INTRODUCTION:

The non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed in pain, inflammation and fever¹. Among the NSAIDs, ketoprofen is the drug of choice which are frequently used in osteo- and rheumatoid arthritis². Chemically ketoprofen belongs to the class of propionic acid derivative and it is non-selective COX-inhibitor³. It is having the side effect of gastric lesion which is due to free carboxylic acid functionality and due to inhibition of COX-1. COX-1 plays a housekeeping role and catalyzes the synthesis of prostacyclin⁴ and Prostacyclin promotes the formation of gastric mucous layer⁵. The NSAIDs including ketoprofen or those which are non-selective COX-inhibitor shared a common side effect of gastric ulceration^16-8.

Therefore, there is need to reduce the gastric ulceration associated with their use and it is achieved by masking their carboxylic acidic functionality by converting them into esters or amides. The side effect could be masked by synthesizing the esters and amides of NAIDs with phytophenols and amino acids respectively. Some of the phytophenols like resveratrol, carvacrol, vanillin, thymol, sesamol etc. are good antioxidant. Here, phytophenols like vanillin, umbelliferon, carvacrol, syringaldehyde, sesamol, and guaiacol are used for making the esters. Amino acids used are glycine, tryptophan, glutamine cysteine etc. for synthesis of amide^9-13. The combinations of NSAIDs with phytophenols act as mutual prodrug because both the chemical moieties have their own pharmacological action¹⁴. The rationale related with the use of phytphenols is that they are directly or indirectly inhibit the formation of ROS (anti-oxidant effect) which are formed at the site of pain and inflammation¹⁵. The synthesized mutual prodrugs had better partition coefficient, less GI-irritancy with improved therapeutic effects^16-17. The main objective of the study is to develop the derivative having improved therapeutic potential with reduced ulcerogenicity.

MATERIALS AND METHODS:

Materials

Syringaldehyde, sesamol and umbelliferone were obtained from M/s Sigma-Aldrich, Mumbai, India and ketoprofen, carvarol, guaiacol and vanillin obtained from Yarrow Chem products Mumbai. All other solvents and reagents used were of analytical grade. The melting points were recorded by thiele tube method and are uncorrected. The infrared spectra of the synthesized prodrugs were recorded on Shimadzu 8201 PC and mass spectra of the synthesized compound were determined by Waters Q-TOF Micromass (ESI-MS). The ¹H spectra were recorded by Bruker Avance Neo 500 MHz using CDCl₃ as the solvent.

Synthetic procedure of prodrugs

The entire chemical compound taken (DCC, 4-DMAP, ketoprofen, and phytophenols) in stoichiometric amount (0.01 mole) in 50 mL DCM as a solvent. Firstly, ketoprofen (0.01 mole) was taken into a flat bottom round flask containing 25 mL of DCM, and stirred the mixture for 10 -20 min. for uniformity of the solution. Then phytophenol (0.01 mole) was added that are previously dissolved in 15 mL of DCM with continuous stirring. After 20 min. 4-DMAP and DCC were added into the above mixture and temperature was maintained at -5 to 0 ֯ C with continuos stirring. The completion of the reaction is confirmed by TLC (solvent system n-hexane: ethyl acetate) the reaction mixture is filtered and the filtrate is washed with 0.1N HCl and then 5% sodium bicarbonate solution. The excess solvent was removed by placing the washed filtrate into a china dish in a desiccators containing anhydrous calcium chloride. The crude solid product was obtained and purified by washing with cold ethanol.^{16, 18-21} Fig.1.

Characterization of prodrugs:

The various physicochemical properties such as R_f – value, melting point, partition coefficient, molecular wt. and color of the synthesized prodrugs were determined. The thin layer chromatography was performed on recoated silica gel G plate and using iodine chamber for spot detection. The solvent system is benzene: methanol (8:2) was taken. Melting point of the synthesized compound was determined by Thiele tube method and which were uncorrected. The partition coefficient is determined by taking 100mg of synthesized prodrugs and transferred to flask containing the 10mL mixture of 5mL n-octanol and 5mL phosphate buffer (pH 7.4). The flask was shaken for 24 hours and set aside for 1 hour. After that the aqueous layer was collected in a 10mL volumetric flask and extracted with 10mL chloroform. The chloroform layer was analyzed by UV-spectrophotometer and amount of drug was calculated with the help of previously plotted standard curves of test drugs^{16, 22}.

Hydrolysis study in acidic and basic medium:

The acidic hydrolysis study was performed in 0.1N HCl (pH 1.2)²³ and basic hydrolysis study was performed in phosphate buffer (pH 7.4).^4,22,24,25. The synthesized prodrugs weighed 100 mg and transferred to single rotatory paddle type dissolution apparatus containing either of 900 mL 0.1N HCl or phosphate buffer and maintained the static temperature at 37 ± 0.5⁰ C and paddle speed 100 rpm. At an interval of 30 minutes 5mL of aliquots were withdrawn and the same quantity of 0.1N HCl or phosphate buffer were added to maintain the constant volume upto 900 mL. The aliquots were extracted with chloroform and collected in 10mL of volumetric flask and left overnight for solvent evaporation. After all the chloroform was evaporated then added 10 mL of methanol in each volumetric flask and observed under UV-spectrophotometer at a wavelength of 280nm.

Pharmacological screening:

The animals selected for the pharmacological screening of the synthesized compounds, were wistar albino rats for anti-inflammatory and ulcerogenic activity, swiss albino mice for analgesic activity. Before performing the experiment, all the animals were divided into groups of 6 animals and housed in acrylic cages, provided standard environmental conditions of relative humidity 45-55% at a temperature of 25 ± 2⁰ C, in a proper ventilated room with 12 hr: 12 hr light/dark cycle, and fed with standard diet and water ad libitum. The animals selected for the study are taken from GLA University animal house, the protocol was approved by Institutional animal ethical committee as per CPCSEA guidelines. The animal house is approved by CPCSEA the approval number is as follows 1260/PO/Re/S/09/CPCSEA.

Anti-inflammatory effect:

Carrageenan induced hind paw edema model was selected for evaluation of anti-inflammatory activity. For this screening, the wistar albino rats weighing between 100-200g were used and divided into 8 groups, having 6 animals in each groups as vehicle control, test drug control and standard drug control (ketoprofen). The initial size of the hind paws was measured. The test drugs and standard drug suspension in 1 % w/v CMC were prepared and administered per oral one hour before the administration of 0.1mL of 1% w/v carrageenan suspension which acts as a phlogistic agent^25-18. For every 2-hour interval and upto 8 hours the size of paws was measured and percentage inhibition was calculated by using the formula:

% Decrease in edema = [(M_C – M_t) / M_C] x 100

Analgesic effect:

The acetic acid induced writhing method was chosen to check analgesic potential of prodrugs. The swiss albino mice weighing between 20-25g were selected as experimental animals. The suspension of test compound and standard drug (ketoprofen) were prepared in 1% w/v CMC and CMC used as a vehicle. The per oral administration of test drugs, standard drugs and vehicle to mice was done before one hour intraperitoneal administration of 0.1mL 6% acetic acid as an analgesic agent. All the animals were placed in glass chamber and the number of writhes were counted for 10 minute^{3, 2}.

% Decrease in writhes = [(N_C – N_t) / N_C] x 100

Ulcerogenic screening:

The wistar rats were selected for the evaluation of anti-inflammatory effects and divided into eight groups viz. vehicle control, test drug control and standard drug control. The suspension of drug and prodrugs were prepared in 1.0% w/v CMC solution, which is used as a vehicle. Each group contained 6 rats and fasted for 24 hours with continuous free access to water ad libitum before challenge for ulcer. The animals were sacrificed 12 hour after they dosed with prodrugs, standard drug and vehicle (1% w/v CMC). The stomach was isolated and opened through its greater curvature, washed with saline and observed for ulcers. Comparative measurement was done between the groups. The ulcer index was calculated by scoring the ulcer as: 0 = no observable damage to GI-mucosa; 1= superficially damage to GI-mucosa; 2 = inside deep ulcer; and 3 = perforations(29), (3).The ulcer index was calculated as

UI = [U_N+ U_S+ U_P] x 10^-1

Where, U_N = Average number of ulcers per animal;

U_S = Average of severity scores;

U_P= Percentage of animals with ulcers.

The data of the ulcerogenic activity represented in table:1

Table:1 Data of Analgesic and ulcerogenic activity

Sr.no.	Group	No. of writhes	% inhibition in writhing	Ulcer index
1.	Vehicle	53.66 ± 3.14
2.	Ketoprofen	21.05 ± 0.39	60.77 ± 0.39	10.75 ± 0.06
3.	Keto –van	17.99 ± 0.16	66.47 ± 0.16*	3.72 ± 0.02
4.	Keto –umbe	22.82 ± 0.33	57.47 ± 0.33	5.88 ± 0.55
5.	Keto –syr	17.16 ± 0.09	68.02 ± 0.09*	4.72 ± 0.55
6.	Keto –sesa	21.94 ± 0.76	59.11 ± 0.14	4.63 ± 0.60
7.	Keto –gua	16.83 ± 0.09	68.63 ± 0.09*	4.81 ± 0.57
8.	Keto –car	17.60 ± 0.05	67.20 ± 0.05*	4.13 ±0.56

*P < 0.05 compared to the standard drug (ketoprofen) are significant, and data were given in mean ± SE of %inhibition and analyzed by ANOVA; Where, N_C = Mean writhes in vehicle control; N_t = Mean writhes in test group.

RESULT AND DISCUSSION:

The synthesized prodrugs of ketoprofen conjugated with different phytophenols were evaluated physio chemically. The results of thin layer chromatography revealed a single spot, substantiate the product formation as well as completion of reaction between the reactants. All the synthesized prodrugs have R_fvalue ranges from 0.68 to 0.84. Also, all the prodrugs have partition coefficients between 4.23 to 6.26 observed in n-octanol and phosphate buffer. The value of partition coefficients exhibited that the synthesized compounds are lipophilic in nature and may be having better absorption across the intestinal membrane or lipoidal membrane. All the synthesized compounds are subjected to infrared spectroscopy and there is presence of –C-O- stretching peaks and absence of –O-H- stretching confirm the product formation. The –C-O- stretching bands appear in the region of 1157.48, 1235.48, 1230.43, 1130.49, 1237.28 and 1223.38 cm^-1for Keto-van, Keto-umbe, Keto-syr, Keto-sesa, Keto-gua and Keto-car respectively. There are–C=O stretching’s were observed at 1735.93 cm-¹,1720.35 cm-¹, 1740.71 cm-¹, 1753.29 cm-¹, 1739.35 cm-¹ and 1716.71 cm-¹ for the above compounds respectively which also revealed the products formed were ester (Table.3). The proton spectra of the synthesized prodrugs of ketoprofen were determined by dissolving them into CDCl₃ and tetramethylsilane as internal standard. There is absence of singlet peaks of phenolic proton as well as carboxylic group proton which are observed at 11.0 ppm and 12.05 ppm in phytophenols and ketoprofen. Hydrolysis studies of the prodrugs were carried out in-vitro in acidic and basic medium. The hydrolysis data revealed that all the prodrugs of ketoprofen were stable at acidic pH than basic. The release of free drug concentration is rapid in basic medium as compared to acidic environment, hence maximum absorption will be from intestine. This result in reduction of gastric lesion. The screening (anti-inflammatory, analgesic and ulcerogenic) of all prodrugs were performed. The carrageenan induced hind paw edema model was used to ascertain anti-inflammatory activity. The anti-inflammatory effect of the synthesized prodrugs was observed after 1 hour of the per oral administration of synthesized prodrug for upto 8 hours. Except keto-umbe and keto-sesa, all the prodrugs have anti-inflammatory action more than the ketoprofen. The data of anti-inflammatory activity was present in the tabulated form. All the prodrugs showed 66.57% to 74.44% inhibition in inflammation. Among the synthesized prodrugs keto-umbe (66.57% inhibition) and keto-sesa (68.05% inhibition) are less potent than ketoprofen (68.33% inhibition) (Table 2). When these prodrugs were screened for analgesic effect the keto-umbe and keto-sesa had not shown promising effect while remaining four drugs were found potent than ketoprofen. It may be due to higher concentration of the free drug was reaching to systemic circulation and the phytophenols may be playing a synergistic role with ketoprofen. Phytophenols have tendency either to suppress or prevent the formation of ROS or scavenge them from the site of action. The ulcerogenic study of the prodrugs and standard ketoprofen were performed and it is found that mean ulcer index for ketoprofen is 10.88, while all the prodrugs exhibited comparatively less ulcerogenicity. The minimized ulcerogenicity of the prodrugs were due to masking of free carboxylic acidic group of ketoprofen as well as ROS scavenging effect of phytophenols. Free carboxylic acid group is responsible for lesions on gastric mucosa by ion trapping mechanism which is minimized by esterification of acidic functionality with phytophenols. Phytophenols have anti-oxidant effects so that they prevent the ROS formation and also scavenge them from the site of formation.

Table: 2 Data of anti-inflammatory activity

Group	Difference in paw volume (mean ± SD)				% Inhibition
Group	2 hr.	4 hr.	6 hr.	8 hr.	2 hr.	4 hr.	6 hr.	8 hr.
Vehicle	0.31 ± 0.075	0.46 ± 0.081	0.43 ± 0.081	0.38 ± 0.075
Ketoprofen	0.17 ± 0.011	0.31 ± 0.009	0.20 ± 0.005	0.11 ± 0.005	43.05 ± 2.77	31.94 ± 2.16	50.83 ± 1.38	68.33 ± 1.27
Keto –van*	0.20 ± 0.005	0.28 ± 0.009	0.17 ± 0.005	0.09 ± 0.005	37.03 ± 1.85	38.61 ± 2.22	55.55 ± 0.00	72.22 ± 1.38
Keto- umbe	0.23 ± 0.005	0.35 ± 0.009	0.22 ± 0.005	0.12 ± 0.005	21.29 ± 2.44	24.25 ± 1.76	46.38 ± 1.11	66.57 ± 1.66
Keto –syr*	0.19 ± 0.005	0.29 ± 0.005	0.20 ± 0.000	0.09 ± 0.005	36.11 ± 1.38	36.94 ± 1.00	53.98 ± 0.46	74.44 ± 1.38
Keto –gua*	0.20 ± 0.009	0.27 ± 0.005	0.23 ± 0.010	0.10 ± 0.005	36.72 ± 2.72	39.25 ± 0.92	42.77 ± 2.72	71.94 ± 1.11
Keto -car *	0.17 ± 0.005	0.31 ± 0.009	0.18 ± 0.009	0.11 ± 0.023	43.51 ± 1.85	30.83 ± 2.40	55.55 ± 2.40	70.00 ± 1.11
Keto –sesa	0.23 ± 0.005	0.24 ± 0.009	0.16 ± 0.005	0.08 ± 0.009	33.79 ± 1.66	45.46 ± 0.96	60.83 ± 2.16	68.05 ± 1.27

*P < 0.05 compared to the standard drug (ketoprofen) are significant, and data were given in mean ± SE of %inhibition and analyzed by ANOVA

Where, M_C = Mean edema in vehicle control; M_t = Mean edema in test group.

Table: 3 Spectral analysis

Prodrug	Spectral analysis
Keto -van	IR: 1742.23 cm^-1 (C=O) Stretching of esters, 1157.48 cm^-1 (C-O) stretching of esters. ¹H-NMR: a & e =7.52 – 7.59(d, 2H), b & d = 7.39 – 7.42 (t, 2H), c=7.31-7.35 (t, 1H), f = 7.49 – 7.51(d, 1H), g=7.36 -7.43(t, 1H), h= 7.27- 7.29(d, 1H), i=7.81(s, 1H), j=2.52 – 2.64(qua, 1H), k=1.32-1.39(d, 3H), L=7.12-7.19(d, 1H), m=7.22-7.25 (d, 1H), n=9.96(s, 1H), o=7.45(s, 1H), p=3.78 (s,3H) ¹³C-NMR: ᵟ = 131.3(C-1), 128.5 (C-2), 132.5(C-3), 128.5(C-4), 130.3(C-5), 139.7 (C-6), 196.3(C-7), 140.1(C-8), 129.1(C-9), 128.9(C-10), 132.5(C-11), 135.2(C-12), 131.3(C-13), 40.1(C-14), 16.5(C-15), 170.0(C-16), 144.6 (C-17), 123.1 (C-18), 122.6(C-19), 134.7(C-20), 191.0 (C-21),114.5 (C₂₂), 157.6 (C₂₃), 55.9 (C₂₄) Mass (m/z): 388.41 (M+), 389.46(M+1) , 237.14(C₁₆H₁₂O₂)
Keto -umbe	IR: 1728.63 cm^-1 (C=O) Stretching of esters, 1235.43 cm^-1 (C-O) stretching of esters. ¹H-NMR: a & e =7.58 – 7.62(d, 2H), b & d = 7.49 – 7.52 (t, 2H), c=7.47-7.50 (t, 1H), f = 7.54 – 7.58(d, 1H), g=7.39 -7.42(t, 1H), h= 7.33- 7.37(d, 1H), i=7.73(s, 1H), j=2.48 – 2.52(qua, 1H), k=1.37-1.39(d, 3H), L=6.74-6.78(d, 1H), m=7.12-7.18 (d, 1H), n=6.83-6.86(d,1H), o=6.68-6.72(d, 1H), p=3.78 (s, 1H) ¹³C-NMR: ᵟ = 130.3(C-1), 129.5 (C-2), 133.5(C-3), 128.8(C-4), 130.3(C-5), 138.7 (C-6), 193.3(C-7), 140.1(C-8), 129.1(C-9), 128.9(C-10), 132.5(C-11), 134.7(C-12), 131.6(C-13), 41.7(C-14), 16.5(C-15), 171.2(C-16), 151.0 (C-17), 118.3 (C-18), 127.2 (C-19), 119.1(C-20), 150.6 (C-21),114.9 (C₂₂), 143.6 (C₂₃), 143.6 (C₂₄), 160.9 (C₂₅) Mass (m/z): 398.41 (M+), 399.42(M+1) 237.14(C₁₆H₁₂O₂)
Keto -syr	IR: 1719.23 cm^-1 (C=O) Stretching of esters, 1230.43 cm^-1 (C-O) stretching of esters. ¹H-NMR: a & e =7.78 – 7.82(d, 2H), b & d = 7.69 – 7.71 (t, 2H), c=7.58-7.64 (t, 2H), f = 7.65 – 7.67(d, 1H), g=7.58 -7.61(t, 1H), h= 7.46- 7.49(d, 1H), i=7.83(s, 1H), j=2.42 – 2.45(qua, 1H), k=1.37-1.39(d, 3H), L=3.78(s, 3H), m=7.26 (s, 1H), n=9.78(s, 1H), o=7.86(s, 1H), p=3.78 (s, 3H) ¹³C-NMR: ᵟ = 131.7(C-1), 128.5 (C-2), 132.5(C-3), 128.5(C-4), 130.3(C-5), 138.4 (C-6), 195.2(C-7), 140.1(C-8), 129.1(C-9), 128.9(C-10), 132.9(C-11), 135.2(C-12), 131.3(C-13), 40.6(C-14), 15.9(C-15), 172.3(C-16), 131.7 (C-17), 158.6 (C-18), 55.9 (C-19), 106.8(C-20), 135.7 (C-21), 191.0 (C₂₂), 106.8 (C₂₃), 158.6 (C₂₄), 55.9 (C₂₅) Mass (m/z): 418.44 (M+), 237.14(C₁₆H₁₂O₂)
Keto -sesa	IR: 1715.48 cm^-1 (C=O) Stretching of esters, 1130.49 cm^-1 (C-O) stretching of esters. ¹H-NMR: a & e =7.78 – 7.89(d, 2H), b & d = 7.62 – 7.69 (t, 2H), c=7.49-7.53 (t, 1H), f = 7.68 – 7.73(d, 1H), g=7.58 -7.61(t,1H), h= 7.39- 7.42(d, 1H), i=7.614(s,1H), j=2.33 – 2.36(qua, 1H), k=1.39-1.43(d, 3H), L=7.13-7.16(d, 1H), m=7.36 –7. 37 (d,1H), n=5.78(s, 2H), o=7.23 (s,1H) ¹³C-NMR: ᵟ = 131.3(C-1), 128.5 (C-2), 132.5(C-3), 128.5(C-4), 130.3(C-5), 139.7 (C-6), 194.8(C-7), 140.1(C-8), 129.1(C-9), 128.9(C-10), 132.5(C-11), 135.6(C-12), 130.3(C-13), 41.2(C-14), 16.5(C-15), 171.4(C-16), 144.7 (C-17), 114.9 (C-18), 115.7 (C-19), 145.6(C-20), 149.2 (C-21), 191.0 (C₂₂), 108.7 (C₂₃), 101.2 Mass (m/z): 374.39 (M+), 375. 43 (M+1) , 237.14(C₁₆H₁₂O₂)
Keto -gua	IR: 1725.27 cm^-1 (C=O) Stretching of esters, 1237.28 cm^-1 (C-O) stretching of esters. ¹H-NMR: a & e =7.68 – 7.70(d, 2H), b & d = 7.61 – 7.65 (t, 2H), c=7.51-7.56 (t, 1H), f = 7.67 – 7.69(d, 1H), g=7.49 -7.51(t, 1H), h= 7.34- 7.36(d, 1H), i=7.71(s, 1H), j=2.49 – 2.54(qua, 1H), k=1.42-1.45(d, 3H), L=7.09-7.12(d, 1H), m=7.29 –7. 32 (t, 1H), n=7.37(t, 1H), o=7.34 -7.35(d, 1H), p=3.86(s, 3H) ¹³C-NMR: ᵟ = 130.3(C-1), 127.4 (C-2), 132.5(C-3), 127.5(C-4), 130.7(C-5), 139.2 (C-6), 196.3(C-7), 140.1(C-8), 129.1(C-9), 128.9(C-10), 132.5(C-11), 135.2(C-12), 131.3(C-13), 40.7(C-14), 16.3(C-15), 170.0(C-16), 138.8 (C-17), 122.6 (C-18), 121.5 (C-19), 126.6(C-20), 114.7 (C-21), 157.1 (C₂₂), 55.7 (C₂₃) Mass (m/z): 360.4 (M+), 361.56 (M+1) 237.14(C₁₆H₁₂O₂)
Keto-car	IR: 1727.68 cm^-1 (C=O) Stretching of esters, 1223.38 cm^-1 (C-O) stretching of esters. ¹H-NMR: a & e =7.993 – 8.007(d, 2H), b & d = 7.41 – 7.53 (t, 2H), c=7.551-7.56 (t, 1H), f = 7.66 – 7.67(d, 1H), g=7.58 -7.611(t, 1H), h= 7.294- 7.308(d,1H), i=7.617(s, 1H), j=2.35 – 2.49(qua, 1H), k=1.48-1.49(d, 3H), L=7.23 (s, 1H), m=3.35 – 3.55 (multiplets, 1H), n=6.94 – 6.96(d, 1H), o=6.82-6.88(d,1H), p=2.94(s, 3H), q = 0.89 – 1.00(d, 6H) ¹³C-NMR: ᵟ = 129.3(C-1), 127.8 (C-2), 132.5(C-3), 127.8(C-4), 129.8(C-5), 139.7 (C-6), 196.1(C-7), 141.1(C-8), 129.1(C-9), 128.9(C-10), 132.5(C-11), 135.2(C-12), 131.3(C-13), 40.2(C-14), 16.3(C-15), 170.6(C-16), 150.1 (C-17), 117.4 (C-18), 146.0 (C-19), 36.3 (C-20), 23.4 (C-21), 23.6 (C₂₂), 122.9 (C₂₃), 129.2 (C₂₄), 129.0 (C₂₅), 14.3 (C₂₆) Mass (m/z): 386.48(M+), 387.49 (M+1) 237.14(C₁₆H₁₂O₂)

CONCLUSION:

The prodrugs of ketoprofen were synthesized by following the Steglich esterification reaction. All the prodrugs have appropriate lipophilicity, and chemically stable. Hydrolysis study of prodrugs showed the ester linkage prodrugs were hydrolyzed faster in basic medium in comparison with acidic medium. Relatively slower hydrolysis in acidic environment and faster hydrolysis in basic medium revealed the greater amount of drug absorb from intestine and also it reduced the ulcerogenic potential of the parent molecule. The synthesized compounds had higher analgesic and anti-inflammatory effects, except keto-umbe and keto-sesa. All of the six compounds were free from ulcerogenic effect which as much with ketoprofen. The main conclusion of the study is that mutual prodrugs are more effective than parent chemical entity and masking of the acidic functionality of NSAIDs with phytophenols make them more effective and reduction in the side effects like gastric ulceration. The main objective of the study is that, there are many NSAIDs which are effective as an analgesic and anti-inflammatory but suffered by their potential side effect on gastric mucosa so, we were trying to develop mutual prodrugs which are more effective with reduce gastric ulceration. The synthesized prodrugs have better physiochemical properties such as better lipophilicity, chemical stability, and hydrolytic behavior. Further advance toxicological studies are required to have better and safe molecule in the market.

CONFLICT OF INTEREST:

The authors declare no competing interests.

ACKNOWLEDGEMENTS:

The authors are thankful to GLA University, Mathura for providing necessary facilities to carry out the work. Authors are also thankful to Punjab University for spectral (NMR and Mass) data.

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Received on 13.06.2023 Modified on 01.07.2023

Research J. Pharm. and Tech 2023; 16(7):3427-3433.

DOI: 10.52711/0974-360X.2023.00567


Keto- Car	Keto-Gua

Keto-sesa	Keto-syng

Keto-umbe	Keto-van