Design, molecular docking studies of oxaprozin linked to 4-thiazolidinone derivatives as a potent anticancer, analgesic and antiinflammatory agents

 

Kishore Kumar Valluri,¹Tejeswara Rao Allaka,² I V Kasi Viswanath,^1*Nagaraju PVVS¹

¹Department of Chemistry, K. L. University, Vaddeswaram, Guntur, Andhra Pradesh, India-522502

²Centre for Chemical Sciences and Technology, Department of Chemistry, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, Kukatpally, Hyderabad, Telangana-500085, India

*CorrespondingAuthorE-mail:viswanath.ivk@gmail.com

In the present study, we introduced acyl hydrazone derivatives of 3-(4,5-diphenyl-1,3-oxazol-2-yl) propanoic acid as new potent and selective anticancer, analgesic and anti inflammatory inhibitors that lack the standard pharmacophoric binding features to PDBID 2ZCS. The key intermediate N-acyl hydrazine is prepared in good yields from oxaprozin, was integrate with a variety of aromatic aldehydes under conventional conditions. The newly synthesized compounds have been characterized by IR, ¹H NMR, ¹³C NMR and Mass spectral analysis. Further, the compounds 5a, 5b, 5e, 5g, and 5h announce promising invitro cytotoxicity than reference compound cisplatin. All the target compounds have been screened for their invivo anti-inflammatory activity on rats by carrageenan-induced ratpaw edema assay. The results of the biological activities showed that the compounds 5b, 5d and 5e exhibited significant invivo analgesic and anti inflammatory activities than reference compound oxaprozin. Further investigation, starting from our lead compound 5i, structure-based drug-design was conducted and more potent analogues were obtained with high selectivity and almost full edema protection, in carrageenan-induced autodock 4.2, in case of compounds 5a, 5g, 5d and 5e showed the good binding energy by adding a substituted phenyl rings afforded excellent active compounds. The activity data is validated by molecular docking studies and are in good corelation with observed trends.

 

 

INTRODUCTION:

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for the investigation of inflammation, fever and pain. From mechanistic point of view, NSAIDs exercise their pharmacological action via inhibition of cyclooxygenase (COX) that catalyzes the conversion of arachidonic acid to the prostaglandins (PGs) [1-3].It was observed that traditional NSAIDs in current use nonselectively inhibit COX-1 and COX-2.

 

 

Cyclooxygenase(COX) has been established to exist mainly in two distinct isoforms, COX-1 and COX-2. COX-1 is constitutively normally expressed in most tissues, and PGs controlled by COX-1 mediate cytoprotection of gastric mucosa and platelet aggregations in addition to some other physiological processes. On the otherhand, COX-2 is undetectable in normal tissues and selectively induced locally by inflammatory stimuli; i.e. pro-inflammatory cytokines, leading to elevating PG levels at the site of inflammation [4-6]. Therefore, the therapeutic interest derives from inhibition of the inducible isoform; i.e. COX-2, at the site of inflammation [1].

 

 

Commonly used anti-inflammatory drugs such as NSAIDs and analgesic agents are associated with some side effects such as myocardial infarction, dyspepsia, congestive heart failure, gastric ulceration, diarrhea and hypertension [7].Consequently, long term therapy with non-selective NSAIDs results in appreciable GI irritation, bleeding and ulceration [8].GI damage from NSAIDs is generally due to two factors i.e. local irritation by the direct contact of carboxylic acid (COOH) moiety of NSAID with GI mucosal cells and decreased tissue prostaglandin production [8]. The NSAIDs may also cause renal failure when used in combination with some diuretic and ACE inhibitors, interstitial nephritis, nephrotic syndrome, acute tubular necrosis and acute renal failure and also causing analgesic nephropathy when used in combination with phenacetin and paracetamol, premature birth, hepatotoxicity, raised liver enzymes, bronchospasm, hyperkalaemia, headache, rash and allergy [9].These adverse clinical manifestations have attracted medicinal chemists to synthesis newer NSAIDs by chemical modification with the aim of improving safety profile.

 

Thiazolidinones have attracted considerable attention in medicinal chemistry due to their broad range of pharmacological response such as antimicrobial, anticonvulsant, analgesic, anti inflammatory, antiplatelet, antitubercular and antitumor activity [10-13].Recently, a series of synthesised NSAIDs analogues have been reported diclofenac [14], celebrex, mefenamic acid [15], ibuprofen [16] have shown excellent bilogical profiles when tested invitro and invivo (Fig. 1) which are associated with strong cytotoxic, analgesic, anti-inflammatory properties.Moreover the presence of thazolidinones from hydrazones (N=CH) has gained special interest for the development of newer drugs. These observations lead to the development of new thiazolidinones that possess varied biological responses. In continuation of the previous efforts to identify more potent antiinflammatory and cytotoxic agents, we have explored the structural features of other anti inflammatory agents that can be incorporated into our target molecules. Accordingly, potent anti inflammatory agent, oxaprozin was selected which belong to group of NSAIDs that are commonly used to treat pain and other inflammatory diseases. The aim of the present investigation is to synthesize new active compounds and detect their biological activities by introducing aromatic rings to serve as a hydrogen bond donor or accepters. Moreover, some oxaprozinthiazolidinone derivatives showed potent cytotoxicity, analgesic and inflammatory activities. In order to investigate the interactions between our designed compounds (5a-5n) and the amino acid residues (Lys46, Asp49, Arg171, Val268 ect.) of the PDBID 2ZCS, a molecular docking study was performed.

 

 

Figure 1. Biological importance of NSAIDs, and bearing 4-thiazolidinones with antiinflammatory drugs

 

 

 

 

 

Scheme 1. Synthesis of novel 4-thiazolidinones

 

 

RESULTS AND DISCUSSION:

Chemistry:

Thiazolidinone derivatives of 3-(4,5-diphenyloxazol-2-yl)-propanoic acid were synthesised via efficient synthetic route transformations of conventional method from 3 and 4a-4n to form product 5a-5n. The key intermediate 3 was prepared in 79 % yield from methyl 3-(4,5-diphenyloxazol-2-yl) propionate (2) and hydrazine hydrate employing methanol as solvent. Reaction of 3 with one equivalent of different aromatic aldehydes (4a-4n) in the presence of ethanol at ambient temperature for 5hr afforded the title compounds 5a-5nin good yields (scheme 1). Results of the study along with the time/yields obtained by conventional method have been presented (see experimental section).The structures of synthesized compounds 5a-5n were confirmed by IR (cm^-1), ¹H NMR, ¹³C NMR and mass spectral analysis.

 

Biological assay:

Anti cancer activity (invitro):

These compounds were also tested invitro against the human colon cancer cell line (HCT-15) based on MTT ((3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)assay. The percentage of cell death was measured for each compound at various concentrations along with IC₅₀ (half maximal inhibitory concentration) values of compounds are shown in Table 1, cisplatin was used as a reference compound. The fact that IC₅₀ is inversely proportional to the cytotoxicity indicates that all these compounds are associated with promising cytotoxic effects and the compounds 5a, 5b, 5e, 5g, 5h, 5i and 5j are most notable among them as they showed IC₅₀ values between 4.2 to 6.8 µg mL^-1 at low concentration.

 

Analgesic activity (invivo):

The synthesized compounds 5a to 5j were screened for analgesic activity by Eddy’s Hot Plate Method taking oxaprozin as standard. The compounds 5a to 5j and standard were tested at an equimolar oral dose relative to 10 mg kg^-1 body weights. The compounds showed good analgesic activity in comparison to their respective standard oxaprozin drug. The compounds showed analgesic activity ranging from 64.96 % to 90.88 % inhibition at 120 min, where as standard drug showed 79.28% inhibition (Table 2, Figure 2).

 

 

Table 1. Cytotoxicity of hydrazone derivatives against human colon cancer cell line (HCT-15)

Compounds	% of cell deaths at various concentration				IC50 (µg mL-1)
	2.0 (µg mL-1)	5.0 (µg mL-1)	10.0 (µg mL-1)	25.0 (µg mL-1)
5a	47.95 ± 0.015	51.15±0.012	52.42±0.001	56.94 ± 0.035	4.2
5b	48.25 ± 0.012	57.81 ± 0.007	58.14 ± 0.026	59.71 ± 0.008	4.4
5c	28.92 ± 0.039	38.72 ± 0.013	50.73 ± 0.031	61.76 ± 0.003	10.5
5d	29.65 ± 0.023	37.74 ± 0.015	46.32 ± 0.016	51.47 ± 0.012	18.3
5e	33.33±0.018	42.89 ± 0.026	51.27 ± 0.014	61.27 ± 0.018	6.8
5f	30.88 ± 0.025	35.04 ± 0.019	44.11 ± 0.006	61.76 ± 0.018	15.2
5g	20.34 ± 0.073	36.37 ± 0.071	40.31 ± 0.038	41.91 ± 0.113	4.5
5h	52.13 ± 0.005	44.71 ± 0.021	48.93 ± 0.064	52.38 ± 0.070	4.3
5i	43.13 ± 0.022	50.24 ± 0.014	53.18 ± 0.011	69.85 ± 0.007	5.0
5j	30.08 ± 0.084	42.40 ± 0.084	45.39 ± 0.010	56.09 ± 0.027	4.3
5k	65.13 ± 0.005	64.71 ± 0.021	58.93 ± 0.064	32.38 ± 0.070	ND
5l	82.13 ± 0.005	75.71 ± 0.021	68.93 ± 0.064	62.38 ± 0.070	ND
5m	52.13 ± 0.005	48.71 ± 0.021	43.93 ± 0.064	22.38 ± 0.070	ND
5n	42.13 ± 0.005	34.71 ± 0.021	28.93 ± 0.064	12.38 ± 0.070	ND
Cisplatin	22.38 ± 0.048	44.24 ± 0.040	49.36 ± 0.022	64.17 ± 0.021	25

All results expressed as MEAN ± SD, n=3, cisplatin is used as the standard.

 

The compound 5b showed highest activity 90.88 % inhibition. Replacement of nitro group by 2-methoxy substituent 5c resulted in slight decrease of analgesic activity (86.18%). The compound 5e showed 87.37 % inhibition. The compounds 5d and 5f showed slightly decreased 85.21 % and 85.75 % respectively. The compound 5h showed least activity (64.96 %) compared to other compounds and standard oxaprozin drug. The results indicate that the 2^nd positions in the aromatic ring

 

should be occupied preferably with electron withdrawing groups like nitro. Presence of OCH₃ in other than ortho position also favored the analgesic activity. Substitution with chloro groups in the aromatic ring drastically decreased the biologically activity. In general the presence of 2-nitro, 2-methoxy, 4-nitro, 2-methoxy-5-bromo, 2,5-dimethoxy, 3,4,5-tri methoxy and 4- methyl substituent of thiazolidinone derivatives resulted in high analgesic activity.

 

Table 2. Analgesic activity data of compounds 5a-5j

Compounds	Dose (mg kg-1)	% Inhibition
		30 min	60 min	90 min	120 min
Standard	10	11.92 ± 0.11	32.19 ± 1.04	71.52 ± 0.50	79.28 ± 0.57
5a	10	58.61 ± 0.52	73.20 ± 0.96	84.79 ± 0.90	85.21 ± 0.50
5b	10	64.96 ± 0.80	80.88 ± 0.64	86.06 ± 0.52	90.88 ± 0.76
5c	10	69.53 ± 0.76	81.80 ± 0.50	84.36 ± 0.57	86.18 ± 0.57
5d	10	64.96 ± 0.76	74.68 ± 0.57	81.04 ± 0.76	85.21 ± 0.50
5e	10	58.61 ± 0.90	85.29 ± 0.50	86.97 ± 0.51	87.37 ± 0.60
5f	10	78.30 ± 0.55	80.88 ± 1.53	84.85 ± 0.28	85.75 ± 1.00
5g	10	11.92 ± 1.24	24.21 ± 3.11	82.47 ± 2.64	83.72 ± 1.21
5h	10	12.84 ± 1.02	33.82 ± 1.02	41.92 ± 1.04	64.96 ± 1.38
5i	10	49.42 ± 0.57	74.72 ± 0.76	80.88 ± 0.57	84.80 ± 0.51
5j	10	29.10 ± 1.15	64.68 ± 1.02	75.21 ± 1.25	81.80 ± 0.57

All results expressed as MEAN ± SEM, n=6 in each group, Results are analyzed by student’s t-test, Oxaprozin is used as the standard.

 

 

Figure 2. Analgesic activity of Compounds 5a-5j

 

Anti-inflammatory activity (invivo):

The compounds which showed good analgesic activity (5a-5e and 5i) were further tested for their anti-inflammatory activity by Carrageenan induced paw oedema method of winter et al., at same oral dose as used for the analgesic activity. The compounds showed anti-inflammatory activity ranging from 34.25 % to 100 % inhibition of paw oedema, where as standard drug oxaprozin showed 88.15% inhibition after 2 hr (Table 3). The compound 5b [3-(4,5-diphenyloxazol-2-yl)-N-(2-(2-nitrophenyl)-4-oxothiazolidin-3-yl)propanamide], 5d [N-(2-(2,5-dimethoxyphenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide] and 5e [3-(4,5-diphenyloxazol-2-yl)-N-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)propanamide]showed highest anti-inflammatory activity i.e., 100 % inhibition of paw oedema in comparison to oxaprozin taken as standard (88.15 %). The compound 5c [3-(4,5-diphenyloxazol-2-yl)-N-(2-(2-methoxyphenyl)-4-oxothiazolidin-3-yl)propanamide] showed very least activity 34.25 % and 5a, 5i showed moderate anti-inflammatory activity (49.02 % and 50.65 %) respectively. It is clear that oxaprozin acyl hydrazone derivative which had the substituent like p-nitro, 2,5-dimethoxy, 3,4,5-tri methoxy substituent groups of aldehydes resulted in good anti-inflammatory activity.

 

Table 3. Anti-inflammatory activity data of 5a-5e and 5i

Comp-ound	Dose (mg kg-1)	Increase in paw volume (MEAN ± SEM)	% Inhibition of paw oedema
5a	10	0.102 ± 0.002	49.02
5b	10	0	100
5c	10	0.1 ± 0.0438	34.21
5d	10	0	100
5e	10	0	100
5i	10	0.075 ± 0.0034	50.65
Control	0.1	0.152 ± 0.0031	-
Standard	10	0.018 ± 0.0027	88.15

All results expressed as MEAN±SEM, n=6 in each group, Results are analyzed by student’s t-test

Oxaprozin is used as the standard , CMC= carboxy methyl cellulose as a suspending agent.

 

 

Molecular docking studies:

The compound 5i shows highest binding energy (-8.73, KI 395.78nM) with two amino acid interactions Asp49, Lys273. In Figure 3 illustrates all the synthesized compounds having promising docking results and compound 5a, 5gexhibits binding energy shows -7.32, -7.17 and KI 4.29, 5.58 values interactions with Lys46, Lys20 aminoacids respectively. Almost all the target compounds show good binding energy, Π-Π interactions, vanderwall interactions etc., Figure 3. The hydrogen bonding distance of all the molecules with proteins is less than 2.0 Å. The docking score and interactions of final compounds are against the 2ZCS protein illustrated in Table 4, Figure 3and the order of the docking scoreis 5i > 5a >5g> 5d > 5k >5n ect,. Some of the compounds 5f, 5j does not show binding interactions with any aminoacids.

 

 

 

 

Figure 3. Docked confirmations of compounds with 2ZCS

 

Table 4. Docked confirmations of compounds with 2ZCS – cancer target

S.No	Interacting amino acids	Grid X-Y-Z coordinates	Binding energy ΔG (Kcal/Mol)	Dissociation constant (kI) (µM)
5a	Lys46	56.026, 5.999, 60.238	-7.32	4.29
5b	Asp49	56.026, 5.999, 60.238	-6.39	20.73
5c	His18, Arg171	56.026, 5.999, 60.238	-6.64	13.67
5d	His18, Lys20	56.026, 5.999, 60.238	-7.03	7.02
5e	Lys20, Arg171, Val268, Lys273	56.026, 5.999, 60.238	-6.73	11.59
5f	No Interactions	56.026, 5.999, 60.238	-8.12	1.12
5g	Lys20, Asp49	56.026, 5.999, 60.238	-7.17	5.58
5h	Lys20	56.026, 5.999, 60.238	-6.71	11.96
5i	Asp49, Lys273	56.026, 5.999, 60.238	-8.73	395.78nM
5j	No Interactions	56.026, 5.999, 60.238	-6.25	26.32
5k	Asp49	56.026, 5.999, 60.238	-6.98	7.63
5l	Lys46	56.026, 5.999, 60.238	-6.37	21.48
5m	Lys46, Arg85	56.026, 5.999, 60.238	-6.62	13.96
5n	Lys20, Arg171, Arg265(2)	56.026, 5.999, 60.238	-6.94	8.17

 

 

 

 

 

MATERIALS AND METHODS:

All the chemicals were purchased from SRL-India, Merck, Finar and have been carried forward without further purification. Melting points were determined by open glass capillary method on a Cintex melting point apparatus. IR spectra were recorded on a JASCO FT/IR-5300 in KBr pellets. ¹HNMR spectra were recorded on a Varian 300 MHz spectrometer using CDCl₃ and DMSO as a solvent. Chemical shift (δ) values are presented as singlet (s), doublet (d), triplet (t), quartet (q) or multiplet (m). Mass spectra were recorded on a LC-MSD-Trap-SL instrument in the electrospray ionization (ESI) mode. All the reactions were monitored by TLC on pre-coated silica gel plates (60F 254; Merck). Column chromatography was performed on 100-200 mesh silica gel (SRL, India) using 10-20 fold excess (by weight) of the crude product. The organic extracts were dried over anhydrous sodium sulphate.

 

General procedure for the preparation of title compounds (5a-5n):

Synthesis of methyl 3-(4,5-diphenyloxazol-2-yl)propionate (2):

3-(4,5-diphenyloxazol-2-yl) propanoic acid (oxaprozin) (1) (2.92 g, 0.01 mol) was dissolved in methanol (25 mL) in a 100 mL round bottomed flask and few drops of conc. H₂SO₄ was added. The resulting solution was refluxed for 5 hr. Progress of the reaction was monitored by TLC using ethylacetate : hexane (3:7) as eluent. After completion of the reaction as indicated by TLC, methanol was removed under reduced pressure and the crude product was diluted with ice water and extracted with ethyl acetate (3 X 10 mL). The organic layer was dried over anhydrous sodium sulphate and the solvent was concentrated. The crude product purified by column chromatography with ethylacetate : hexane (1:5 v/v) as eluent. The solid obtained was recrystallized from ethylacetate to afford colorless crystals of compound (2). mp 150-152°C, IR spectrum, ʋ, cm^-1: 3052 (Ar=CH), 2953, 2843 (CH), 1736 (CO), 1583, 1495 (Ar-C=C), 1435 (C=N), 1227 (COC), 1167 (COC). ¹H NMR spectrum, δ, ppm: 2.93 t (2H, J = 6.0, CH₂), 3.20 t (2H, J = 6.0, CH₂), 3.74 s  (3H, OCH₃), 7.26-7.38 m (6H, ArH), 7.56-7.64 dd (4H, J = 6.3, ArH). M308.

 

Synthesis of 3-(4,5-diphenyloxazol-2-yl)propanehydrazide (3):

Compound 2 (3.07 g, 0.01 mol) was taken in a 100 mL RB flask followed by the addition of methanol (30 mL) to obtain clear solution. To the resulting solution hydrazine hydrate (3 mL, 0.06 mol) was added drop wise and refluxed for 7 hr. Progress of the reaction was monitored by TLC using ethylacetate : hexane (3:7) as eluent. After the completion of the reaction, methanol was distilled off and the reaction mass was diluted with cooled water and extracted with chloroform (3 X 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford crude mass and has been purified by column chromatography to afford the compound as light yellow crystalline solid. mp 166-168 °C; IR spectrum, ʋ, cm^-1: 3484 (NH), 3282 (NH), 3057 (=CH), 1654 (CO), 1610, 1435 (ArC=C), 1210 (C=N), 1057 (COC); ¹H NMR spectrum, δ, ppm: 2.73 t (2H, J = 6.0, CH₂), 3.20 t (2H, J = 6.3, CH₂), 4.72 s (1H, NH, D₂O exchange), 4.77 s (2H, NH₂, D₂O exchange) 7.26-7.38 m (6H, ArH), 7.54-7.65 dd (4H, J = 6.3, J = 6.0, ArH). M308.

 

Synthesis of schiff bases (4a-4n):

Compound 3 (0.307 g, 0.001 mol) was dissolved in 10 mL of ethanol in a 25 mL round bottomed flask. To the resulting solution 3-bromo benzaldehyde(substituted aromatic corbonyl compounds)(0.185 g, 0.001 mol) was added and stirred at rt for 5 hr. Progress of the reaction was monitored by TLC using ethylacetate : hexane (4 : 6) as eluent. After the completion of the reaction, methanol was removed by distillation. The obtained crude product was diluted with water, the resulting precipitate was filtered and then dried, followed by recrystallisation in hot ethanol to furnish colorless N'-(3-bromobenzylidene)-3-(4,5-diphenyloxazol-2-yl)propanehydrazide(4a).yield 69 %, mp 149-150 ° C;

 

General synthetic procedure for the target compounds (5a-5n):

Compound 4a (0.5 g, 1 mmol) was dissolved in dry THF (10 mL) at ambient temperature. Then, a solution of the corresponding thioglycolic acid (0.05 mmol), a pinch of anhydrous ZnCl₂ was added. The mixture was refluxed for 6 hr, cooled to room temperature and it was poured into crushed ice. The solid material was filtered off, neutralized with distilled water, dried in the air, and recrystallized from hot methanol. The reaction was monitored on TLC on silica gel using EtOAC to Hexane (2:8). Combined organic layers were dried over sodium sulphate and concentrated under pressure followed by purification with column chromatography technique employing 60-120 silica gel mesh, eluted by 10% MeOH/CHCl₃ to afford the desired compound N-(2-(3-bromophenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide (5a) Other oxoprocin 4-thiazolidinone derivatives have been prepared by the same method.

 

Yield 68%, mp 140-141 °C. IR spectrum, ʋ, cm^-1: 3462 (NH), 3057 (=CH), 2964, 2909 (CH), 1660 (CO), 1572, 1402 (ArC=C), 1358 (C=N), 1265 (CSC), 1216 (COC). ¹H NMR spectrum, δ, ppm: 2.72 t (2H, J = 7.5, CH₂CH₂), 3.25 t (2H, J = 7.5, CH₂CH₂), 3.94 s (2H, SCH₂), 4.50 s (1H, NCH), 6.90 d (2H, J = 7.0, ArH), 7.12 m (3H, ArH), 7.43 d (1H, J = 7.2, ArH), 7.75 dd (3H, J = 6.4, 5.6, ArH), 8.12-8.20 m (2H, ArH), 8.31 d (2H, J = 7.0, ArH), 8.51 d (1H, J = 6.5, ArH), 8.62 s (1H, CONH); ¹³C NMR spectrum, δC, ppm: 14.5, 18.8,  26.7, 30.1, 113.6, 115.9, 119.4, 122.7, 123.0, 128.7, 130.5, 135.2, 139.8, 144.9, 147.1, 149.7, 155.3, 188.3, 170.2, 183.3; LC-MS549 [M+1]⁺. Found, %: C, 59.84; H, 4.95; Br, 15.02; N, 8.02; S, 5.72. C27H22BrN3O3S. Calculated, %: C, 59.13; H, 4.04; Br, 14.57; N, 7.66; S, 5.85. M548.

 

3-(4,5-diphenyloxazol-2-yl)-N-(2-(2-nitrophenyl)-4-oxothiazolidin-3-yl)propanamide (5b):

Yield 72 %, mp 147-148 °C. IR spectrum, ʋ, cm^-1: 3451 (NH), 3019 (=CH), 2914 (CH), 1660 (CO), 1523 (ArC=C), 1435 (C=N), 1353 (CSC), 1249 (COC), 1172, 1068. ¹H NMR spectrum, δ, ppm: 3.26 t (2H, J = 7.5, CH₂CH₂), 3.40 t (2H, J = 7.5, CH₂CH₂), 3.96 s (2H, SCH₂), 4.53 s (1H, NCH), 7.30-7.39 m (6H, ArH), 7.51 d (1H, J = 8.3, ArH), 7.53-7.65 m (5H, ArH), 8.03 d (1H, J = 8.3, ArH), 8.10 d (1H, J = 6.7, ArH), 9.27 s (1H, CONH). ¹³C NMR spectrum, δC, ppm: 23.0, 30.0, 124.8, 126.4, 127.8,127.9, 128.0,128.4, 128.6, 128.7, 128.8, 129.0,129.3, 130.2,132.5, 133.4, 135.1, 138.8, 145.4, 148.0, 162.2, 173.6. Found, %: C, 63.82; H, 4.88; N, 11.09; S, 6.88. C27H22N4O5S. Calculated, %: C, 63.02; H, 4.31; N, 10.89; S, 6.23. M515.

3-(4,5-diphenyloxazol-2-yl)-N-(2-(2-methoxyphenyl)-4-oxothiazolidin-3-yl)propanamide (5c):

Yield 72 %, mp 160-161 °C. IR spectrum, ʋ, cm^-1: 3440 (NH), 3068 (=CH), 2947, 2838 (CH), 1665 (CO), 1599, 1435.5 (ArC=C), 1380.7 (C=N), 1342.4 (CSC), 1254.7 (COC). ¹H NMR spectrum, δ, ppm: 3.27 t (2H, J = 7.5, CH₂CH₂), 3.38 t (2H, J = 7.5, CH₂CH₂), 3.85 s (3H, OCH₃), 3.96 s (2H, SCH₂), 4.51 s (1H, NCH), 6.90 d (1H, J = 7.9, ArH), 6.95 t (1H, J = 7.9, 6.9, ArH), 7.28-7.39 m ( 7H, ArH), 7.57 d (2H, J = 5.9, ArH), 7.63 d (2H, J = 6.9, ArH), 7.91 d (1H, J = 7.9, ArH), 8.71 s ( 1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 30.1, 55.5, 111.0, 120.9, 122.0, 126.3, 126.4, 127.9, 127.9, 128.3, 128.5, 128.5, 128.6, 129.1, 131.4, 132.6, 139.6, 145.3, 157.9, 162.4, 173.3. Found, %: C, 68.12; H, 5.54; N, 8.91; S, 6.82. C28H25N3O4S. Calculated, %: C, 67.32; H, 5.04; N, 8.41; S, 6.42. M500.

 

N-(2-(2,5-dimethoxyphenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide (5d):

Yield 78 %, mp 169-170°C. IR spectrum, ʋ, cm^-1: 3440 (NH), 3068 (=CH), 2947, 2838 (CH), 1665 (CO), 1599, 1435 (ArC=C), 1342 (C=N), 1254 (CSC), 1139 (COC). ¹H NMR spectrum, δ, ppm: 3.26 t (J = 7.5, 2H, CH₂CH₂), 3.40 t (J = 7.5, 2H, CH₂CH₂), 3.76 s (3H, OCH₃), 3.81 s (3H, OCH₃), 3.92 s (2H, SCH₂), 4.65 s (1H, NCH), 6.84 d (1H, J = 7.9, ArH), 6.91 dd (1H, J = 3.0, ArH), 7.28-7.40 m (6H, ArH), 7.43 d (1H, J = 3.0, ArH), 7.60 dd (4H, J = 8.1, 5.2, ArH), 8.73 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 30.1, 55.5,56.1,  111.0, 120.9, 122.5, 126.3, 126.4, 127.9, 128.3,128.4, 128.6, 129.1,131.4, 132.6, 139.5, 145.3, 157.9, 162.2, 173.4. Found, %: C, 66.17; H, 5.94; N, 8.13; S, 6.85. C29H27N3O5S. Calculated, %: C, 65.77; H, 5.14; N, 7.93; S, 6.05. M530.

 

3-(4,5-diphenyloxazol-2-yl)-N-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)propanamide (5e):

Yield 75%, mp 178-179°C. IR spectrum, ʋ, cm^-1: 3441 (NH), 3068 (=CH), 2947, 2838 (CH), 1665 (CO), 1599, 1435 (ArC=C), 1380 (C=N), 1254 (CSC), 1139 (COC). ¹H NMR spectrum, δ, ppm: 3.26 t (2H, J = 7.5, CH₂CH₂), 3.42 t (2H, J = 7.5, CH₂CH₂), 3.66 s (2H, SCH₂), 3.86 s (9H, OCH₃), 4.68 s (1H, NCH), 6.87 s (2H, ArH), 7.30-7.40 m (6H, ArH), 7.58 dd (4H, J = 9.8, 7.5, ArH), 9.42 s  (1H,  O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 29.9, 56.0, 56.1, 60.8, 104.2, 104.6,126.3, 127.7, 127.8, 128.0, 128.3, 128.4, 128.5, 128.6, 128.9, 129.0,132.3, 135.0, 139.8, 144.1, 145.3, 153.3, 162.3, 174.2. Found, %: C, 64.80; H, 5.72; N, 7.91; S, 5.92. C30H29N3O6S. Calculated, %: C, 64.39; H, 5.22; N, 7.51; S, 5.73. M560.

 

3-(4,5-diphenyloxazol-2-yl)-N-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)propanamide (5f):

Yield 67 %, mp 152-153 °C. IR spectrum, ʋ, cm^-1: 3177 (NH), 3051 (=CH), 2958, 2909 (CH), 1671 (CO), 1610, 1408 (ArC=C), 1271 (C=N), 1216 (CSC), 1062 (COC). ¹H NMR spectrum, δ, ppm: 2.36 s (3H, CH₃), 3.26 t (2H, J = 7.5, CH₂CH₂), 3.40 t (2H, J = 7.5, CH₂CH₂), 3.66 s (2H, SCH₂), 4.53 s (1H, NCH), 7.15 d (2H, J = 6.9, ArH), 7.27-7.40 m (7H, ArH), 7.50-7.65 m (5H, ArH), 9.46 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 21.5, 23.2, 30.0, 126.4, 127.2, 127.9, 128.3, 128.5, 128.6,128.7, 129.4, 130.6, 132.5, 135.1, 140.4, 144.1, 145.3, 162.4, 174.0. Found, %: C, 67.82; H, 5.54; N, 8.81; S, 6.92. C28H25N3O4S. Calculated, %: C, 67.32; H, 5.04; N, 8.41; S, 6.42. M500.

 

3-(4,5-diphenyloxazol-2-yl)-N-(2-(4-hydroxy-3-methoxyphenyl)-4-oxothiazolidin-3-yl)propanamide (5g):

Yield 73%, mp 182-183 °C. IR spectrum, ʋ, cm^-1: 3512 (NH), 3009 (=CH), 2924, 2845 (CH), 1655 (CO), 1649, 1512 (ArC=C), 1429 (C=N), 1280 (CSC), 1174 (COC). ¹H NMR spectrum, δ, ppm: 3.26 t (2H, J = 7.5, CH₂CH₂), 3.40 t (2H, J = 7.5, CH₂CH₂), 3.26 s (3H, OCH₃), 3.68 s (2H, SCH₂), 4.59 s (1H, NCH), 5.45 s (1H, OH), 7.15 d (2H, J = 6.9, ArH), 7.27-7.40 m (6H, ArH), 7.50-7.65 m (5H, ArH), 9.46 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 30.1, 55.5, 111.0, 120.9, 122.0, 126.3, 126.4, 127.9, 128.3, 128.5, 128.6, 128.6, 129.1, 131.8, 132.6, 139.6, 145.3, 157.9, 162.4, 173.3. Found, %: C, 65.83; H, 4.99; N, 8.85; S, 6.82. C28H25N3O5S. Calculated, %: C, 65.23; H, 4.89; N, 8.15; S, 6.22. M515.

 

 

N-(2-(2,6-dichlorophenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide (5h):

Yield 70 %, mp 150-151°C. IR spectrum, ʋ, cm^-1: 3319 (NH), 3059 (=CH), 2972, 2920 (CH), 1678 (CO), 1604, 1579, 1554 (ArC=C), 1417 (C=N), 1134 (CSC), 1057 (COC). ¹H NMR spectrum, δ, ppm:3.25 t (2H, J = 7.5, CH₂CH₂), 3.40 t (2H, J = 7.5, CH₂CH₂), 3.66 s (2H, SCH₂), 4.53 s (1H, NCH), 7.30-7.40 m (9H, ArH), 7.60-7.72 m (4H, ArH), 9.23 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.0, 29.9, 30.3, 126.3, 127.8, 128.2, 128.4, 128.5, 128.6, 129.0, 129.5, 130.0, 132.4, 135.0, 138.6, 145.2, 162.2, 174.3. Found, %: C, 60.83; H, 3.98; Cl, 13.67; N, 7.98; S, 6.00. C27H21Cl2N3O3S. Calculated, %: C, 60.23; H, 3.93; Cl, 13.17; N, 7.80; S, 5.96. M 537.

 

3-(4,5-diphenyloxazol-2-yl)-N-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)propanamide (5i):

Yield 82 %, mp 170-171 °C. IR spectrum, ʋ, cm^-1: 3470 (NH), 3061 (=CH), 2964, 2928 (CH), 2852, 1674 (CO), 1585, 1523 (ArC=C), 1421 (C=N), 1145 (CSC), 1105 (COC). ¹H NMR spectrum, δ, ppm: 3.28 t (2H, J = 7.5, CH₂CH₂), 3.41 t (2H, J = 7.5, CH₂CH₂), 3.88 s (2H, SCH₂), 4.23 s (1H, NCH), 7.28-7.37 m (6H, ArH), 7.58 dd (4H, J = 6.9, 5.9, ArH), 7.76 d (2H, J = 7.9, ArH), 8.18 d (2H, J= 8.9, ArH), 9.81 s (1H,  O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 29.9, 126.9, 126.3, 127.7, 127.8, 128.1, 128.5, 128.6, 128.9, 132.3, 135.1, 139.6, 141.6, 145.4, 148.3, 162.1, 175.0.  Found, %: C, 63.92; H, 4.81; N, 11.02; S, 6.63. C27H22N4O5S. Calculated, %: C, 63.02; H, 4.31; N, 10.89; S, 6.23. M 514.

 

N-(2-(5-bromo-2-methoxyphenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide (5j):

Yield 70 %, mp160-161°C. IR spectrum, ʋ, cm^-1: 3244 (NH), 3051 (=CH), 2964, 2852 (CH), 1693 (CO), 1568, 1537 (ArC=C), 1433 (C=N), 1259 (CSC), 1176 (COC). ¹H NMR spectrum, δ, ppm: 3.24 t (2H, J = 7.5, CH₂CH₂), 3.40 t (2H, J = 7.5, CH₂CH₂), 3.82 s (3H, OCH₃), 3.96 s (2H, SCH₂), 4.53 s (1H, NCH), 6.77 d (1H, J = 8.87, ArH), 7.27-7.36 m (7H, ArH), 7.60 dd (4H, J = 9.2, 6.5, ArH), 7.98 d (1H, J = 2.6, ArH), 9.07 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.0, 29.8, 55.7, 112.7, 113.3, 124.0, 126.4, 127.9, 127.9, 128.1, 128.2, 128.4, 128.5, 128.6, 128.9, 132.4,  133.6, 138.5, 156.8, 173.8. Found, %: C, 59.04; H, 4.78; Br, 13.92; N, 7.86; S, 5.94 C28H24BrN3O4S. Calculated, %: C, 58.14; H, 4.18; Br, 13.81; N, 7.26; S, 5.54. M578.

 

N-(2-(2,5-dichlorophenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide (5k):

Yield 68 %, mp 153-154°C. IR spectrum, ʋ, cm^-1: 3219 (NH), 3042 (=CH), 2970, 2921 (CH), 1677 (CO), 1603, 1578, 1555 (ArC=C), 1414 (C=N), 1134 (CSC), 1057 (COC). ¹H NMR spectrum, δ, ppm: 3.24 t (2H, J = 7.5, CH₂CH₂), 3.41 t (2H, J = 7.5, CH₂CH₂), 3.72 s (2H, SCH₂), 4.51 s (1H, NCH), 7.32-7.41 m (9H, ArH), 7.61-7.74 m (4H, ArH), 9.20 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.0, 29.9, 126.3, 127.8, 128.2, 128.4, 128.2, 128.6, 129.0, 129.5, 130.1, 132.5, 135.0, 138.7, 145.2, 162.2, 174.3. Found, %: C, 61.02; H, 4.04; Cl, 13.87; N, 7.88; S, 5.99. C27H21Cl2N3O3S. Calculated, %: C, 60.23; H, 3.93; Cl, 13.17; N, 7.80; S, 5.96. M539.

 

N-(2-(4-bromophenyl)-4-oxothiazolidin-3-yl)-3-(4,5-diphenyloxazol-2-yl)propanamide (5l):

Yield 70 %, mp 152-153°C. IR spectrum, ʋ, cm^-1: 3462 (NH), 3183, 3057 (=CH), 2964, 2909 (CH), 1660 (CO), 1572, 1402 (ArC=C), 1358 (C=N), 1265 (CSC), 1216 (COC). ¹H NMR spectrum, δ, ppm: 3.25 t (2H, J = 7.5, CH₂CH₂), 3.42 t (2H, J = 7.5, CH₂CH₂), 3.66 s (2H, SCH₂), 4.53 s (1H, NCH), 7.23 t (1H, J = 7.8, 7.6, ArH), 7.30-7.40 m (6H, ArH), 7.50 t (2H, J = 8.3, 7.5, ArH), 7.60 dd (4H, J = 6.6, 5.4, ArH), 7.76 s (1H, ArH), 10.09 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 29.9, 122.9, 125.9, 126.4, 127.9, 128.0,128.4, 128.5, 128.6, 128.7, 129.0,129.7, 130.2, 132.5, 132.9,135.2, 135.7,142.3, 145.3, 162.3, 174.3. Found, %: C, 60.13; H, 4.94; Br, 14.90; N, 8.26; S, 5.90. C27H22BrN3O3S. Calculated, %: C, 59.13; H, 4.04; Br, 14.57; N, 7.66; S, 5.85. M547.

3-(4,5-diphenyloxazol-2-yl)-N-(2-(3-nitrophenyl)-4-oxothiazolidin-3-yl)propanamide (5m):

Yield 80%, mp 149-150°C. IR spectrum, ʋ, cm^-1: 3452 (NH), 3198, 3020 (=CH), 2914 (CH), 1660 (CO), 1523, 1523, 1435 (ArC=C), 1353 (C=N), 1249 (CSC), 1172 (COC). ¹H NMR spectrum, δ, ppm: 3.25 t (2H, J = 7.5, CH₂CH₂), 3.40 t (2H, J = 7.5, CH₂CH₂), 3.84 s (2H, SCH₂), 4.68 s (1H, NCH), 7.32-7.38 m (6H, ArH), 7.50 d (1H, J = 8.2, ArH), 7.52-7.63 m (5H, ArH), 8.02 d (1H, J = 8.5, ArH), 8.12 d (1H, J = 6.6, ArH), 9.28 s (1H, O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.0, 30.0, 124.8, 126.4, 127.8,127.9, 128.0,128.5, 128.6, 128.7, 128.8, 129.0,129.3, 130.2,132.5, 133.4, 135.1, 138.8, 145.4, 148.1, 162.2, 173.6. Found, %: C, 63.79; H, 4.92; N, 11.39; S, 6.20. C27H22N4O5S. Calculated, %: C, 63.02; H, 4.31; N, 10.89; S, 6.23. M515.

 

3-(4,5-diphenyloxazol-2-yl)-N-(2-(3-methoxyphenyl)-4-oxothiazolidin-3-yl)propanamide (5n):

Yield 75 %, mp 162-163°C. IR spectrum, ʋ, cm^-1: 3440 (NH), 3068 (=CH), 2947, 2838 (CH), 1665 (CO), 1599, 1435 (ArC=C), 1380 (C=N), 1342 (CSC), 1254 (COC). ¹H NMR spectrum, δ, ppm: 3.29 t (2H, J = 7.5, CH₂CH₂), 3.39 t (2H, J = 7.5, CH₂CH₂), 3.66 s (2H, SCH₂), 3.86 s (3H, OCH₃), 4.58 s (1H, NCH), 6.90 d (1H, J = 7.8, ArH), 6.96 t (1H, J = 7.6, 6.9, ArH), 7.28-7.39 m (7H, ArH), 7.55 d (2H, J = 5.9, ArH), 7.63 d (2H, J = 6.6, ArH), 7.91 d (1H, J = 7.7, ArH), 8.71 s (1H,  O=C-NH). ¹³C NMR spectrum, δC, ppm: 23.1, 30.1, 55.5, 112.0, 121.0, 122.0, 126.3, 126.5, 127.0, 127.9, 128.3, 128.5, 128.6, 129.1,131.4, 132.6, 139.5, 145.3, 158.0, 162.5, 173.3. Found, %: C, C, 67.90; H, 5.46; N, 8.49; S, 6.48. C28H25N3O4S. Calculated, %: C, 67.32; H, 5.04; N, 8.41; S, 6.42. M499.

 

Anticancer activity (invitro) of test compounds:

All fine chemicals/reagents used in this study were of cell culture grade and obtained from Sigma-Aldrich, Merck. Human colon cancer cell line (HCT-15) was obtained from National Centre for Cell Science, Pune, India. The cells were grown in DMEM (Dulbecco’s Modified Eagler Medium) culture medium supplemented with 2 mM L-glutamine, 10 % FBS (Foetal Bovine Serum), pencillin (50 IU mL^-1) and streptomycin (50 µg mL^-1) at a temperature of 37 °C in a humidified incubator with a 5 % CO₂ atmosphere and passaged twice weekly to maintain a sub confluent state.

 

The viability of the cells was assessed by MTT ((3,4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay[17].This is based on the reduction of MTT by the mitochondrial dehydrogenase of intact cells to a purple formazan product is platina known anticancer drug was used as a reference compounds in the assay [18]. Cells (1 x 10⁴) were placed in a 96-well plate. After 24 hr, they were treated with different concentration (2.0-25 µg mL^-1) of different test compounds diluted appropriately with culture media for 48 hr. Cells grown in media containing equivalent amount of DMSO served as positive control and cells in medium without any supplementation were used as negative control. After the treatment, media containing compound were carefully removed by aspiration. 100 µL of DMSO was added to each well and kept in an incubator for 4 hr for dissolution of the formed formazan crystals. Amount of formazan was determined by measuring the absorbance at 540 nm using an ELISA plate reader. The data were presented as percent of dead cells, whereas absorbance from non-treated control cells was defined as 100 % live cells.

 

Anti-inflammatory activities (invivo) of test compounds:

The anti-inflammatory activity of synthesized compounds were screened by Carrageenan induced paw oedema method [19, 20]. Female Swiss albino mice weighing 20 g to 30 g were used for the experiment. They were housed in the clean polypropylene cages and kept under room temperature (25 ⁰C), relative humidity (60-70 %) in 12 hr of light dark cycle. The animals were given standard laboratory diet and water ad labium. Food was withdrawn 12 hr before and during experimental hrs.

 

Swiss albino mice divided into eight groups with each group containing six animals. A mark was made on the right hind paw just below the tibiatarsal junction. So that every time the paw was dipped in the mercury column up to fixed mark to ensure constant paw volume, the initial paw volume of each mice was noted by plethysmometrically. The group I was kept as control and received only 0.5 % carboxy methyl cellulose (CMC) solution. Group II was kept as standard and received oxaprozin (10 mg kg^-1 po). Group III to VIII were kept as test and received test compounds of a dose 10 mg kg^-1 (suspended in 0.5 % CMC given p.o). Carrageenan solution (0.1 % in sterile 0.9 % NaCl solution) in a volume of 0.1 mL was injected subcutaneously into the sub-plantar region of the right hind paw of each mice. 2 hr after the administration of the test compounds and standard drug. The right hind paw volume was measured by means of a plethysmometer. The percentage inhibition by the drugs was calculated according to the following formula.

 

Percentage of paw oedema inhibition = 100-V_T /V_C) X 100

Where

V_C = volume of paw edema in control group

V_T = volume of paw edema inthe treated group with test compounds

 

The results were expressed as % inhibition of oedema over the untreated control group.

 

Analgesic activity (invivo) of the test compounds:

Analgesic activity was carried out by Eddy’s Hot Plate Method using Female swiss albino mice of weighing 20 g to 30 g [21, 22]. In this method heat is used to induce pain. Animals are individually placed on a hot plate maintained at constant temperature (55 ± 1°C) and the reaction of animals, such as licking of the paw or jump response is taken as the end point. Swiss albino mice are divided into twelve groups with each group containing six animals [23]. Group I was kept as control, group II was kept as standard and group III to XII were kept as test and analgesic activity was evaluated after oral administration of the test compounds. The test compounds and standard drug are administered orally at the dose of 10 mg kg^-1 body weight, as suspension in 0.5 % CMC (Carboxy Methyl Cellulose) solution. The analgesic activity was observed as the reaction time of animals at 30 min, 60 min, 90 min and 120 min after compound administration. The percentage analgesic activity shown by the tested compounds is presented.

 

Molecular docking studies:

The ligands were sketched in Sybyl 6.7 and saved it in .mol2 format [24].All the sketched molecules were converted to energy minimized 3D structures by using Gasteiger-Huckel charges[25] for in silico protein–ligand docking using AutoDock Tools. Each molecule was docked separately. Initially the molecule was loaded, torsions were set and saved it in PDBQT format. All the heteroatoms were removed from the 2ZCS.PDB (Crystal structure of the C(30) carotenoid dehydrosqualene synthase from staphylococcus aureus complexed with bisphosphonate BPH-700) [26], to make complex receptor free of any ligand before docking [27]. The PDB was also saved in PDBQT format. All calculations for protein-ligand flexible docking were performed using the Lamarckian Genetic Algorithm (LGA) method. A grid box with the dimensions of X: 56.026, Y: 5.999 and Z: 60.238 Å, with a default grid spacing of 0.375 Å was used. The best conformation was chosen with the lowest docked energy [28],after the docking search was completed. The interactions of 2ZCS protein and ligand conformations, including hydrogen bonds and the bond lengths were analyzed.

 

Molecular docking study was performed by using AUTODOCK 4.2 which was a suite of automated docking tools and was used to predict the affinity, activity, binding orientation of ligand with the target protein and to analyze best conformations [29],the protein with all the 14 compounds were loaded individually into ADT and evaluate ten finest conformations. In the present investigation we focused mainly on the binding energy, hydrogen bonds, and distance between the protein and ligand. 

 

CONCLUSIONS:

In conclusion, we have described the synthesis, invitro and invivo pharmacological properties of a number of acyl hydrazone derivatives of oxaprozin a well known NSAIDS. All compounds were found to be active when tested against human colon cancer (HCT-15) cell line invitro and all the compounds exhibited more potent cytotoxic activity compared to reference compound cisplatin. In vivo studies, many of them exhibited potent analgesic and anti inflammatory activity compared to reference compound oxaprozin. Among these 5b, 5d and 5e presented maximum anti inflammatory, analgesic and anticancer activity. The docking analysis indicated the importance of hotspots (Lys46, Lys20, Arg171) within the 2ZCSbinding pocket, such as compounds5i, 5a, 5g, 5d, 5k and 5n showed highest binding energy. In conclusion, the synthesized hydrazones NO/hybrids offer promising GIT-friendly substitute to conventional NSAIDs and should be considered as future goal for medicinal chemists working in the area of anticancer, antioxidant and anti-inflammatory agents.

 

ACKNOWLEDGEMENTS:

One of the authors (KKV) is thankful to our Research Supervisor Dr. I. V. Kasi Viswanath for providing us required facilities and motivation for completion of the research work. We also extend our gratitude towards Department of Chemistry, KL University.

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Received on 26.02.2018         Modified on 03.04.2018

Accepted on 09.04.2018         © AJRC All right reserved