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ARKIVOC 2006 (xiv) 87-102

**QSAR study on inhibition of E. Coli by sulfonamides
**

Abhilash Thakur,a* Mamta Thakur,b and Padmakar V. Khadikarc Department of Chemistry, Rishiraj Institute of Technology, Indore India Department of Chemistry, Kailash Chand Bansal Academy of Technology, Indore India c Research Division, Laxmi Fumigation and Pest control, Pvt. Ltd, 3, Khatipura, Indore 452007, India E-mail: abhilashthakur@yahoo.com, pvkhadikar@rediffmail.com

b a

Abstract The paper describes a QSAR study on inhibition of E. Coli by sulfonamides using distance-based topological indices. The sulfonamides discussed consists of 39 derivatives with substitution at 2-, 3- and 4- positions as well as having some di-substitution. Application of multiple linear regression analysis indicated that combination of distance-based topological indices with ad hoc molecular descriptors and indicator parameters yielded statistically significant model for modeling inhibitory activity (log1/C) of E. Coli. Predictive potential of the model is obtained by cross-validation parameters as well as by using a variety of other statistics. The results have indicated that there is no involvement of a positive hydrophobic term (logP) in the inhibition process, suggesting that the binding of the sulfonamides to the active center does not depend on hydrophobic interactions. Final selection of potential sulfonamide is made by molecular modeling. Keywords: QSAR, sulfonamides, E. Coli inhibition, molecular descriptors

Introduction

Bacteria have been one of the most studied test systems. The current data-base of Hansch1 indicated that out of 1775 QSAR’s on a single organism, 649 are for bacteria and that bacteria vary enormously in their response on treatment with various organic compounds acting as a drugs. It is worthy to mention the antibacterial activity of sulfa- drugs having similar structure is due to their activity as 4-aminobenzoic acid antagonist. These drugs inhibited the incorporation of 1,2 p-aminobenzoic acid into folic acid by folate synthetase. The folate synthetase incorporates the drug sulfamethoxazole in pterin, thus completely blocking folate synthesis2,3. A plethora of literature exists on the action of sulfa-drugs on all kind of bacteria. Needless to state that p-

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Coli by sulfonamides using a set of molecular descriptors consisting of some distance-based topological indices together with some adhoc molecular descriptors. and in continuation of our earlier work4-15.……. In case of sulfonamides the inhibition of CA is caused mainly by the binding (coordination) of the SO2NHanion to the Zn2+ of the enzyme. We have used earlier data1 for this purpose. Earlier. class of sulfa-drugs are inhibited by sulfonamides. ISSN 1424-6376 Page 88 © ARKAT . Table 1). Prompted by the above. we have shown that inhibition of carbonic anhydrase by sulfonamides and Schiff base derived from them can be modeled excellently using distance-based topological indices. miming the bicarbonate anion in the transition state4. General structure of sulfonamides used in the present study.it seems timely to examine those instances where hydrophobic terms are not significant”.Coli by sulfonamides. we have undertaken the present study in that we have made QSAR analysis on the inhibition of E. Another objective of our study was to investigate the need (if any) of hydrophobic parameter (logP) in modeling inhibition of E. (Figure 1. The ring substituted benzenesulfonamides containing -SO2NH2 groups have similar activities. Recently1 Hansch stated that “over the year we have been impressed by the great importance of hydrophobic effects in chemical-biological interactions as brought out by quantitative structureactivity relationships (QSAR’s). NH 2 O S NH O X Figure 1. Furthermore. Carbonic anhydrase(CA’s). in many cases hydrophobic parameters were used for this purpose.General Papers ARKIVOC 2006 (xiv) 87-102 aminobenzoic acid is a component of folic acid and is needed by bacteria for their survival and multiplication.

10 4.04 5.2-CF3 2-Cl 2-I log1/C 4.85 4. IO = 1 if substitution at ortho position.4-NO2 2-Br.4-Cl 2-Cl.00 5. IM = 1 if Substitution at meta position. IP = 1 if substitution at para position.4-NO2 4-NO2.41 5.3-di-Me 2-Me.45 4.4-OMe 2-OMe.95 5.60 5.55 4.55 5.49 4.68 IX 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 0 1 1 1 1 1 INO2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 IDS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 0 0 0 IO 0 1 1 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 1 1 1 1 1 1 1 1 1 IM 0 0 0 0 0 0 0 1 0 1 1 0 0 0 0 1 1 1 1 1 0 0 0 0 0 1 1 0 1 1 0 0 0 0 0 0 0 0 0 IP 1 0 0 1 1 1 0 0 0 0 0 1 1 0 1 0 0 0 0 0 1 1 1 1 1 0 0 0 1 0 1 1 1 1 1 1 0 0 0 IX = 1 if halogen substitution. INO2 = 1 if NO2 substitution.47 4.4-di-Cl 3.99 4.80 4.25 5.80 5.6-Cl 3. Structural details and assumed indicator parameter for the sulfonamides used in present study Comp.10 5.89 4.64 5.46 4.35 4.95 5. No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Substituents 4-NMe2 2-OMe 2-OC2H5 4-OMe 4-OC2H5 4-Me 2-Me 3-Me H 3-OC2H5 3-OMe 4-Cl 4-Br 2-Br 4-I 3-I 3-Cl 3-Br 3-NO2 3-CF3 4-CF3 4-CN 4-COCH3 4-NO2 4-SO2CH3 2.70 6.10 5.5-Cl 2-Me.40 5.40 6.35 4.4-NO2 2-Me.32 5.32 4. IDS = 1 if di-substitution. ISSN 1424-6376 Page 89 © ARKAT .5-di-Cl 2-Cl.80 4.60 4.66 4.55 5.4-NO2 2-Me.77 5.80 4.80 4.89 4.00 5.General Papers ARKIVOC 2006 (xiv) 87-102 Table 1.

3.5. In Table 2 the calculated values of topological indices: W. J and Sz are recorded. on one hand and the substitutents 3-Cl. Thus. 1χ. All these indices are important distance-based topological indices out of which W and Sz are first generation while 1χ.16 Szeged. For obtaining appropriate QSAR model we have used maximum R2 method and followed stepwise regression analysis. Consequent to the occurrence of degeneracy in the activity it became essential to examine the degeneracy in the molecular descriptors also. 2-Cl.22-24 The predictive ability of the model is discussed on the basis of predictive correlation coefficient. density(d) and polarizability(α) in addition to logP and HE (hydration energy). and 2-Me. 2-OC2H5 have independently an analogous effect on the activity.di. Consequently. 4-NO2 on the other hand have an identical effect on the activity. 6-Cl substitution does not change the activity (log1/C)of the parent (unsubstituted) sulfonamide. 5-Cl. substitution at ortho-position. and Balaban indices21. disubstitution. Likewise. We have. 4-Cl. substitution at meta.Coli and finally we have aimed at the most appropriate model using molecular modeling. Preliminary statistical analysis indicated the need of some indicator parameters for obtaining statistically significant models. the substituents 3. 4-NO2 (ii) 4-CF3. 2-Cl.Cl. used six indicator parameters IP1 to IP6 accounting for the presence/absence of substitution at X: nitro-substitution. 2-Me. surface tension(ST). inspite of their degeneracy they can be successfully used in drug modeling28. The adhoc molecular descriptors used were molar refractivity (MR). therefore. The log1/C value is lowest for 2.25-27 However. Results and Discussion The set of 39 sulfonamides and their adopted inhibition (MIC) values of E-Coli expressed as log1/C are presented in Table 1 which shows that log1/C are highly influenced by the substitution on the aromatic nucleus. 4-NO2.5 di-Cl and (iii) 4-NH2. the effect due to electronic nature of these substitutents mimic that of hydrogen substitution.29. we have the following sequence of activity values: 22 = 24>25>23>39>36>19>30 = 34 = 38>35>21 = 29>37>20>17 = 32 = 33>16>14>15> = 18>12 = 13>9 = 10 = 11 = 27 = 28>31>6>8>5>4>7>2>1 = 3> 26 (1) This eq(1) shows that 3-OC2H5. Similarly. 2-OMe. Comparison of the observed activity and the corresponding topology of the sulfonamides used shows that the topology of the sulfonamides alone is not responsible for the ISSN 1424-6376 Page 90 © ARKAT . the three pairs (i) 4-CN. 3-OMe. These indicator parameters are dummy parameters and assume only two values: one (for presence) and zero (for absence). 2-Me. We have separated a set of potential inhibitors of E.17-19 first order molecular connectivity20. molar volume(MV). refractive index(η).3-di-Me substitution. parachor(Pc). The data presented in Table 1 also shows the occurrence of degeneracy in the activity (log1/C) values.position and substitution at para-position respectively. and J are the second generation topological indices.General Papers ARKIVOC 2006 (xiv) 87-102 The topological indices used for the QSAR analysis were Wiener.

3415)d (2) 2 n = 39. However. such cases are nicely dealt with Randic30 and we will use his recommendations to analyze such cases.4783x10-4)Sz – 0.9825(±0.686 ISSN 1424-6376 Page 91 © ARKAT . MV. The triparameteric model containing three descriptors (Sz. However. d) is found as below: log1/C = 7.3550. while this is not the case with the other physicochemical parameters used. Se = 0.General Papers ARKIVOC 2006 (xiv) 87-102 variation of the activity. statistically significant models are obtained when three descriptors are used and that the quality of the model goes on improving with higher parameteric modeling (Table 5).0281(±0. F = 11. The same is found to be the case with hydrophobic (logP) and other parameters (Table 3) used for modeling the activity.4576. From this we conclude that no single variable model is capable of modeling the activity and that the refereed descriptors can be combined to obtain a statistically significant multiparametric model for modeling the activity.0016(±3.5491 + 0. The intercorrelatedness among molecular descriptors including topological indices with the activity shows (Table 4) that except J all other topological indices are highly mutually correlated. R = 0. that models containing two or more topological (except J) indices may suffer from defect due to correlation2224 .7074. data presented in Table 4 show that none of the molecular descriptors.0076)MV + 0. including topological indices correlate well with the activity (log1/C). Furthermore. R A = 0. Also. Initial regression analysis indicated that out of the 12 molecular descriptors used Sz in combination of physicochemical descriptor plays a dominating role in modeling the activity.

420 9.880 1.825 1.800 1.471 8.009 8.509 8.488 8. Sz = Szeged index ISSN 1424-6376 Page 92 © ARKAT .825 1.382 9.836 1.825 1.825 1.882 8. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 W 880 714 831 758 897 638 616 627 536 864 736 638 638 616 638 627 627 627 847 960 1004 758 880 880 1004 710 712 700 732 722 847 825 974 974 974 974 1325 616 616 χ 9.509 9.816 1.004 8.899 8.793 11.052 1.855 1.381 9. J= Balaban index.800 1.382 9.488 1 J 1.912 1.900 1.488 8.471 8.882 8.793 9.009 9.875 1.900 Sz 1324 1060 1209 1148 1341 974 930 952 818 1275 1140 974 974 930 974 952 952 952 1258 1414 1502 1148 1324 1324 1502 1068 1072 1048 1112 1092 1273 1229 1456 1456 1456 1456 1921 930 930 W = Wiener index.471 8.880 1.682 9.869 1.026 9.924 1.855 1.471 8.880 2.890 1.816 1.General Papers ARKIVOC 2006 (xiv) 87-102 Table 2.950 1.890 1.921 1.471 9.880 1.865 9.801 1.471 8.912 1.382 9.801 1.488 8.899 8.471 8.077 9.471 8.887 1. 1χ = Connectivity index.009 9.420 9.771 1.793 9.837 1.682 8. Calculated values of distance-based topological indices used in present study Comp.682 9.861 1.793 9.526 9.No.900 1.800 1.916 1.855 1.853 1.855 1.

627 1.8 192.47 80.7 216.44 30.32 1.1 192.0 78.3 575.8 51.8 221.723 1.475 1.442 1.23 31.641 1.27 73.40 78.653 1.8 67.663 1.9 202.1 197.4 60.2 589.8 588.77 31.466 1.75 28.3 76.627 1.5 608.538 1.4 564.3 61.9 192.611 1.3 64.74 78.597 1.096 0.3 631.79 76.17 72.548 2.57 72.295 1.0 571.678 1.99 76.092 2.5 513.658 1.58 30.99 76.208 2.373 1.1 66.279 2.436 2.58 72.7 202.3 62.74 78.660 1.0 571.29 32.91 73.653 1.52 30.30 31.54 78.3 204.8 64.69 29.627 1.8 221.423 3.7 58.689 1.674 1.669 1.90 31.0 209.90 28.178 1.7 587.69 31.4 67.7 208.8 51.601 1.723 STd/ cm 63. ST = Surface Tension.706 1.61 28.3 575.442 1.331 1.9 612.7 66.21 31.4 70. D = Density.17 72.0 192.388 2.7 197.8 204.7 197.419 1.5 551.664 2.4 564.30 78.789 1.6 214.692 1.6 222.7 204. η = Index of Refraction.674 1.330 1.6 213.7 212.3 61.00 34.657 1.54 73.98 29.20 77.8 62.475 1.952 1.17 67.728 0.104 MR = Molar Refractivity.0 197.592 1.549 1.419 1.49 29.10 30.50 81.53 72.466 1.General Papers ARKIVOC 2006 (xiv) 87-102 Table 3.658 1.3 190.3 192.844 1.017 2.664 2.674 1.7 204.646 1.470 1.320 1.172 1.6 60.13 29.8 226.0 202.4 60. ISSN 1424-6376 Page 93 © ARKAT .378 0.3 61.330 1.47 MV cm3 218.91 78.9 214.7 62.658 1.68 73.1 Dg/ cm3 1.3 197.320 1.912 1.5 551.466 1.782 1.3 214.20 78.738 1.37 80.644 1.9 58.8 74.370 1.8 67.4 632.13 29.9 612.3 62.522 1.3 612.0 66.27 80.723 1.8 570.844 1.830 2.789 1.20 86.029 2.8 62.54 72.653 1.3 570.592 1.689 1.2 587.0 204.678 1.83 29.7 216.1 197.149 1.27 75.30 28.4 587.646 1.639 1.844 Pol cm3 31.08 31.99 77. Pc = Parachor.466 1.017 2.0 551.3 204.9 571.91 78.8 221.30 31.689 1.178 2.60 30.104 2. logP = Octanol/Water partition coefficient.83 31.9 81.58 80.6 208.1 70.61 28.647 1. MV = Molar Volume.3 77.2 η 1.358 1.4 67.662 2.522 1.641 1.664 2.6 644.3 70.91 72.231 1.515 2.6 71.83 29.689 1.2 550.3 621.7 588.842 2.641 1.3 587. Pol = Polarizability.1 180.11 76.3 67.53 72.37 75.3 209.61 26. No.663 1.0 607.21 31.367 1.13 28.671 1.7 58.4 61.430 1.6 58.689 1.75 28.69 29.5 587.9 550.52 30.330 1.0 609.47 72.90 logP 1.549 1.660 1.9 Pc cm3 617.378 2.17 32.358 1. Hydrophobic (logP) and other physicochemical parameters used in the present study Comp.14 28.680 1.54 73.279 1.660 1.789 1.819 2.5 609.3 560.3 564.9 596.3 550.17 28. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 MRcm3 80.3 76.358 1.60 31.37 75.

11908 .89890 .2983 .23999 -. Correlation matrix log1/C log1/C W 1 χ J Sz MR MV Pc η ST D Pol IX INO2 IDS IO IM IP logP HE ST D Pol IX INO2 IDS IO IM IP logP HE 1.25931 .33288 .01580 .3857 .0477 .2741 -.52918 -.0000 .08591 .3813 -.46304 .2925 .69373 .31676 -.29776 .3333 -.44094 -.50108 .74297 .31581 .3328 .24501 .7148 .6398 .0000 -.33595 .19358 .24707 .89905 .66649 -.15964 .74315 -.02685 IM 1.21368 -.05307 .000 .09096 -.24729 -.36834 -.1331 -.16635 .20405 .0000 .000 .1477 .5728 .34125 .39225 .0749 .6180 .2314 .11600 -.0319 -.0993 1.04494 .06417 .1336 .000 .03416 1.6699 W 1 χ J Sz MR MV Pc η 1.5215 .61900 -.35253 .86563 -.2836 IP logP HE 1.45818 .13511 .16625 .2877 1.26380 IO 1.0370 -.61094 .21576 .43270 .1256 .1138 .0000 .98683 1.51391 ST D 1.3301 -.1358 .60338 .3388 -.99894 .5734 1.13459 .27406 -.000 .37890 -.2306 .4631 .61353 Pol IX 1.0707 -.01188 .45804 -.23296 .57485 .6415 .66687 .9490 1.0602 .47723 -.32063 .0000 .20213 .05076 .05143 .26829 -.77441 -.3537 1.0000 .98149 .0000 .3364 .12708 -.60734 .35814 .000 .2111 -.0335 .09581 -.25993 .52151 1.0309 .3790 .12674 .3221 -.8694 .32646 .2044 1.3163 .1708 -.3972 .2641 1.7516 .34538 .36906 .0000 .2734 .0237 .2225 1.40367 .43726 .43696 .30913 .09413 .0846 .3487 -.General Papers ARKIVOC 2006 (xiv) 87-102 Table 4.34624 .00590 .10381 -.70236 . Its positive coefficients indicate that the presence of an aromatic nucleus is essential ISSN 1424-6376 Page 94 © ARKAT .17694 .000 1.15665 -.12368 .43711 -.000 -.000 -.3075 .33860 -.11613 .0000 .40665 -.00149 -.14239 -.41359 .5614 -.000 .0514 -.1674 .2052 .37239 .09542 -.4209 .73619 .39276 -.4120 .1782 .00083 -.14093 .20892 -.30763 .6387 .38288 -.30180 .00 The Szeged index (Sz) is the modification of Wiener index (W) for cyclic (cycle containing) compounds.52011 .09123 INO2 1.20018 -.000 .07540 .53810 .30864 .26855 -.44937 .1236 .71949 .000 .20883 -.07714 .25482 -.62532 IDS 1.04500 .2890 -.43253 .

0404(±0.0359(±0. d Sz. R = 0.0025(±5. Parameters Sz. and ST yielded still better results: log1/C = 5. The positive coefficient of ST indicates that the activity goes on increasing with the increase in the magnitude of ST. F = 11.d. F = 10. The same is the case with the density parameter d. 2.686 10.General Papers ARKIVOC 2006 (xiv) 87-102 for the exhibition of the activity.7450.6033 + 0. IP n 39 39 39 39 39 35 Se 0. ST Sz.0089)MV + 0.340 0. MV.745 0.292 0. ST. R A = 0.825 0.707 0.5820.6663x10-4)Sz – 0.458 0. 6. MV. MV.288 The successive regression analysis indicates that a penta-parametric model containing Sz. INO2. INO2. MV. which thus is responsible for the improved statistics of above model.367 0. the negative coefficient of MV indicates that the activity goes on decreasing with the increasing value of MV. ST Sz.0246(±0.5351(±0. ST.581 The physical significance attached to Sz.2998(±0. Regression parameters and quality of correlation of the proposed models Model 1. 4. d. I NO2.0095)MV + 1. ISSN 1424-6376 Page 95 © ARKAT . Se = 0. This molar volume (MV) is one of the important polarizability parameters.3481x10-4)Sz – 0. In our recent publication31 we have stated that surface tension (ST) can be considered as an inverse steric parameter.620 0.581 11. thus we can safely say that polarizability plays a negative role in the exhibition of the activity.2620)I NO2 (3) 2 n = 39.3620)d – 0.2) then its statistics is significantly improved. IP Sz. Thus. When an indicator parameter INO2 is added to the above model (Eq. R = 0.2997)I NO2 +0. Se = 0.384 0. INO2.355 0. R A = 0.6914(±0.312 0.602 11. The physical significance of the remaining three parameters (Sz. However.345 28.7981.MV.911 R2A 0. d and I NO2 gives the following mode: log1/C = 8.213 R 0.015 11. MV.3991)d – 1.503 0. MV.3400. INO2 Sz.0408(±0.0148)ST (4) 2 n = 39.633 0.798 0. MV. 3. d.3117.582 0. the resulted tetra-parametric model containing Sz.602 The negative coefficient of the indicator parameter I NO2 indicates that the presence of an NO2 group is not favorable for the exhibition of the activity. d.5027.0029(±5. and INO2 are the same as discussed for the model expressed by equation 3.MV and d) is the same as discussed for the model expressed by eq(2).6451 + 0. 5. d. Table 5.800 F 12.

the difference between observed and calculated log1/C. Furthermore.3912x10-4)Sz – 0. This hexa-parametric model containing Sz. R A = 0. Such models are not allowed statistically.22.29-33 In order to confirm our findings we have compared the calculated log1/C values from equations 5 and 6 with the observed values of log1/C. d.2971 + 0.0355(±0. evidence in our favour are obtained by calculating predictive correlation coefficients (Rpred) using Figures 2 and 3. F = 28.0154)ST – 0. MV. This parameter is responsible for the presence of substituents at the para-position.8248. Instead.0682 + 0. Se = 0.33. ST and IP and is found as below: log1/C = 4. analysis of equation 5 indicates that compounds 1. The added indicator parameter IP has a negative coefficient. Further. F = 11. R = 0.3147)I NO2 +0.General Papers ARKIVOC 2006 (xiv) 87-102 The quality of above model is significantly improved by the addition of an indicator parameter IP. its negative coefficient indicates that substitution at the para-position is not favorable for the exhibition of the activity. they can be considered as outliers and can be removed from the regression procedure.2282)INO2-0.3051).288 The physical significance of parameters contained in the model is the same as discussed above.6326(±0.62003.0663(±0.3108(±0.9110.0936)IP (6) 2 n = 35.345 The physical significances attached with Sz. the resulting six parametric model suffers from the defect in that coefficient of the d (0.2971.0035(±6.0096)ST – 1. R A = 0.6802 and 0. INO2. and St are the same as discussed above.3821)d – 1. Thus. Se = 0.9110.e.1283)IP (5) 2 n = 39.2127. INO2.8298 respectively. ST and IP is found as below: log1/C = 0.0062)MV + 0. R = 0. Further.0219) was smaller than its standard deviation (0.0087)MV + 0. The residual. Thus. MV.1001x10-4)Sz – 0. d.. Such a comparison is shown in Table 6 and demonstrated in Figures 2 and 3.1817(±0. supporting that the model expressed by eq(6) is the best model. ISSN 1424-6376 Page 96 © ARKAT . This is a penta-parametric model containing Sz.8248 to 0. When we did so a tremendous improvement in the statistics was observed so that the correlation coefficient increases from 0.0533(±0. this improved model requires less correlating parameters.0037(±4. And there is no significant improvement in the statistics when the parameter d is added to the above equation. that is the difference between observed and calculated log1/C indicates that the model expressed by equation 6 is the best for modeling log1/C.0394(±0.2293(±0. INO2.2669(±0.38 and 39 gave high residues i. which comes out to be 0. MV.8005.

74 4.35 4.11 -0.32 4.01 0. 9.03 5.01 0.23 -0.38 5.13 5.67 5.56 5.10 4.09 -0.57 Calc log1/C 5.46 4.73 *Data point not incorporated in calculations. 30.13 -0. 8.10 0.15 -0.14 5.02 -0.26 0.21 0.40 5. 5.19 5.41 4.07 0. 6. 2.80 4. 25.07* 4.25 -0.30 -0. 5.08 5.66 4.54 4.07 0.09 -0.01 5.37 0.42 -0.72 4.46 5.11 -0.71 5.64 5. 27.84* 5.General Papers ARKIVOC 2006 (xiv) 87-102 Table 6.85 4. 13.66 4.80 4.16 -0.95 5. No 1.10 5.74 5.21 -0.57 5.93 5.23 -0.54 -0.91 5.68 4.11 0.62 5.25 -0. 34.32 0.56 4. log1/C 4.07 -0.45 4.92 4. 37. 23.31 5. 19.05 -0.11 Residual -0.48 0.74 0.30 0.15 5.15 5.21 -0. 29.78 4.77 5.02 0.19 6.89 4.31 0.10 5.87 5.05 -0.31 4.52 0.95* Residual -0.34 5. 22.70 5. 31.18 0.06 -0.98 4.32 5.49 4.67 5.80 4.32 0.07 5. 32. 12. 39.23 5.35 4. a Calculated from eq.83 4.98 4.55 4. 24.80 4.18 -0. 3.47 4.80 4.55 5. 16. 10.06 -0.73 5.13 5.21 4.47 0.16 -0. 20.40 6.27 0. 18.83 4.54 4.16 0.07 -0.96 4. 14.42 -0. 36.68 Calc log1/C 4.05 4. Comparison of observed and calculated antibacterial activity against E-Coli using different models S.01 0.02 0.01 4.57 0.20 0.07 5.00 5.43 4.12 0.96 4.07 0.10 -0.99 4.69 5.48 5. 21.23* 4.38 0.62 5.95 5. 11.10 5.55 5.55 5.08 -0.00 -0.11 0.52 5.86 4.24 -0.60 4. 35.57 -0.15 5.56 4. 17.88 -0.82 4.01 -0.17 0.96 5.27 6. 4.14 0.09 0.41 5.06 5.08 0.64 4. 28.10 -0.06 0.89 4.29 -0.32 5.04 5. 6 ISSN 1424-6376 Page 97 © ARKAT .71 4.00 5.05 -0.70 6.21 -0. 26.58 4.12 -0.80 5.23 -0.30 4. bCalculated from eq.11 0. 38.60 5.00 5.03 -0. 7.60 4.89 4.25 5. 33.03 4. 15.46 0.

Coli we have used logP as one of the correlating parameters.5 5 4.5 7 Figure 2.5 5 4. log1/C 6 6.5 6 Calc. Graph obtained between observed and calculated log1/C from (eq. 6. Such models are not allowed statistically.5). In majority cases we obtained model in that the coefficients of logP term was considerably smaller than its standard deviation.22.29-33 ISSN 1424-6376 Page 98 © ARKAT . Graph obtained between observed and calculated log1/C from (eq.5 obs.5 4 4 4.6).5 5 5.5 Obs. log1/C 5. log1/C 6 6.5 Calc log1/C 6 5.General Papers ARKIVOC 2006 (xiv) 87-102 6.5 7 Figure 3. In order to investigate the role of hydrophobic parameter (logP) for modeling the antibacterial activity of the sulfonamides against E.5 4 4 4.5 5 5.

Experimental Section Antibacterial activity against E-Coli.to penta-parametric models supports this conclusion.5 i. The consistent increase in R2A value as we pass from bi. The MIC values expressed as log1/C for the inhibition of E-Coli by these sulfonamides were taken from the literature1. Like earlier cases4-15 here also a model containing five descriptors yielded excellent results. j=1 where. Topological indices. Szeged index (Sz) The Szeged index. Edges equidistance from both the ends of an edges.Coli by sulfonamide and that for the present set of sulfonamides Szeged index (Sz) is found to be prominent. (D)ij is the ijth element of the distance matrix which denotes the shortest graph – theoretical distance between sites i and j of G. d(j)]-0. is calculated17-19 according to the following expression: Sz = Sz (G) = Σ nu . e = uv are not taken into account. The set of 39 sulfonamides used in the present study is given in Table1. below we have given the final expression for the calculation of these indices. Also. However. that this index (Sz) yields statistically significant models upon combination with other molecular descriptors. nv edges where nu is the number of vertices lying closer to one end of the edge e = uv.General Papers ARKIVOC 2006 (xiv) 87-102 Conclusions From the results and discussion made above we conclude that the distance-based topological indices can be used successfully for modeling inhibition of E. their detailed calculations are not given here.j ISSN 1424-6376 Page 99 © ARKAT . The connectivity index(1χ) The connectivity index 1χ= 1χ(G) of G is defined20 by Randic as: 1 χ = 1χ(G) = Σ [ d(i) . Sz = Sz(G). Wiener index (W) Wiener index W = W(G) of G is defined16 as the half-sum of the elements of the distance matrix: W = W (G) = ½ Σ Σ (D)ij i=1. The calculations of these indices are well documented in the literature and therefore. All the used topological indices were calculated using all hydrogen suppressed graph by deleting all the carbon hydrogen as well as hateroatomic hydrogen bonds from the structure of the sulfonamides. the meaning of nv is analogous.

Reference and Notes 1.C. Bioorg.V. We have used maximum R2 method22-24 and adopted step-wise regression for obtaining statistically significant models.. 619-672. Med.. C.. Thakur. Chem-Bioinformatics and QSAR: A Review of QSAR Lacking Positive Hydrophobic Terms.2. Lett. 5. N is the number of vertices in G) is the distance sum. C. Beteringh. P.Kurup. Chem. Supuran. ISSN 1424-6376 Page 100 © ARKAT . QSAR Study using Topological Indices for Inhibition of Carbonic Anhydrase II by Sulfanilides and Schiff’s Bases. S. QSAR study on Benzene Sulphonamide Carbonic Anhydrase Inhibitors:Topological Approach Using Balaban Index. 6. S. Basak.General Papers ARKIVOC 2006 (xiv) 87-102 Balaban index (J) The Balaban index J = J(G) of G is defined21 as: J = M/µ+1 ∑(di.V. A..N. A. Khadikar. Chem. Quant. Khadikar. M. K.C. Pc (parachor). Supuran.C. 12.. Jaiswal. J. J. 4.. P. various physicochemical parameters (descriptors) Viz. The cyclomatic number µ = µ(G) of a cyclic graph G is equal to the minimum number of edges necessary to be erased from G in order to transform it into the related acyclic graph.P. 8.. 14.. 2004. 3283-3290..dj)-0. 2004. 20. 593598.. Chem. C. 1981. 39... Singh. Hansch. In case of monocyclic graph µ = 1 otherwise it is calculated by means of the following expression Μ = M-N+1 Physicochemical parameters. η(refractive index). Med. Eur. 2004.3.V. 2004. MV (molar volume).T... Effect of Molecular Size on Carbonic Anhydrase Inhibition by Sulfonamides. S. MR (molar refraction). A. Chem.. Int... Kumar. 2004.. Surface tension (ST)..Garg.A.35 The expressions for the calculation of these parameters are available in the literature. M..T.K. 4. C. 14. Bindal. Molecular Diversity. P. C. Supuran. Agrawal. Bioorg.…. Med. D.. Supuran. Sudele. 2. and di (i = 1. Bano. P. 3.Rev 2001. Mills. Scozzafavo. Regression analysis. Supuran. α (polarizability) and logP (logarithm of octanol/water partition coefficient) were calculated using ACD Labs software. Jaiswal... M.. 401-412. Lett.T.. Chem.T. Gupta. Carbonic anhydrase inhibitors: the first QSAR study on inhibition of tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides Bioorg. Khadikar.. Chem. 789-793. 7. Khadikar.Gao. Med. P.H.R. density (d).T. Balaban.. 2477. Thakur... 101. M. V. 123-129.5 Bonds where M is the number of bonds in G.T.V. A. P. µ is the cyclomatic number of G.

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