Synthesis and antitubercular screening of novel imidazoline ...

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T.Shalina Begum et al., Int J Pharm Biomed Sci 2013, 4(1), 40-45 43 Table 1 Physical characteristics data of the new imidazolinone derivatives S. No. Name M.P. °C 1 4-Benzylidene-2-p-hydroxyphenyl-2-Imidazolin-5-one 254 76 1687 391 10.50 10.61 2 4-(4-Chlorobenzylidene)-2-p-hydroxyphenyl-2-imidazolin-5-one 288 72 1680 394 9.27 9.38 3 4-(4-Methylbenzylidene)-2-p-hydroxyphenyl-2-imidazolin-5-one 258 54 1682 396 10.01 10.07 4 4-(4-Methoxybenzylidene)-2-p-hydroxyphenyl-2-imidazolin-5-one 272 45 1676 401 9.40 9.52 5 4-(2-Hydroxybezylidene)-2-p-hydroxyphenyl-2-imidazolin-5-one 262 60 1699 410 10.10 10.00 6 4-(2-Chlorobenzylidene)-2-p-hydroxyphenyl-2-imidazolin-5-one 224 41 1710 393 9.26 9.38 7 4-Benzylidene-2-pyrazinyl-2-imidazolin-5-one 248 30 1684 388 22.38 22.40 8 4-(4-Chlorobenzylidene)-2-pyrazinyl-2-imidazolin-5-one 272 35 1677 308 19.55 19.68 9 4-(4-Methylbenzyllidene)-2-pyrazinyl-2-imidazolin-5-one 273 40 1698 314 21.00 21.21 10 4-(4-Methoxybenzylidene)-2-pyrazinyl-2-imidazolin-5-one 261 59 1697 314 19.90 20.00 11 4-(2-Chlorobenzylidene)-2-pyrazinyl-2-imidazolin-5-one 215 20 1741 392 19.54 19.68 12 4-(Amino2-pyrazinyl)methylene-2-(2-pyrazinyl)-2-imidazolin-5-one 192 37 1673 422 36.41 36.70 Yeild (%) ʋ co (cm -1 ) λ max (nm) N% Found Calculated Table 2 General druglike descriptors of imidazolinone derivatives S.No. Mol.weight (130/ 725) Dipole (1.0/ 12.5) Hydrophilic SASA(7.0/ 330) Hydrophobic SASA(0.0/ 750) Log p oct/water (-2.0/ 6.5) Log BB ( -3.0 to1.2) Caco-2 ( 500 greater) Molecules similarity (>80%) 1 264.283 5.053 148.982 12.387 2.177 -1.088 382 Valdecoxib, Sulfaphenazole, Oxazepam, Mebendazole, Phenytoin. 2 298.728 5.481 153.573 12.436 2.637 -1.011 346 Flubendazole, Lorazepam, Valdecoxib, Sulfaphenazole, Mebendazole. 3 278.310 4.162 144.009 100.627 2.477 -1.060 426 Afloqualone, Valdecoxib, Rosoxacin, Mebendazole, Sulfaphenazole. 4 294.309 5.365 148.350 105.151 2.062 -1.175 388 Sulfaphenazole, Valdecoxib, Dantrolene, Oxyphenbutazone, Letrozole. 5 280.282 5.341 193.426 9.512 1.508 -1.593 145 Sulfaphenazole, Dantrolene, Valdecoxib, Letrozole, Papaveroline. 6 298.728 4.919 142.044 17.895 2.598 -0.886 445 Valdecoxib, Mebendazole, Sulfaphenazole, Flubendazole, Lorazepam. 7 250.259 3.784 139.636 11.829 1.377 -0.917 469 Azathioprine, Valdecoxib, Piroxicam, Afloqualone, Tenoxicam. 8 284.704 3.886 129.768 12.349 1.892 -0.638 582 Afloqualone, Valdecoxib, Nifenazone, piroxicam, Alosetron. 9 264.286 4.003 134.917 100.517 1.681 -0.893 520 Valdecoxib, Afloqualone, Piroxicam, Rofecoxib, Metopon. 10 280.285 5.027 129.797 105.066 1.529 -0.876 582 Piroxicam, Tenoxicam, Lornoxicam, Valdecoxib, Letrozole. 11 284.704 3.643 132.763 17.832 1.731 -0.667 545 Valdecoxib, Afloqualone, Piroxicam, Nifenazone, Tenoxicam. 12 267.249 2.307 222.592 0.000 -0.292 -1.766 76 Sulfacytine, Didanosine, Azathioprine, Isoxicam, Sulthiame. Imidic acid ester of pyrazine carbonitrile and glycine ester were taken in the molar ratio 2:1 and refluxed in benzene in presence of sodium bicarbonate base, resulted in the formation of 4-(amino 2-pyrazinyl)methylene-2-(2- pyrazinyl)-2-imidazolin-5-one by tandem reaction. The synthesised compound was recrystallized from ethanol. The elemental analysis and spectral data obtained supported the proposed structure. The physical characteristics of the new compounds were determined and are tabulated (Table 1). All the compounds given are reported for the first time. All the compounds synthesised gave satisfactory spectral data for their proposed structures. Some typical cases are as follows. i. 4-Benzylidene-2-p-hydroxyphenyl-2-imidazolin-5-one: IR:1684cm -1 (C=O), 3186cm -1 (b, N-H str), 3391cm -1 (O- H), 1637cm -1 (C=N). Mass spectrum m/z 265(M + +1) ©2013 PharmaInterScience Publishers. All rights reserved. www.pharmainterscience.com
T.Shalina Begum et al., Int J Pharm Biomed Sci 2013, 4(1), 40-45 corresponds to its molecular mass 264. 1 H NMR: δ 6.89– 8.29 (9H, aromatic protons and methyne proton), δ11.94 (1H, NH of imidazolinone ring), δ10.94 (1H, O-H). ii. 4-Benzylidene-2-pyrazinyl-2-imidazolin-5-one: IR: 1687cm -1 (C=O), 3181cm -1 (b, N-H str) and 1635cm -1 (C=N). In mass spectrum m/z=250 corresponds to its molecular mass. 1 H NMR: δ7.1–9.5 (8H, aromatic protons and methyne proton) and δ12.1 (1H, NH of imidazolinone ring). iii. 4-(Amino2-pyrazinyl)methylene-2-(2-pyrazinyl)-2- imidazolin-5-one: IR : 1673cm -1 (C=O), 3195 to 3290cm -1 (3 medium intensity peaks, NH 2 and NH of imidazolinone ring ). Mass spectrum m/z 268 (M + +1) corresponds to its molecular mass 267. 1 H NMR: δ8.4–9.2 (6H, aromatic protons), δ10.2 and δ9.2 (2H of NH 2 chemically non equivalent) and δ12.12 (1H, NH of imidazolinone ring). 3.1. Druggability The new imidazolinone molecules synthesised were modelled, energy minimised and uploaded for the descriptor and toxicity prediction using Qikprop (Schrodinger version 9.2). All the imidazolinones analysed showed more drug like properties. The summarised results of each molecule are presented in Table 2 (molecules are numbered in the order of Table 1). The drug molecules similar to the imidazolinones were also tabulated. 3.2. Anti Mtb activity The imidazolinones were screened for their antitubercular activity by using Weka classifier. It was found that 4-(amino 2-pyrazinyl)methylene-2-(2-pyrazinyl)-2-imidazolin-5-one (Fig.4) is active towards tuberculosis. analysed for their antituberculosis activity by virtual screening. Thier analytical results are given below. Filename: J48.model Scheme: weka.classifiers.meta.CostSensitiveClassifier -costmatrix "[0.0 2.0; 1.0 0.0]" -S 1 -W weka.classifiers.trees.J48 - - -C 0.25 -M 2 Relation: AID434987_train Attributes:132 Predictions on test set Inst#Actual Predicted Error Probability Distribution 1 1:Active 2:Inactive + 0 *1 2 2:Inactive 2:Inactive 0 *1 3 2:Inactive 2:Inactive 0 *1 4 2:Inactive 1:Active + *0.857 0.143 5 1:Active 2:Inactive 0 *1 6 2:Inactive 2:Inactive 0 *1 7 2:Inactive 2:Inactive 0 *1 8 2:Inactive 2:Inactive 0 *1 9 2:Inactive 2:Inactive 0 *1 10 1:Active 2:Inactive + 0 *1 11 2:Inactive 2:Inactive 0 *1 12 2:Inactive 2:Inactive 0 *1 13 2:Inactive 2:Inactive 0 *1 14 1:Active 2:Inactive + 0 *1 15 2:Inactive 2:Inactive 0 *1 16 2:Inactive 2:Inactive 0 *1 17 2:Inactive 2:Inactive 0 *1 4. CONCLUSIONS Tuberculosis active The new imidazoline derivatives synthesised were obtained in good yield, their proposed structure were confirmed by spectral analysis. All the novel molecules synthesised showed drug-like properties. Most of the molecules are similar to non-steroidal antiinflammatory drugs, anticonvulsant and analgesic. Insilico screening of the synthesised compounds showed that, 4-(amino 2- pyrazinyl)methylene -2-(2-pyrazinyl)-2-imidazolin-5-one (Fig.4) possess antitubercular activity. Interestingly, the structure of 4-(amino 2-pyrazinyl)methylene -2-(2- pyrazinyl)-2-imidazolin-5-one closely resembles with didanosine, a well known anti-HIV drug. 44 REFERENCES Fig.4.Structure of 4-(amino 2-pyrazinyl)methylene -2-(2-pyrazinyl)-2- imidazolin-5-one Virtual screening - Model information Eleven 4-Arylidene-2-aryl-2-imidazolin-5-ones and six 4- (amino,arylmethylene)-2-aryl-2-imidazolin-5-ones were [1] Desai NC, Bhavsar AM, Baldaniya BB. Synthesis and antimicrobial activity of 5-imidazolinone derivatives. Indian J Pharm Sci 2009, 71, 90. [2] Solankee A, Kapadia K, Patel, Thakor I. Synthesis and antimicrobial Activity of 1-Phenyl/Substituted Phenyl/Benzyl/ Naphthyl-2-Phenyl-4- (3´ -Phenoxy Benzylidene)-Imidazoline-5-ones. Asian J Chem 2002, 14, 699. [3] Mesaik MA, Khan KM, Rahat S, Zia-Ullah, Choudhary MI, Murad S et al. Immunomodulatory Properties of Synthetic Imidazolone Derivatives. Lett Drug Des Discov 2005, 2, 490. [4] Giorgioni G, Claud F, Ruggier S, Ricciutelli M, Palmier G, Di-Stefano A et al. Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs. Bio Org Med Chem 2010, 18, 1834. ©2013 PharmaInterScience Publishers. All rights reserved. www.pharmainterscience.com
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