Synthesis of methanesulphonamido-benzimidazole derivatives as gastro-sparing antiinflammatory agents with antioxidant effect

Bioorganic & Medicinal Chemistry Letters 27 (2017) 3007–3013

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Synthesis of methanesulphonamido-benzimidazole derivatives as gastro-sparing antiinflammatory agents with antioxidant effect Ratika Sharma, Alka Bali ⇑, Bhim Bahadur Chaudhari University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab University, Chandigarh 160014, India

a r t i c l e

i n f o

Article history: Received 24 February 2017 Revised 12 April 2017 Accepted 5 May 2017 Available online 6 May 2017 Keywords: Anti-inflammatory activity Benzimidazole Carrageenan-induced paw edema Similarity studies Methanesulphonamide Non-ulcerogenic

a b s t r a c t A series of 5-methanesulphonamido benzimidazole derivatives were designed by combining the structural features of clinically useful anti-inflammatory drugs (nimesulide and rofecoxib) and antiulcer drugs (lansoprazole, omeprazole, etc.) based on physicochemical and 3D similarity studies. The compounds were evaluated for their anti-inflammatory activity in carrageenan induced rat paw edema model taking rofecoxib and indomethacin as standard drugs. In vitro antioxidant activity of the compounds was assessed by potassium ferricyanide reducing power (PFRAP) assay. The compounds 9, 10 and 11 showed anti-inflammatory activity comparable to the standard group and were also non-ulcerogenic at the test doses. Compounds 6–11 exhibited good antioxidant effect in the concentration range (1.0–50.0 mmol/ml. Preliminary theoretical ADME profiling of the compounds based on computation of selected physicochemical properties showed an excellent compliance with Lipinski’s rule. Ó 2017 Elsevier Ltd. All rights reserved.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are accepted as a keystone in the treatment of inflammatory diseases and possess anti-inflammatory, antipyretic, and analgesic effects. These are the most widely used medications worldwide for their anti-inflammatory, antipyretic, and analgesic effects1 and are prescribed as first choice in the treatment of various rheumatic disorders and other degenerative inflammatory joint diseases. These are also used for some distinct indications in paediatrics such as Kawasaki disease, Patent Ductus Arteriosus (PDA) closure, and Juvenile Idiopathic Arthritis (JIA).2 The important mediators of inflammation3,4 accounting for the characteristic vasodilation and erythema at the site of inflammation include the prostaglandins PGE25, PGD26 and PGI27 which are produced via arachidonic acid metabolism. NSAIDs cause inhibition of the enzyme cyclooxygenase resulting in disruption of the biosynthesis of prostaglandins (PGE2, PGD2 and PGI2) and thromboxanes.8 Although NSAIDs are generally well tolerated agents, but their chronic use has been associated with several undesirable side effects including gastrointestinal PUB (perforation, ulceration and bleeding), dyspepsia9 and renal toxicity.10 The strategic designing of the inhibitors of the inducible form of cyclooxygenase enzyme (selective COX-2 inhibitors)11 has yielded several new generation anti-inflammatory drugs with improved gastric and renal tolerance. However, several of these agents had to face an early withdrawal from the market in many ⇑ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Bali). http://dx.doi.org/10.1016/j.bmcl.2017.05.017 0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.

countries on cardiotoxicity (rofecoxib, valdecoxib, parecoxib) and hepatotoxicity (nimesulide and more recently, lumiracoxib) concerns.12,13 The local generation of reactive oxygen species is known to play an important role in the gastric ulceration associated with conventional NSAIDs therapy14 and could be possibly involved in cardiovascular complications of coxibs.15 Radical scavenging antioxidant activities of some benzimidazole derivatives have been recently investigated.16 Hence, anti-inflammatory molecules with reducing (antioxidant) potential should exhibit lower gastrointestinal toxicity.17 In this context, the present work describes the design and synthesis of a novel class of benzimidazole derivatives, investigation of their anti-inflammatory activity, antioxidant and ulcerogenic potential. Benzimidazole nucleus is the parent nucleus present in clinically useful antiulcer agents (proton pump inhibitors PPIs) such as omeprazole, lansoprazole, rabeprazole and pantoprazole and several synthetic routes are reported in literature for preparation of benzimidazole derivatives.18,19 Hence, the present work was envisaged to explore the benzimidazole nucleus for developing anti-inflammatory compounds with the underlying hypothesis that these should potentially retain gastric tolerability of this nucleus. Compound 4a (Fig. 1), a butyl phenyl ether derivative had emerged as a representative lead compound from our recently reported series of 3-alkoxy-4-methanesulfonamido acetophenone based anti-inflammatory agents lacking gastrointestinal toxicity.20 A benzimidazole core was envisaged as a probable replacement for the phenyl alkyl ether moiety in 4a (or nimesulide) with the

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CH3

Br CF3

O

N N

N N

NHSO 2CH3 O

CF3

O

COCH3 SO2NH2

SO2NH2

SO2CH3

4a

SC-558

Celecoxib

Rofecoxib

CH3

NHSO 2CH3 NHSO2CH3 O

NHSO2CH3 O

F NO2

NHSO 2CH3

N F

N

O Flosulide

Nimesulide

10

Fig. 1. Chemical structures of gastro-sparing anti-inflammatory agents.

50% shape similarity to derive overall similarity. Design strategy showing the benzimidazole group borrowed from the PPIs replacing the central aryloxy/substituted groups in nimesulide/rofecoxib (retaining the methanesulphonamido function) is depicted in Fig. 2. Chemical structures of the prepared compounds are shown in Table 1 and the various descriptors for physicochemical similarity studies are shown as Table S1 (supplementary data). The results for the similarity studies of the designed compounds with respect to 4a and the standard drugs are shown in Tables 2 and 3. Excellent physicochemical and 3D similarity values were obtained for compounds 2 to 11 with respect to 4a, as well as the standard drugs. The tanimoto coefficient for the proposed compounds 2 to 11 ranged from 0.756 to 0.991 (Table 2) and 3D similarity ranged from 0.671 to 0.858 (Table 3) indicating that inclusion of benzimidazole parent nucleus afforded very good structural similarity to the standard drugs which should possibly translate to their pharmacological profiles also. Fig. 3 shows near perfect alignment of compound 10 with nimesulide.

underlying hypothesis that the designed series of compounds would have a combined anti-inflammatory effect and GI tolerability. The present series of methanesulphonamido-substituted benzimidazole derivatives was designed based on physicochemical similarity (descriptor-based; tanimoto association coefficient) and 3D similarity studies (based on assessment of field similarity and shape similarity) with respect to 4a and clinically useful gastro-sparing anti-inflammatory agents including diaryl substituted heterocycles/carbocycles (like celecoxib and rofecoxib) and methanesulfonyl substituted aryl ethers/thioethers represented by nimesulide and flosulide (Fig. 1). The computational studies were carried out using Dell XPS L502X, (Core i7; 6 GB RAM) running on Windows 10Ò. Three dimensional similarity studies were carried out with Forge V10TM (10.4.2 Revision 248766; evaluation version) (Cresset BioMolecular Discovery Ltd.). The standard drugs (reference molecules) in a defined 3D conformation generated using Chem3D 15.1 and energy minimized with MM2 force field to minimum RMS gradient of 0.100 were imported to Forge V10TM in .sdf (MDL file) format. Default settings were employed and standard scoring function was used based on 50% field similarity and

NHSO 2CH3 O

H3C-O 2S-HN

NO2

N

O

N

O H3CO 2S

Nimesulide (Anti-inflammatory)

9-11

Rofecoxib (Anti-inflammatory)

R CH3

H N N

N

OCH3

H N

S H2C O

CF3

N

Lansoprazole (Anti-ulcer)

H3CO

Omeprazole (Anti-ulcer)

N S O

OCH3 CH3

H N N

N

N S O

OCH3 CH3

Ilaprazole (Anti-ulcer)

Fig. 2. Design strategy for compounds 9–11: Benzimidazole nucleus from antiulcer drugs lansoprazole, omeprazole and ilaprazole coupled with methanesulphonamido function similar to anti-inflammatory agents nimesulide and rofecoxib.

R. Sharma et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 3007–3013

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Table 1 Chemical structures of the synthesized compounds.

R1

N N R2

Compound No.

R1

R2

1 2 3 4 5 6 7 8 9 10 11

-H -NO2 -NO2 -NO2 -NO2 -NH2 -NH2 -NH2 -NHSO2CH3 -NHSO2CH3 -NHSO2CH3

-H -H -C4H9 -C5H11 -C6H13 -C4H9 -C5H11 -C6H13 -C4H9 -C5H11 -C6H13

Table 2 Tanimoto similarity studies of test compounds with standard drugs. Compounds

Nimesulide

Rofecoxib

Celecoxib

Flosulide

1 2 3 4 5 6 7 8 9 10 11

0.751 0.811 0.924 0.968 0.935 0.858 0.894 0.899 0.991 0.949 0.942

0.742 0.796 0.896 0.934 0.902 0.837 0.869 0.870 0.971 0.983 0.984

0.722 0.756 0.820 0.844 0.850 0.782 0.803 0.805 0.868 0.848 0.845

0.732 0.775 0.857 0.888 0.898 0.809 0.835 0.832 0.918 0.956 0.950

Table 3 Three dimensional similarity of the test compounds to reference drugs. Compound No.

1 2 3 4 5 6 7 8 9 10 11

3D Similarity with respect to: Nimesulide

Flosulide

Rofecoxib

Celecoxib

4a

0.620 0.669 0.707 0.752 0.718 0.742 0.770 0.730 0.790 0.840 0.809

0.617 0.670 0.710 0.766 0.719 0.745 0.764 0.746 0.792 0.852 0.794

0.646 0.689 0.708 0.741 0.718 0.746 0.759 0.729 0.783 0.858 0.798

0.654 0.675 0.719 0.715 0.707 0.739 0.765 0.735 0.780 0.861 0.800

0.650 0.671 0.722 0.732 0.710 0.742 0.752 0.729 0.775 0.805 0.794

The synthetic scheme for the preparation of test compounds is summarized in Fig. 4 and the chemical structures of the test compounds 1–11 are depicted in Table 1. In the first step, 2-propyl-1Hbenzo[d]imidazole (1) was prepared by refluxing o-phenylene diamine with n-butyric acid. Nitration of 2-propyl-1H-benzo[d]imidazole (1) was carried out in ice cold water with conc. nitric acidsulphuric acid mixture forming 5-nitro-2-propyl-1H-benzo[d]imidazole (2). Subsequent N-alkylation with n-butyl-, n-pentyl- and n-hexyl bromide yielded 1-n-alkyl-5-nitro-2-propyl-1H-benzo[d] imidazoles (3, 4 and 5). Reduction of the nitro imidazole derivatives (3–5) was carried out with stannous chloride dihydrate in anhydrous ethanol forming the corresponding 1-butyl-2-n-propyl-1H-benzo[d]imidazol-5-amines (6–8). The methods under

Fig. 3. Alignment of compound 10 (violet thin capped sticks) with nimesulide (shown as thick blue ball and sticks). Spheres, and dodecahedra depict field points for 10 and nimesulide respectively. Cyan, maroon, yellow and brown colors depict negative field, positive field, surface field and hydrophobic field points.

acidic conditions like Sn/HCl, Fe/HCl, Fe/CH3COOH and basic conditions like Zn/NaOH afforded lower yields due to the formation of other by-products. The amino derivatives (6–8) were subjected to methanesulphonylation by reacting with methanesulphonyl chloride in pyridine and dichloromethane yielding the N-(1alkyl-2-n-propyl-1H-benzo[d]imidazol-5-yl)methanesulfonamides (9–11). The prepared test compounds 1–11 were subjected to in vivo anti-inflammatory studies employing carrageenan-induced rat paw edema model.21 Prior permission of the Institutional Animal Ethics Committee (IAEC), Panjab University, Chandigarh, India was obtained and all experiments were conducted according to the approved protocol. Rofecoxib and indomethacin were taken as standard drugs for anti-inflammatory studies. Indomethacin served as a positive control for ulcerogenic potential. Doses were selected by initial titration at different dose levels. Three dose levels were employed for the standard drugs as well as the test compounds, i.e., rofecoxib (15; 30; 45 mg/kg p.o.); indomethacin (5; 10; 15 mg/kg p.o.); test compounds 1–8 (5; 25; 75 mg/kg p. o.); 9–11 (2.5; 10; 40 mg/kg p.o.). Lower dose levels were selected for compounds 9–11 due to their higher potency. The standard drugs and the target compounds were suspended in the vehicle (0.5%w/v solution of carboxy methylcellulose CMC). Solution of carrageenan was prepared in 0.9% saline solution. All the animals were allowed free access to food and water (ad libitum), in a constant light-dark cycle. The general behaviour of the animals was normal during the course of the experiment. The experimental protocol was similar to our previously reported procedure.18 The test compounds (or standard drugs) were administered p.o. as a suspension in CMC, 30 min after the carrageenan injection. The paw volume was noted before and after treatment at different time intervals with a plethysmograph. Percentage edema and percentage reduction in edema were calculated as: % edema = 100
[(1
V t =V c Þ  100 ]; % reduction in edema = (1
V t =V c Þ  100: Here, Vt and Vc designate edema volume in drug treated and control groups. Statistical comparison of the results obtained in the test groups with control and standard groups was carried out using one way ANOVA (p < 0.001) (Jandel Sigmastat version 2.0) followed by TUKEY test fixing the significance level at p < 0.05.

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NH2

HO

N

a O

NH2

N H

n-Butyric acid

o-phenylene diamine

1

b O2N

N

O2N

N

c N

N H

R 3 4 5

R n-butyl n-pentyl n-hexyl

2

d

H3C

H2N

N

O2S

6 7 8

N

e

N R n-butyl n-pentyl n-hexyl

HN

N

R 9 10 11

R R n-butyl n-pentyl n-hexyl

Reagents and conditions: (a) Reflux, 7 h (b) conc. HNO3, conc. H 2SO 4, 10 h (c) Alkyl bromide, DMF, anhydrous K2CO 3, room temp. (d) SnCl2.2H2O, anh. EtOH, 75 oC (e) CH 3SO2Cl, DCM, room temp. Fig. 4. Synthetic scheme for preparation of the test compounds.

Table 4 Results for anti-inflammatory activity (paw edema assay) and ulcerogenic potential of the tested compounds.

a b c d

Treatment Compd (Dose in mg/kg)

Maximum% edemaa

Maximum% Reduction in edema

ED50 (mg/kg)

Control Rofecoxib (30) Indomethacin (10) 1 (75) 2 (75) 3 (75) 4 (75) 5 (75) 6 (75) 7 (75) 8 (75) 9 (40) 10 (40) 11 (40)

100.00 21.05b 25.00b 22.73b 93.18b 47.73b 31.82b 21.75b 40.91b 36.36b 30.87b 7.27b 4.36b 2.38b

0.00 78.95 75.00 77.27 6.82 52.27 68.18 78.25 59.09 66.36 69.13 92.73 95.64 97.62

– 2.61 2.20 5.53 – 4.79 4.80 3.97 5.52 5.47 5.16 2.58 2.55 2.45

c

Lesion score (mm)d 0 2.92 ± 0.24 19.40 ± 1.56 0.42 ± 0.009 0.32 ± 0.02 1.04 ± 0.16 1.03 ± 0.16 1.26 ± 0.71 1.13 ± 0.06 1.06 ± 0.04 1.06 ± 0.04 1.10 ± 0.06 1.01 ± 0.15 1.02 ± 0.40

Values expressed at the selected dose levels after 5 h. Statistically significant vs. control (p < 0.001); one way ANOVA. Calculated from results for anti-inflammatory activity at three graded doses. Lesions, streaks and red spots noted at the three dose levels employed.

The results obtained for the maximum percentage edema and maximum percentage inhibition of edema in the control (carrageenan treatment), standard (rofecoxib and indomethacin) and test groups are given in Table 4 (complete data as Table S2 in supplementary file) and graphically represented in Fig. 5. With the exception of compound 2, all compounds demonstrated statistically significant reduction in edema at employed doses. Compound 1 demonstrated anti-inflammatory activity only at higher dose levels of 25 mg/kg and 75 mg/kg. The methane sulphonamide derivatives 9–11 demonstrated the best anti-inflammatory activity amongst the tested compounds showing maximum reduction in edema ranging from 92.7 to 97.6% (Table 4).

These results were much higher than those obtained for the standard drugs rofecoxib and indomethacin (78.95% and 75.00% respectively). It is pertinent to note here that our previously reported lead compound 4a had also shown good anti-inflammatory activity but the maximum percent reduction in edema was lower than the standard drugs rofecoxib and indomethacin (4a 72.66%; rofecoxib 81.8%; indomethacin 79.74%).20 Hence, introduction of benzimidazole nucleus has led to potentiation of activity with retention of non-ulcerogenic potential. The nitro derivatives 3, 4 and 5 also demonstrated a reasonably good anti-inflammatory activity (maximum reduction in edema after 5 h; 52.27% to 78.25%). Similar results were obtained for the aminobenzimida-

R. Sharma et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 3007–3013

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Maximum % edema at 5 hrs

150

100

50

In Rof do ec m ox et ib C ha (3 on ci 0 t r n m ol (1 g/ 0 kg m 1( g/k ) 5 1( mg g) 25 /k 1( mg g) 75 /k m g 2 ( g/ ) 5 k 2( m g g) 25 /k 2( mg g ) 75 /k m g 3( g/ ) 5 k 3( mg g) 25 /k 3( m g g ) 75 /k m g 4( g/ ) 5 k 4( mg g) 25 /k 4( m g g ) 75 /k m g 5( g/ ) 5 k 5( mg g) 25 /k 5( mg g) 75 /k m g 6( g/ ) 5 k 6( mg g) 25 /k 6( mg g) 75 /k m g 7( g/ ) 5 k 7( mg g) 25 /k 7( mg g) 75 /k g 8 mg/ ) (5 k 8( m g g ) 25 /k 8( mg g) 7 /k 9( 5mg g) 2. /k 5 9( mg g) 10 /k 9( mg g) 10 40m /kg (2 g/ ) 10 .5m kg) (1 g/ 10 0m kg) ( g 11 40m /kg (2 g/ ) 11 .5m kg) ( 1 g/ 11 0m kg) (4 g/k 0m g g/ ) kg )

0

Treatment

Fig. 5. Maximum percentage edema in the test, standard and control groups.

zoles 6–8. A significantly higher anti-inflammatory activity (p < 0.05) was noted in case of n-pentyl derivatives in comparison to their n-butyl analogs for the nitro- and amino- substituted benzimidazole derivatives. However, for the methanesulphonamido derivatives 9–11, the change in the N-alkyl chain did not produce statistically significant change in the activity. These results emphasize the positive contribution of the increasing size of the alkyl substituent towards anti-inflammatory activity possibly for nitroand amino derivatives (3–8). In case of compounds 9–11, the effect of the methanesulphonyl group supersedes the effect of N-alkyl substituent and all compounds show similar activity. This is in accordance with several literature reports that highlight the requirement of methanesulphonyl function for antiinflammatory activity.22 ED50 values were calculated for the test compounds and the standard drugs from the results obtained at three dose levels and the results are given in Table 3. The values were found to compare well with standard drug groups. The potential ulcerogenicity of all the compounds 1–7 was assessed and compared with the results obtained with standard drugs rofecoxib (negative control) and indomethacin (positive control).23 The animals were sacrificed by cervical dislocation and their stomachs were removed, inflated by injecting 7.0 ml 2% formalin, immersed in 2% v/v formalin solution for 10 min to fix the gastric wall, and then opened along the greater curvature. The lengths of the longest diameters of the lesions were measured and summated to give a total lesion score (in mm) for each animal, the mean count for each group being calculated. Table 3 shows the results for ulcerogenic potential of the test and standard drug groups. None of the test compounds were shown to demonstrate suggestive ulcerogenic effect at their highest employed doses in the three level doses studied and the values were lower than those obtained for rofecoxib. Only indomethacin showed red coloration, streaks and spots which increased with increase in the employed dose levels. The in vitro antioxidant activity of the compounds was assessed by potassium ferricyanide reducing power (PFRAP) assay24 with methanolic solutions of the test compounds (1.0–50.0 mmol/ml). Ascorbic acid was used as the standard. The method relies on

reduction of potassium ferricyanide by antioxidants and subsequent reaction of potassium ferrocyanide with Fe3+. The sample solution (2.5 ml) was mixed with phosphate buffer (0.2 M; pH 6.6; 2.5 ml) and potassium ferricyanide solution [K3Fe(CN)6] (1%; 2.5 ml) and incubated at 50 °C for 20 min. The mixture was rapidly cooled, mixed with trichloroacetic acid (10%; 2.5 ml). To an aliquot (2.5 ml) of this mixture diluted with distilled water (2.5 ml), ferric chloride solution (0.5 ml, 0.1%) was added and the solution allowed to stand for 10 min. An aliquot of methanol (control) was treated similarly. The absorbance was read spectrophotometrically at 700 nm. All test samples were analysed in triplicate and the data presented as mean ± S.D. (Table 5). The percentage of reducing power was calculated using the formula: Reducing power (%) = [Atest
Acontrol/Atest]  100. Compounds 3–11 displayed varying degrees of reducing power in the PFRAP assay with the methanesulphonamido derivatives 9–11 showing the highest antioxidant activity (EC50 values 3.7–5.1 mmol/ml vs ascorbic acid 7.4 mmol/ ml). The amino analogs 6–8 also exhibited activity comparable to ascorbic acid. Selected molecular parameters were computed for the compounds 1–11 as well as four representative anti-inflammatory drugs having gastrointestinal tolerability (Table S1 in supplementary data) and selected values are listed in Table 6. Amongst these, we included the prototypic drugs nimesulide and flosulide and two drugs belonging to the ‘diaryl substituted heterocycle’ category viz rofecoxib and celecoxib. Computation was done employing Chem3D (version 15.1) after carrying out MM2 minimization of the compound structures. The parameters such as log P and topological polar surface area (TPSA) are well recognized parameters for prediction of drug transport properties. Further, TPSA, a measure of a molecule’s hydrogen bonding capacity has been linked to drug bioavailability. Passively absorbed molecules with a TPSA > 140 are thought to have low oral bioavailability.25 Compliance with the Lipinski’s ‘rule of five’26 has been widely used as a filter for novel compounds in drug design and discovery programs in order to assess their likelihood for further development. This is one amongst the several theoretical ADME prediction methods used to assess the bioavailability of the inves-

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Table 5 Evaluation of in vitro antioxidant activity (PFRAP assay). Percent antioxidant activitya at concn (mmol/ml)

Compound

3 4 5 6 7 8 9 10 11 Ascorbic acid a b c

1.0

2.5

5.0

10.0

25.0

50.0

EC50b

0.6 ± 0.0 0.4 ± 0.1 0.9 ± 0.0 6.3 ± 0.0 8.7 ± 0.1 6.0 ± 0.1 12.2 ± 0.1 15.4 ± 0.6 10.6 ± 0.1 6.8 ± 0.1

2.5 ± 0.1 2.1 ± 0.0 2.8 ± 0.1 15.4 ± 1.2 18.7 ± 0.2 12.9 ± 1.2 31.3 ± 3.0 32.7 ± 0.7 29.2 ± 0.3 15.5 ± 0.2

6.8 ± 0.2 5.8 ± 0.1 6.8 ± 0.2 29.9 ± 1.0 30.2 ± 0.3 34.5 ± 2.4 59.8 ± 1.6 58.0 ± 1.8 49.7 ± 0.7 39.8 ± 1.8

16.8 ± 0.7 10.7 ± 0.5 17.9 ± 0.5 44.8 ± 1.8 49.0 ± 2.0 48.0 ± 1.5 61.8 ± 2.4 66.5 ± 1.2 66.5 ± 1.8 60.8 ± 3.1

29.2 ± 1.9 20.8 ± 0.5 30.1 ± 1.7 55.6 ± 1.8 60.1 ± 1.1 57.1 ± 4.9 70.3 ± 2.6 72.8 ± 2.1 69.6 ± 1.7 65.2 ± 3.0

45.4 ± 3.0 39.8 ± 1.1 45.9 ± 2.3 62.5 ± 1.4 67.3 ± 1.9 65.9 ± 1.2 73.5 ± 3.7 79.1 ± 2.5 75.4 ± 2.2 69.4 ± 3.3

–c – – 18.2 ± 0.5 10.2 ± 0.5 10.3 ± 0.1 4.0 ± 0.2 3.7 ± 0.2 5.1 ± 0.4 7.4 ± 1.7

Calcd as = [Atest
Acontrol/Atest]  100. Concentration exhibiting 50% antioxidant activity. EC50 value >50.0 mmol/ml.

Table 6 Selected molecular properties of the target compounds.

a

Compd.

Mol.Weight (MW)

CLogP

Topol. polar surface area (TPSA) (Å 2)

No. of H-bond acceptors

No. of H-bond donors

No. of violations LRa

1 2 3 4 5 6 7 8 9 10 11 Nimesulide Rofecoxib Celecoxib Flosulide

160.210 205.213 261.325 275.346 289.379 231.337 245.370 259.397 309.427 323.454 337.480 309.310 316.370 369.360 351.360

3.2341 3.1940 3.9131 4.4661 5.0010 3.9587 3.7548 4.3078 3.7692 2.5881 4.3868 3.080 2.148 2.882 2.201

24.39 76.20 67.41 67.41 67.41 41.62 41.62 41.62 61.77 61.77 61.77 95.71 60.44 75.76 63.24

4 4 3 3 3 3 3 3 4 4 4 4 4 7 6

2 2 0 0 0 1 1 1 1 1 1 1 0 1 1

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Number of violations from Lipinski’s rule of five.

tigational compounds. Hence, the active compounds 4–7 as well as the reference drugs were checked for compliance with this rule. According to this rule, poor absorption or permeation is more likely when there are more than five H-bond donors, ten H-bond acceptors, the molecular weight (MW) is greater than 500 and the calculated Log P (CLogP) is greater than 5. Molecules violating more than one of these factors may have problems with bioavailability. Data for prediction of ADME properties for the studied compounds is given in Table 6. The results show that the synthesized compounds comply with Lipinski’s rule and the standard drugs also do not show any violation. Theoretically, these compounds should present good passive oral absorption and differences in their bioactivity may not be attributed to this aspect.

of anti-inflammatory activity. The compounds 9, 10 and 11 have shown anti-inflammatory activity significantly higher than the standard drugs and these were also found to be non-ulcerogenic at the test doses. Additional preliminary investigations include the theoretical ADME profiling of the active compounds based on selected physicochemical properties and excellent compliance was shown with Lipinski’s rule. Acknowledgements The research grant provided by the University Grants Commission is duly acknowledged. We acknowledge the contribution of Sophisticated Analytical Instrumentation Facility, CIL and UCIM, Panjab University, Chandigarh, India for conducting NMR and CHN analysis.

Conclusion A series of 5-methanesulfonamido substituted benzimidazole derivatives have been designed combining the structural features of clinically useful anti-inflammatory and antiulcer agents. The design strategy was based on physicochemical and 3D similarity studies with respect to the standard anti-inflammatory drugs and our previously reported lead compound 4a. Pharmacological evaluation for the anti-inflammatory activity was carried out in carrageenan induced rat paw edema model taking rofecoxib and indomethacin as standard drugs for comparison. Excepting compound 2, all other compounds have demonstrated varying degrees

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