INTRODUCTION:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs for the treatment of pain and inflammation in a variety of diseases. However, chronic treatment with NSAIDs has demonstrated some adverse effects like gastrointestinal and renal damage. The most serious complication associated with NSAID use is gastroenteropathy. Several strategies have been used to minimize NSAID gastrointestinal toxicity; the most successful one is the development of the new generation of anti-inflammatory drugs that are known as selective COX-2 inhibitors.

However, the long-term treatment of patients with COX-2 selective inhibitors is also associated with an increase of thrombotic risk and an increase in blood pressure in certain patients.

The discovery of new dual COX-2 and 5-LOX inhibitors may represent an opportunity for the design of safer anti-inflammatory and analgesic agents. During the last years, the interest in the design of bi-functional anti-inflammatory drugs has increased.¹^,2. Inflammation and tissue damage are two of the diverse biological responses triggered by trauma signaling. The release of mediators causes the dilation of blood vessels, an increase in blood flow, alteration in the permeability of the capillaries, and a series of chemical changes inducing compression of the surrounding cells. It is known that the treatment of inflammation is important to control the signs and symptoms. Anti-inflammatory drugs are intended to treat both the symptoms and the natural course of the disease. Hence, the search for newly synthesized compounds has increased³. NSAIDs work on the cyclooxygenase enzyme (COX), which catalyzes the conversion of arachidonic acid into prostaglandins and thromboxanes. An essential function of prostaglandins is to regulate physiological processes including pain, fever, immunity, and homeostasis.^4,5.

Traditional NSAIDs can be further sub classified into carboxylic acid, enolic acids and non acidic compounds⁶. Two key distinctions exist between selective COX-2 inhibitors and conventional NSAIDs: Coxibs do not impair platelet function and are less likely to cause NSAID-induced gastropathy. As a result, compared to traditional NSAIDs, selective COX-2 inhibitors cause less clinically significant GI damage and bleeding⁷. These selective COX-2 inhibitors all have a core five- or six-membered heterocyclic or carbocyclic motif that is linked to two vicinal aryl rings. Celecoxib, rofecoxib, valdecoxib, and SC57666 are common examples of selective COX-2 inhibitors. These examples demonstrate that a wide range of five- or six-membered carbo or heterocycles can bind to the cyclooxygenase active site⁸^,9.Compounds with azomethine (-NH-N=C-) moiety are called hydrazones⁹^.The importance of hydrazones and their wide applications in different fields including the medicinal chemistry and organic synthesis arises from the presence of (N-N=C) unit in its structure. This unit has unique characteristics: two nucleophilic nitrogens (imine and amino) with lone pair of electrons, an electrophilic and nucleophilic character of imine carbon atom, configurational isomerism due to the presence of C=N double bond and an acidic N-H proton¹⁰. Hydrazone have many pharmacological activities¹¹ like anti-inflammatoryanalgesic¹² antiviral¹³ anticancer¹⁴ antibacterial¹⁵anti platelet¹⁶^,17.

Chemical synthesis:

Represents the stepwise chemical synthesis of all compounds.

Synthesis of L-Phenyl alanine ethyl ester HCl; compound (P1)

Phenyl alanine (25mmol, 4.125g) was suspended in 60 ml of absolute ethanol, cooled to -5⁰C. Thionyl chloride (27mmol, 2ml) was then added dropwise; the temperature should be kept below -5⁰C. The reaction mixture was then left on cold conditions for 25 minutes, at room temperature for 60minutes, reflux started for 3 hours, and stirred at room temperature overnight. The solvent was evaporated to dryness under vacuum, redissolved in methanol, and evaporated; this process was repeated multiple times and resulted in white crystals with a 96% yield percentage and a 153ºC melting pointand R_f was 0.54 from (7:3, MeOH: CHCl₃). methanol–ethyl acetate (3:1) to get off white crystals of yield percentage of 75.6%, m.p. 158ºC and Rf was 0.73 from (7:3, MeOH: CHCl₃)¹⁸.

Synthesis of L- Histidine Ethyl ester; compound (H1):

A suspension of (10mmole, 1.55g) of histidine and an excess of ethanol (30mL) in a 100ml round bottom flask was stirred till a clear solution is achieved. Then the solution was cooled to 0⁰C by using ice bath and 3mL of concentrated hydrochloric acid (HCl) was added drop wise with continuous stirring; the mixture was kept in cold condition for 25 minutes then at room temperature 60 minutes after that was set to reflux with stirring for 3 h. After completion of the reaction (monitored by TLC), at the end of the reaction the solution was then dried and redissolved in methanol and evaporated, this process was repeated several times and recrystallize from methanol–ethyl acetate (3:1) to get off white crystals of yield percentage of 98%, m.p. 238ºC and Rf was 0.48 from (7:3, MeOH: CHCl₃)^18-25.

Synthesis of naproxen phenyl alanine ethyl ester amide; compound (P2):

10mmole (2.3g) of Naproxen was dissolved in 50ml of DCM in an ice bath at a temperature of approximately -5°C in a hood. Next, 11mmole (2.12g) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) was added, stirring continuously for 20 minutes. Next, 10mmole (2.29g) of phenylalanine ethyl ester. HCl salt was added slowly to the reaction mixture, stirring continuously for at least one hour. Finally, the mixture was refluxed for an additional three hours. The product was then poured into a separatory funnel and rinsed three times with distilled water, 5% HCl, and lastly with anhydrous magnesium sulphate. Following trituration, the product was cleaned three times with petroleum ether (60–95%) and then with ether to get a white ppt yield of 69%.^26-29.

Synthesis of naproxen phenyl alanine Hydrazide; compound (P3):

Naproxen phenyl alanine ethel ester amide P2(2.2 mmol) (0.9g) was dissolved in (5mL) ethanol then added 1.5ml of 100% hydrazine hydrate and refluxed for three hours. Following the reaction, which was tracked by TLC, the mixture was cooled to room temperature (R.T.), at which point the crystals that had formed were filtered out and recrystallized from pure ethanol 75%^{30, 31}.

Synthesis of naproxen phenyl alanine Schiff base of benzaldehyde; compound (P4):

To mixture of (0.23ml benzaldehyde with 5 ml absolute methanol two drops of glacial acetic acid was put in. After stirring for 10 minutes) 2.2mmol. 0.86g. of naproxen phenyl alanine ethel ester hydrazide P3 was added. Reflux was done on 150°C for 3 hours. Yield 88%³².

Synthesis of L-Histidine Hydrazide; compound (H2):

Histidine ethyl ester. 2HCl salt H1(5mmol) (1.28g) was dissolved in 50ml ethanol then added 1.8ml hydrazine hydrate 100%, refluxed for overnight. At the end of reaction, as monitored by TLC, the mixture was cooled to room temperature (R.T), the crystals formed collected by filtration and recrystallized from absolute EtOH. Yield 62%^30,31.

Synthesis of L-Histidine Schiff base of benzaldehyde; compound (H3):

To mixture of (3mmol 0.32ml benzaldehyde with 5ml absolute ethanol two drops of glacial acetic acid was put. After stirring for 10minutes) 3mmol. 0.5g. of Histidine hydrazide H2 was added. Reflux was done on 150°C for 3 hours. Yield 40%³³.

Synthesis of Thiozolidinone derivative 3; compound (H4):

15 ml of 1,4-dioxane was mixed with 3 mmole of H3 0.77g. Then, dropwise addition of mercaptoacetic acid (3.3mmole, 0.3g) was made to this mixture. At room temperature, the mixture was stirred for six hours. Following the removal of the solvent under decreased pressure, 20mL of a 10% sodium bicarbonate water solution was applied three times to the residue before being cleaned. Filtered off and re-crystallized from ethanol was the precipitate that had formed³⁴.

Synthesis of naproxyl chloride N1:

0.01mmole on Naproxen 2.3g was dissolved in 50ml DCM and then cold to -5°C and then equivalent amount of thionyl chloride 0.8ml was added gradually with vigorously stirring, the reaction was then left on ice bath for 30min and then at room temperature for further 30 min and then refluxed for 3hrs the crude product is then filtered and recrystallized from chloroform.

Synthesis of compound H5.

1.5mmole of H40.5g was dissolved in 25 ml DCM and then cooled to zero°C and naproxyl chloride N1(1.5 mmole, 0.37g) is then added gradulally with stirring.The reaction mixture was left on ice bath for half an hour then in R.T. for further half an hour and was then refluxed for 3 hours, the crude product is then filtered and recrystallized from chloroform.

RESULTS AND DISCUSSION:

ChemistryThe synthesis of compounds (P1-P4, and H1-H5) are outlined in the scheme (1), and involved the preparation of amino acid esters of [phenyl alanine, and histidine] by refluxing the suitable amino acids in absolute ethanol in the presence of conc. HCl as catalyst or by acylation of ethanol by acid halides which prepared by reaction of thionyl chloride with the amino acids of concern. Amino acid esters were refluxed with 80% hydrazine hydrate in absolute ethanol to give hydrazides for corresponding amino acid esters.

Synthesis of (P4, and H3) was carried out by the conventional method which involved refluxing of ethanolic or methanolic solution or suspension of aromatic aldehydes with appropriate hydrazides like in an acidic medium to yield Schiff’s bases (hydrazones). Stirring a mixture of appropriate Schiff’s bases (hydrazones) and thioglycolic acid in 1,4-dioxane lead to formation of 1,3-thiazolidine-4-one.Amide bond formation was carried out by two methods; first involve synthesis of acid halide from Naproxen (dissolved in DCM) by reaction of it with thionyl chloride; which then refluxed with amine part of compound to prepare amide derivative.

Characterization and identification of the synthesized compounds:

Determination of melting points The melting points of the synthesized compounds and their intermediates were measured, and are (uncorrected). They were found to be different from the melting points of their starting materials as shown in table (1).

Table 1: Chemical formula, molecular weight ,melting points, percent yields, R_f values, physical appearance and recrystallization solvent of the titled compounds (P1-P, and H1-H4).

*Sym*	*Chemical Formula*	*M.wt*	*M.P C˚*	*% Yield*	*Physical appearance*	*R_f*	*Crystallization solvent*
P1	C₁₁H₁₆O₂NCl	229.7	60-62^*	90	Off-white powder	0.776^a 0.8^b	-
P2	C₂₅H₂₇NO₄	405	208-210^**	75	White powder	0.612^a 0.267^b	-
P3	C₂₃H₂₅N₃O₃	391	186-189	59	Faint yellow powder	0.612^a 0.693^b	Absolute ethanol or base-acid precipitation
P4	C₃₀H₂₉N₃O₃	479	118-120	65.5	White crystals	0.776^a 0.8^b	Absolute ethanol
H1	C₈H₁₅N₃O₂Cl₂	256	195-197	44.5	Dark yellow powder	0.6^a 0.836^b	Methanol
H2	C₆H₁₁N₅O	169	226-228	75	White powder	0.791^a 0.627^b	Absolute ethanol or methanol
H3	C₁₃H₁₅N₅O	257	167-169	65.5	White crystals	0.776^a 0.733^b	Absolute ethanol-2-methoxy ethanol mixture
H4	C₁₅H₁₇N₅O₂S	331	228-232	65	White powder	0.716^a 0.52^b	-
H5	C₂₉H₂₉N₅O₄S	543	200-202	70	White powder	0.601^a 0.303^b

Thin layer chromatography (TLC)R_f values of the synthesized compounds which, after exposing the chromatograms to UV₂₅₄ light, exhibited single round spots appeared in different positions from that of the starting materials, indicating the purity and the accomplishment of the reactions. Infra-red (ATR-FTIR) spectroscopy:The IR spectra of the target compounds (P1-P4 and H1-H5) recorded characteristic bands in cm^-1. H1 showed aliphatic ester carbonyl stretching vibration at 1734cm^-1, and C-O stretching vibration of aliphatic ester at 1165cm^-1. H2 was hydrazinolysis product of H1 so that it was showed characteristic bands of hydrazide CONHNH₂ groupwhich were NH₂ asymmetric stretching vibration at 3252cm^-1, NH amide stretching vibration at 3125cm^-1, and shifting of carbonyl group from 1734cm^-1 to 1633cm^-1due to amide formation. H5 characterized byappearance of two vibration bands 1726cm^-1and 1682cm^-1 due carbonyl of cyclic amide and acylation of amine with acid halide. P2 was showed characteristic bands of hydrazide CONHNH₂ groupwhich wereNH₂ asymmetric stretching vibration at 3414cm^-1, NH amide stretching vibration at 3317cm^-1, and 1643cm^-1due to amide carbonyl group. P3 characterized by stretching vibration band at 1666 cm^-1 due to formation of imine group (-C=N-)^35-38.

¹HNMR spectroscopy:

¹HNMR of H5 was found to have 2H_s as doublet, doublet at 3.68 and 3.72 p.p.m. and one proton as singlet at 5.99 p.p.m that had attributed to thiozolidinone ring. ¹HNMR of P3 was characterized by signals related to CONHNH₂ protons at 9.18 p.p.m and 4.18 p.p.m., respectively both of them as singlet. ¹HNMR of P4 was characterized by appearance of new protons related to CONHN which showed 2 signals due cis and trans isomers between 11.39-11.56 p.p.m and CONHN=CH which also showed 2 signals due to syn/anti-syn conformersbetween 7.95-8.08 p.p.m^36-39.

In silico Study of the designed compounds:

The proteins crystal structures were obtained from protein data bank, the PDB code for COX1 was 3N8Z and for COX2 was 6BL3. All water, ions, and non-standard residues were deleted. The proteins structures were minimized by steepest descent method by 500 steps and then prepared for docking by addition of charges (AMBER ff14SB force field) and hydrogens^40-45. The MM2 force field was used to minimize and optimize the ligands. Autodock Vina was used to perform the docking process and the visualization was carried by UCSF chimera. 1 The box grid dimensions for COX-1 and COX-2 were as following.The calculated ∆G of Naproxen and its derivatives was shown below in the table 2, 3.

Table 2: The box grid dimensions for COX-1 and COX-2

COX-1
Center	-23.47	40.14	7.445
Size	31.08	27.32	28.012
COX-2
Center	-48.56	-11.234	19.95
Size	36.46	34.74	38.46

Table 3 Showed the calculated ∆G of Naproxen and its derivatives

ID	Structure	∆G/COX-1	∆G/COX-2
Naproxen		-6.1	-8.3
P4		-9.0	-9.3
H5		-8.5	-7.6

All compounds occupied roughly the same space within the COX-1 binding pocket (Figure 1). In contrast to COX-2, the compounds have become somewhat dispersed, particularly P4A and Naproxen (Figure 2). Regarding COX-1, all compounds accept H-bonds from arginine residues with the exception of Naproxen (which has no discernible tendency to form H-bonds) (Figure 4). Regarding COX-2, most of the compounds have made H-bonds with totally different residues. Because, it was unable to form H-bonds and pi-pi stacking, Naproxen was unable to target COX-1 with a binding activity that was comparable to that of novel compounds. Due to the abundance of VDW forces and the favorable conformation inside the pocket, P4A has shown the best binding energy score against COX-1. P4A has shown excellent binding affinity to COX-2. P4A has moved to a different environment close to the naproxen binding site, as shown in figure 2. Overall, all compounds have shown promising interactions with both enzymes^43.46.

Anti-inflammatory evaluation:

Using the egg-white produced paw edema technique, the synthetic target compounds (P4 and H5) were assessed for their immediate anti-inflammatory properties in vivo.The newly synthesized compounds' anti-inflammatory efficacy is screened based on the reduction in paw thickness.³⁴ 24 albino rats of each sex, weighing 100±5g, were provided by a private animal house and kept at the animal house at Baghdad University's College of Pharmacy under controlled circumstances. The animals were given ad libitum access to commercial chaw. The animals were split up into the following four groups, each with six rats: Group A: Dimethyl sulfoxide (DMSO) was administered to six rats as a vehicle and control group.

2ml/kg³⁵. Group B: Six rats were treated with Naproxen as a reference substance in a dose of 10mg/kg^21,36,37 dissolved in DMSO. Groups C: Six rats/groups treated with the tested compounds (P4 and H5) in doses that were determined below. (dissolved in DMSO)

Dose correction was done for both (P4 and H5) to be equivalent to that of Naproxen which used as a reference substance of dose 10mg/kg dissolved in DMSO. The intraperitoneal (i.p.) method was used to give the reference and tested compounds^47–51.

Design of an experiment: Using the egg-Albumin model of edema, the anti-inflammatory efficacy of the examined substances was investigated. Following the intraperitoneal (i.p.) injection of the freshly synthesized molecules or their vehicle (control), 0.1ml of undiluted egg-Albumin was SC-injected into the plantar side of the rats' left hind paw, causing an initial, fast swelling. Five time intervals (0, 30, 60, 90, and 120) were used to measure the thickness of the paws using a Vernier after the medicines or their vehicle (control) were administered intraperitoneally (i.p.), which was regarded as time zero.⁵²^-56 Here we can see the result by using ANOVA test, analysis of variance and also the p value as mentioned below in the table almost significant compared with the standard Naproxen see table 4.

Table 4 . Comparing the effect of naproxen Vs P4 and H5

Two hours comparison	P value 120 min	P value 90 min	P value 60 min	P value 30 min
Naproxen vs P4	0.008	0.053	0.291	0.098
Naproxen vs H5	0.039	0.491	0.887	0.150

Here we can also mentioned that best group compared with Naproxen and give faster effect as an anti-inflammatory was group D and then group E just after two hours.

CONCLUSION:

The biological evaluation of the newly synthesized analogs was done through induction paw edema, calculating the decrease in paw thickness in comparison with negative control DMSO and positive control naproxen. These results showed that all analogs got better anti-inflammatory action than Naproxen; the best result was for the analog P4, which showed more powerful anti-inflammatory action than the others with a significant p-value (0.008 as compared with Naproxen).

ACKNOWLEDGMENT:

Special thanks to Dr Hany Akeel Institute, Iraqi Medical Research Center, for there great support.

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Received on 09.11.2022 Modified on 24.10.2023

Research J. Pharm. and Tech 2024; 17(8):3560-3566.

DOI: 10.52711/0974-360X.2024.00556