometer. Chemical shift values are given in δ scales. The mass spectra were recorded on TOF- LC/MS system. The completion of the reaction was checked by thin layer chromatography (TLC) on silica gel coated aluminium sheets (silica gel 60 F254). Commercial grade solvents and reagents were used without further purification. The entire synthesized compounds were prepared as per the scheme-1.

General procedure for synthesis of Benzylidene acetophenone (Chalcone)¹⁷:

Place a solution of 22g of sodium hydroxide in 200ml of water and 100g (122.5ml) of rectified spirit in a 500ml bolt held flask provided with a mechanical stirrer. Immerse the flask in a bath of crushed ice, pour in 52g (0.43mol) of freshly distilled acetophenone, start the stirrer and then add 46g (44ml, 0.43mol) of pure benzaldehyde. Keep the temperature of the mixture at about 25⁰C and stir vigorously until the mixture is so thick that stirring is no longer effective (2-3 h). Remove the stirrer and leave the reaction mixture in an ice chest or refrigerator overnight. Filter the product with suction on a bucchner funnel, wash with cold water until the washings are neutral to litmus, and then with 20 ml of ice cold rectified spirit. The crude chalcone, weighed after drying in the air. The percentage of yield of the synthesized compound was found to be 87%. The final products were (a pale yellow solid) recrystallized from rectified spirit, m. p 59⁰C.

General procedure for synthesis of 3, 5-diphenyl-4, 5-dihydro-1H-pyrazole³:

A mixture of chalcone (0.1mol), hydrazine hydrate (0.1mol) and acetic acid (50ml) in ethanol was refluxed for 8h. The reaction mixture was cooled and poured over ice water. The solid separated was filtered, washed with water, dried and the percentage of yield was found to be 83.45%. The compounds were recrystallized from ethanol gave pale yellow crystals, m. p. 156⁰C. The completion of reaction was monitored by TLC using chloroform: petroleum ether (8:2) as mobile phase.

Synthesis of 2-chloro-1-(3, 5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-ethanone (1)¹⁷:

Compound 3, 5-diphenyl-4, 5-dihydro-1H-pyrazole (0.01mol) was dissolved in beaker containing 20ml of dry benzene placed on a magnetic stirrer at below 15⁰C. In another beaker containing 20ml of dry benzene, chloroacetyl chloride (0.01mole), was added dropwise with stirring to the other beaker containing pyrazoline derivative, stirring was continued vigorously until the mixture is so thick that stirring is no longer effective (2-3 h). Then removed and crushed ice was added and after few hour the product was filtered off, washed with water, dried and the percentage of yield was found to be 75.28, which was then recrystallised by using appropriate solvent.

General procedure for synthesis of substituted Pyrazole derivatives, 2(a-e):

The 2-chloro-1-(3, 5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-ethanone (0.01mole) was taken in about 25 ml of dry alcohol and 0.01 mol of different amine was added to it and the mixture was heated on water bath for 11 h. The reaction mixture was cooled in ice bath until the product precipitated. The crude products, after drying in the air weighed. The obtained crude product was recrystallized from absolute ethanol. The completion of reaction was monitored by TLC using suitable solvent system as mobile phase.

1-[2-(3, 5-diphenyl-4, 5 dihydro-1H-pyrazol-1-yl)-2 -oxoethyl]-thiourea (2a):

MF: C₁₈H₁₈N₄OS; M Wt: 338; Colour: Pale Yellow; Nature: Crystalline Powder; % Yield: 96.15; Solubility (37⁰C±0.5⁰C): Ethanol, Chloroform, Benzene, Acetone; M.P (⁰C): 110-113; R_f: 0.47; UV (ethanol) λmax: 290; IR (KBr): Vmax in cm^-1: N–H(st), 3431; N-N (st), 3300; Ar. C-H, 3050; C=O (st), 1950, 1687; C=N (st), 1586; -CH_2,1218; -NH₂(wag & twis), 772; Ar-C-C,726; C-H (def), 596; ¹H NMR (DMSO-d6, 400 MHz) δ: 3.82-3.89 (m, 2H, CH2); 3.0-3.15 (m, 2H, CH2); 7.16-7.37 (m, 5H, H-Ar); 7.44-7.88 (m, 5H, H-Ar); 3.15(s, 1H, NH); 2.30 (m, 2H, NH2); Mass: 338(M⁺).

N-[2-(3,5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl)-2- oxoethyl]-hydrazine carbothio-amide (2b):

MF: C₁₈H₁₉N₅OS; M Wt: 353; Colour: Pale Yellow; Nature: Crystalline Powder; % Yield: 91.74; Solubility (37⁰C±0.5⁰C): Ethanol, Chloroform, Benzene, Acetone, Diethyl Ether; M.P (⁰C): 106-108; R_f: 0.79; UV (ethanol) λmax: 385; IR (KBr): Vmax in cm^-1: N-H (st), 3450; N-N (st), 3058; C=O (st),1649; C=N(st),1411; -CH_2,954; C=S (st), 1328; -NH₂(wag & twis), 858; Ar. C-H, 2975; Ar- C-C,756; ¹H NMR (DMSO-d6, 400 MHz) δ: 3.82-3.89 (m, 2H, CH2); 3.0-3.14(m, 2H, CH2); 7.25-7.43 (m, 5H, H-Ar); 7.45-7.88(m, 5H, H-Ar); 5.54 (s, 1H, NH); 3.25(s, 1H, NH); 2.30(m, 2H, NH2); Mass: 352(M-1)⁺, 354(M+1)⁺.

N-[2-(3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl]-hydrazine carboxamide (2c):

MF: C₁₈H₁₉N₅O_2;M Wt: 337 Colour: Pale Yellow; Nature: Crystalline Powder; % Yield: 80.38; Solubility (37⁰C±0.5⁰C): Ethanol, Methylated spirit, Chloroform, Benzene, Acetone, Diethyl Ether; M.P (⁰C): 152-153; R_f : 0.63; UV (ethanol) λmax: 345; IR (KBr): Vmax in cm^-1:N-H(st), 3420; N-N (st), 3059; C=O (st), 1648; C=N(st),1410; -CH₂,954; C=S (st),1329; -NH₂(wag & twis), 856; Ar-C-C,757; Ar- C-H,2938;¹H NMR (DMSO-d6, 400 MHz) δ: 2.82-3.15 (m, 2H, CH2); 8.82 (m, 5H, H-Ar); 9.92 (m, 5H, H-Ar); 6.53 (s, 1H, NH); 2.45 (m, 2H, NH2); Mass: 337(M⁺).

1-(3, 5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-2 (piperidine-4-yl) ethanone (2d):

MF: C₂₂H₂₅N₃O; M Wt: 347 Colour: Colourless; Nature: Crystalline Powder; % Yield: 87.01; Solubility (37⁰C±0.5⁰C): Chloroform, Benzene, Acetone, Diethyl Ether; M. P(⁰C): 92-93; R_f: 0.66; UV (ethanol) λmax: 415; IR (KBr): Vmax in cm^-1: N-H(st), 3470; N-N (st), 3058; C=O ( st), 1648; C=N (st), 1409; C-O (st), 1327; -CH_2, 952; C-H (def), 693; Ar-C-C,757; Ar-C-H,2885;¹H NMR (DMSO-d6, 400 MHz) δ: 3.81-3.89 (m, 2H, CH2); 3.09-3.14 (m, 2H, CH2); 7.16-7.33 (m, 5H, H-Ar); 7.44-7.78 (m, 5H, H-Ar); 5.51-5.55 (s, 8H, -CH₂-Piperidine); Mass: 348(M+1)⁺_.

1-(3, 5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-2 (morpholin-4-yl) ethanone (2e):

MF: C₂₁H₂₃N₃O₂; M Wt:349; Colour: White; Nature: Crystalline Powder; % Yield: 86.68; Solubility (37⁰C±0.5⁰C): Chloroform, Benzene, Acetone, Diethyl Ether; M.P ( ⁰C): 114-116;R_f: 0.75; UV (ethanol) λmax: 275; IR (KBr): Vmax in cm^-1: N-H (st), 3425; N-N(st), 3150; C=O (st), 1648; C=N (st), 1409; C-N( st),1031; C-H (def), 621; Ar-C-H, 2926; Ar-C-C,756;¹H NMR (DMSO-d6, 400 MHz) δ: 3.81-3.89 (m, 2H, CH2); 3.09-3.15 (m, 2H, CH2); 7.16-7.31 (m, 5H, H-Ar); 7.44-7.78 (m, 5H, H-Ar); Mass: 349(M⁺), 350(M+1)⁺.

Anti-microbial Activity:

Determination of ozone of inhibition¹⁸:

The synthesized compounds were evaluated in vitro against Staphylococcus aureus-NTCC-6571

Escherichia coli-(TG₁) 4, Bacillus subtilis-SB, Pseudomonas aeruginosa-(A₂)_,Vibrio choleri-(V₁) using cup plate method. This method is simple, inexpensive and requires minimum skill to perform. Conical flask with the medium was cooled to 46⁰C and inoculated with test organism (20ml of subculture medium/100ml of the assay medium) 30 ml of inoculated media distributed into Petri dishes. Four cups (6 mm diameter) per plate were made by using a sterile cork borer. The whole operation was carried out under the laminar flow aseptically. Cups were filled with 0.1 ml of test solution and 0.1 ml of standard solution (100µg/ml, 250µg/ml,) and solvent dimethyformamide (control) were placed in each cups separately under aseptic condition. Then the Petri dishes uniform diffusion of drug into the agar medium. All the Petri dishes were then incubated at 37⁰C for 24 hours. The diameters of the inhibition zones were measured in millimeters and results were summarized in Figure 1. The antibacterial activity of each compound was compared against standard Amoxycilline.

Fig.1: Antimicrobial activity of synthesized compounds Zone of inhibition (250µg/ml)

Zone of inhibition (mm); MIC: Minimum inhibitory concentration (μg/mL); S .a:- Staphylococcus aureus- NTCC-6571; E. c:-Escherichia coli- (TG₁)4; B.s:- Bacillus subtilis - SG 4, P.a:- Pseudomonas aeruginosa- (A₂); V_.c:-Vibrio choleri- (V1); Std= Amoxycilline; Data are expressed as means ± standard deviation (n = 3).

Determination of Minimum Inhibitory Concentration (MIC)¹⁹:

The MICs were determined by the standard agar dilution method. The synthesized compounds were dissolved in 10µg/ml of DMF, as they were not fully soluble in water and then diluted by sterile distilled water to make up the solution. The drug solutions were then added to the molten nutrient agar in different tubes to give final concentration of 25,50,100 µg/ml. The molten nutrient agar media containing various concentrations of the synthesized compounds were poured and solidified into sterile 100 mm Petri-dishes to give sterile nutrient agar plates with varying dilution of synthesized compounds. Then these plates were kept in a refrigerator (4⁰C) for 24 hours for uniform diffusion of the synthesized compounds into the nutrient agar media. The plates were then dried at 37⁰C for 2 hours before spot inoculation. One loopful (diameter: 3mm) of the overnight grown peptone water culture of each test organism was placed in Petri-dish marked by Checker Board Technique. The final number of CFU inoculated on to the agar plates 10¹⁰for all stains. The spot inoculated plates were incubated at 37⁰C for 24 hours and the MIC values were obtained. The lowest concentration of the plates, which did not show any visible growth after incubation, was considered as MIC. The agar plate containing only sterile distilled water served as control. All the synthesized compounds were tested for their antibacterial activity (MIC-minimum inhibition concentration) against Staphylococcus aureus-NTCC-6571, Escherichia coli-(TG₁) 4, Bacillus subtilis-SB, Pseudomonas aeruginosa-(A₂)_,Vibrio choleri-(V₁) organisms. The minimum inhibitory concentration (MIC) was noted as the concentration of the test substance, which completely inhibits the growth of the microorganism i.e. 100% transparency. The results are depicted in Figure 2.

Fig. 2: Antimicrobial activity of synthesized compounds, Minimum inhibitory concentration (μg/mL)

S .a:- Staphylococcus aureus- NTCC-6571; E. c:-Escherichia coli- (TG₁)4; B.s:- Bacillus subtilis - SG 4, P.a:- Pseudomonas aeruginosa- (A₂); V_.c:-Vibrio choleri- (V1); Std= Amoxycilline; Data are expressed as means ± standard deviation (n = 3).

Anthelmintic Activity²⁰:

Anthelmintic screening was done on the synthesized novel pyrazole derivatives. Albendazole was used as standard. Adult earthworms Eudrilus eugenia, washed with normal saline to remove all the faecal matter, were used for the anthelmintic study. The earthworms of 3-5 cm in length and 0.1-0.2 cm in width were used for all the experimental protocol due to its anatomical and physiological resemblance with the intestinal roundworm parasites in human beings. Albendazole was diluted with normal saline to obtain 0.075 % w/v, 0.150 % w/v and 0.225% w/v. as standards and poured into Petri dishes. All the test compounds were prepared in minimum quantity of DMF and diluted to 15 ml with normal saline to obtain same concentration as like as standard and taken into the Petri dishes. Normal saline serves as control for standard. Six earth worms of nearly equal size were placed in each Petri dish at room temperature. The compounds were evaluated by the time taken for complete paralysis and death of earthworms. The mean lethal time for each test compound was recorded and compared with standard drug. The time taken by worms to become motionless was noted as paralysis time. To ascertain the death of the motionless worms were frequently applied with external stimuli, which stimulate and induce movement in the worms, if alive. The mean lethal time and paralysis time of the earthworms for different test compounds and standard drug are tabulated in Figure 3 and Figure 4.

Haemostatic Activity²¹:

Clotting time of blood in presence of various synthesized compound was determined in vitro using Lee White’s Method as follows-

Human venous blood was collected in a clean, dry and corning glass tube. Clotting time determination in presence and absence of various compounds was determined and compared. Hundred milligrams of dried compound was suspended in distilled water and final volume was made to 0.5ml. This extract preparation was used in experimental sets. One millilitre of freshly withdrawn human venous blood was taken in a clean, grease and detergent free corning glass tube of 1cm diameter containing 0.5ml of various compound preparations. Control determination was performed using 0.5ml of distilled water instead of solution of compound. The clotting time of the different test compounds and control drug were shown in Figure 5.

Fig. 3: Anthelmintic activity of synthesized compounds (Data are expressed as means ± standard deviation (n = 3).

Fig. 4: Anthelmintic activity of synthesized compounds

Fig. 5: Study of haemostatic activity and amount of time required for clot formation was measured. Data are expressed as means ± standard deviation (n = 3). *Coagulation time was under 230s.

RESULT AND DISCUSSION:

At the end of the experiment, it has been concluded that the compounds synthesized in the project have good yield value. The structures of synthesized compounds were confirmed by TLC, mp, IR, NMR and mass spectroscopy methods. The synthetic procedure adopted to obtain the target compounds are depicted in Scheme 1.

2-chloro-1-(3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl)-ethanone (1) was prepared by the reaction of 3, 5-diphenyl-4, 5-dihydro-1H-pyrazole (which in turn was prepared by reaction of chalcone , hydrazine hydrate and acetic acid in ethanol) with chloroacetic acid using dry benzene as solvent. Then different pyrazole derivatives were obtain by the condensation of 2-chloro-1-(3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl)-ethanone with different amine using dry alcohol as solvent.

The most characteristic IR data of synthesized pyrazole analogues clearly shows C=N and C=O stretching band around 1409-1586 and 1950 , 1687 cm^-1 which indicates ring closure of pyrazole ring. Presence of C=S bonds (2b and 2c) was confirmed by presence of absorption band around 1328 cm^-1. All the final compounds have strong absorption around 3059-3300 cm^-1 which is evidence for the presence of N-N stretching band in pyrazole ring. The ¹H-NMR and mass spectra of title compounds were in conformity with the assigned structure. The mass spectra of all the compounds showed molecular ion peaks corresponding to their molecular formula.

Then, the pharmacological activity was done. The compounds are tested for antimicrobial activity by Agar defused cup plate mean zone of inhibition and Minimum inhibitory concentration method the bacterial strains used here are Staphylococcus aureus (NTCC-6571), Escherichia coli (TG₁) 4, Bacillus subtilis (SG-4), Pseudomonas aeruginosa (A₂) and Vibrio choleri (V1), the test compounds readings are compared with Amoxycilline standard drug for bacterial which are shown in table 1. Compound 2d shows prominent action on Gram +ve bacteria and compound 2e shows against Gram (-ve) bacteria as well as Gram + ve bacteria. It is because of the presence of unsaturated piperidine ring. Among all these compounds 2e have shown profound antibacterial activity against Gram (-ve) bacteria i.e. Vibrio choleri, due to the presence of highly unsubstituted and unsaturated morpholine ring in the structure. Presence of the ether oxygen in the morpholine ring which is withdraws electron density from the nitrogen, rendering it less nucleophilic. The remaining synthesized compounds were shown moderate to poor activity (Figure 1 and 2).

In Anthelmintic activity compounds are prepared as per procedure and Indian earth worm i.e Eudrilus eugenia which resembles the intestinal live stocks are collected and grouped 5 worms in test, control and standard. Albendazole was used here as standard the paralysis time followed with death time was recorded the compound 2a and 2d shows prominent action as compared with test and remaining shows mild to moderate (Figure 3)

All the synthesized compounds were subjected for haemostatic activity determined in vitro using Lee White’s Method. Human venous blood was collected in a clean, dry and corning glass tube. Clotting time determination in presence and absence of various compounds was determined and compared. Distilled water has been taken as control instead of synthesized compound solution. Compounds 2a and 2b were found to be better active among all the synthesized compounds when compare to distilled water taken as control solution where as remaining compounds found to be moderate to less active (Figure 5).

CONCLUSION:

All in all, a progression of substituted Pyrazole derivatives have been synthesized and there in vitro antimicrobial, anthealmintic and heamostatic activity were assessed against gram (+ve), gram (- ve) microorganisms, Eudrilus eugenia and Human venous blood, separately. The antimicrobial information given for the compound exhibited in this paper enabled us to express that the variety of antimicrobial activity might be related with the nature of tested microorganisms and furthermore is because of the chemical structure of the tested compounds. Performed SAR perception has demonstrated the significance of electronic condition on antimicrobial, anthealmintic and heamostatic action. The aftereffects of antimicrobial examination demonstrated that the connection of unsaturated piperidine and morpholine moiety appended specifically to the pyrazole ring through - COCH2-chain, improved antibacterial activity, though the presence of amino group (particularly – NH₂) and C=S as an afterthought chain has expanded the action of the compound (2a and 2d) contrasted with those with different substituents which might be because of the presence of the flexible pharmacophore which may build the lipophilic character of the molecules and in this way encouraged to loss of motion or to death of the worm. Besides, the pyrazole appended to the sulfur group indicated higher heamostatic action than the relating pyrazole derivatives. The reported results in this article may be helpful guide for the researcher who is working in this area.

ACKNOWLEDGMENT:

The author acknowledges the Assam down town University for providing laboratory facility, Library facility and the direct contributions of the support staff from the Faculty of pharmaceutical Science.

CONFLICT OF INTERESTS:

The authors declare that they have no conflict of interests regarding the publication of this paper.

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Received on 08.03.2019 Modified on 10.04.2019

Research J. Pharm. and Tech 2019; 12(9):4225-4230.

DOI: 10.5958/0974-360X.2019.00726.1