Prodrugs for Masking Bitter Taste of Antibacterial Drugs - A Computational Approach
Rafik Karaman*
Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University Box 20002, Jerusalem.
*Corresponding author: Rafik Karaman,
Supplementary Material
Contents:
Table S1 and xyz Cartesian coordinates for the DFT optimized GM and TS in processes 1-12, Inter , acyclovir ProD 1- ProD 4 and cefuroxime ProD 1- ProD 4.
It .should be noted that TS2 and TS3 are the transition states for the tetrahedral intermediate formation and breakdown, respectively. In the xyz files where TS is indicated it refers to the transition state for the tetrahedral intermediate formation
Table S1. DFT (B3LYP/6-31G (d,p)) calculated properties for the acid catalyzed hydrolysis of acid amides 1-12, acyclovir ProD 1- ProD 4, cefuroxime ProD 1- ProD 4 and Inter.
Compound / Enthalpy, H(gas phase)
In Hartree / (gas phase)
Entropy, S,
Cal/Mol-Kelvin / Frequency
Cm-1
1GM / -551.6209552 / 115.71 / ------
1INT2 / -551.5899873 / 113.12 / ------
1TS / -551.9510979 / 100.58 / 29.18i
2GM / -630.2556684 / 133.45 / ------
2INT2 / -630.2424070 / 125.08 / ------
2TS / -630.6125865 / 117.89 / 57.26i
3GM / -590.9452364 / 126.16 / ------
3INT2 / -590.9162845 / 124.52 / ------
3TS / -591.284155 / 109.50 / 45.91i
4GM / -668.3716758 / 131.90 / ------
4INT2 / -668.3272626 / 125.09 / ------
4TS / -668.7001822 / 116.95 / 73.72i
5GM / -707.6805570 / 136.69 / ------
5INT2 / -707.6689275 / 122.73 / ------
5TS / -707.6321442 / 122.88 / 118.05i
6GM / -630.2606708 / 132.74 / ------
6INT2 / -630.2326178 / 132.45 / ------
6TS / -630.60156591 / 116.93 / 52.77i
7GM / -669.5780833 / 138.31 / ------
7INT2 / -669.5495044 / 137.75 / ------
7TS / -669.9185072 / 124.96 / 68.64i
8GM / -888.6478787 / 140.60 / ------
8INT2 / -888.6201859 / 137.62 / ------
8TS / -888.9742696 / 120.84 / 37.75i
9GM / -1225.6575172 / 145.62 / ------
9INT2 / -1225.6422023 / 147.77 / ------
9TS / -1225.9938255 / 140.05 / 33.82i
10GM / -849.3302758 / 134.63 / ------
10INT2 / -849.3095129 / 114.95 / ------
10TS / -849.2721283 / 122.84 / 92.14i
11GM / -1186.3372601 / 145.78 / ------
11INT2 / -1186.3271376 / 136.12 / ------
11TS / -1186.2730867 / 135.57 / 148.15i
12GM / -1523.3652973 / 163.37 / ------
12INT2 / -1523.3731299 / 154.94 / ------
12TS / -1523.3352867 / 149.02 / 119.78i
Aciclovir
ProD1 GM / -1268.8689365 / 172.98 / ------
Aciclovir
ProD1 INT2 / -1268.8710712 / 171.06 / ------
Aciclovir
ProD1 TS / -1268.8183062 / 169.43 / 134.62i
Aciclovir
ProD2 GM / -1864.2702113 / 193.14 / ------
Aciclovir
ProD2 INT2 / -1864.2731292 / 190.94 / ------
Aciclovir
ProD2 TS / -1864.2190556 / 186.37 / 79.43i
Aciclovir
ProD3 GM / -1229.5483175 / 164.26 / ------
Aciclovir
ProD3 INT2 / -1229.5446492 / 162.24 / ------
Aciclovir
ProD3 TS / -1229.5029859 / 157.29 / 92.96i
Aciclovir
ProD4 GM / -1190.2238966 / 161.03 / ------
Aciclovir
ProD4 INT2 / -1190.2183473 / 156.05 / ------
Aciclovir
ProD4 TS / -1190.1752961 / 149.14 / 102.40i
Cefuroxime
ProD1 GM / -820.1196031 / 183.03 / ------
Cefuroxime
ProD1 INT2 / -1820.1072976 / 180.68 / ------
Cefuroxime
ProD1 TS / -1820.0787016 / 177.71 / 127.02i
Cefuroxime
ProD2 GM / -1859.4428471 / 194.51 / ------
Cefuroxime
ProD2 INT2 / -1859.4337326 / 193.52 / ------
Cefuroxime
ProD2 TS / -1859.4105339 / 187.23 / 108.77i
Cefuroxime
ProD3 GM / -1898.7696851 / 197.75 / ------
Cefuroxime
ProD3 INT2 / -1898.7583509 / 201.19 / ------
Cefuroxime
ProD3 TS / -1898.7308297 / 191.84 / 103.97i
Cefuroxime
ProD4 GM / -2494.1524194 / 214.78 / ------
Cefuroxime
ProD4 INT2 / -2494.1736956 / 218.64 / ------
Cefuroxime
ProD4 TS / -2494.1345681 / 212.80 / 104.36i
InterGM / -631.4579281 / 141.61 / ------
InterINT2 / -631.4282861 / 129.50 / ------
InterTS / -631.7933134 / 130.70 / 57.27i
GM, INT and TS are global minimum, intermediate and transition state structures, respectively.
1GM
O 0.000000 0.000000 0.000000
H 0.000000 0.000000 0.972557
O 0.103940 0.000000 2.955850
C -0.887138 0.242026 3.630726
O -2.064599 0.485390 3.093546
H -2.763279 0.664073 3.793927
O -3.654316 0.908630 5.047128
C -2.999556 0.801639 6.098595
C -1.549454 0.476310 6.150232
C -0.706222 0.250999 5.127312
H 0.326465 0.027058 5.377585
H 0.921585 -0.181627 -0.220072
H -1.123777 0.415034 7.150394
N -3.577288 0.980128 7.310620
H -3.005449 0.878562 8.135536
C -4.985221 1.303235 7.480972
H -5.503174 0.508881 8.027893
H -5.101226 2.245217 8.025795
H -5.427417 1.403372 6.490622
1TS2
O 0.000000 0.000000 0.000000
C 0.000000 0.000000 2.300000
C 1.488131 0.000000 2.191998
C 2.106892 0.003465 1.009580
C 1.261300 0.040459 -0.249237
O 1.832990 0.096728 -1.342907
H 3.188988 -0.016887 0.923797
H 2.020508 -0.010903 3.141212
O -0.748625 -1.074386 2.090760
H -0.538480 -1.279255 1.141255
N -0.565067 0.980923 2.977121
H 0.038092 1.753107 3.229720
C -1.994708 1.108173 3.257295
H -2.333785 2.100293 2.951678
H -2.185280 0.970622 4.325212
H -2.528989 0.346550 2.693573
H 0.418056 0.114052 -2.652631
O -0.331152 0.114979 -3.277384
H -1.077997 0.218394 -2.674518
1TS3
N 0.000000 0.000000 0.000000
C 0.000000 0.000000 1.842000
C 1.424098 0.000000 2.302630
C 1.687023 -1.210479 2.804805
C 0.494049 -2.070738 2.611690
O -0.553274 -1.222830 2.131428
O 0.309324 -3.242744 2.726837
O -0.717562 1.070391 2.185936
C -1.334994 0.331169 -0.551035
H -1.302964 0.268532 -1.640701
H -1.614454 1.342553 -0.255289
H -2.050942 -0.399811 -0.174588
H 0.254259 -0.962401 -0.285602
H 2.054080 0.880033 2.273406
H 2.605830 -1.583248 3.237821
H -1.662472 0.848138 2.252983
H 0.726751 0.660237 -0.282791
H -0.022904 -2.848425 0.621437
O -0.121234 -2.665682 -0.323159
H 0.103919 -3.483313 -0.784024
2GM
C 0.000000 0.000000 0.000000
N 0.000000 0.000000 1.456672
C 1.148969 0.000000 2.172872
O 2.243720 -0.059865 1.583555
C 0.993886 0.024245 3.668381
C 1.847858 0.640262 4.527846
C 3.095723 1.450446 4.188003
O 3.454502 2.327235 4.960771
O 3.801559 1.175584 3.105238
C 1.550033 0.642375 6.013266
C -0.239871 -0.684428 4.204023
H -0.874116 0.145854 1.937095
H 0.817178 -0.628426 -0.354475
H 0.140958 1.008334 -0.405126
H -0.950922 -0.400082 -0.356921
H 3.320145 0.535200 2.496992
H -0.583077 -1.461992 3.517930
H -0.033648 -1.162076 5.162960
H -1.074496 0.011016 4.372940
H 2.211596 1.341249 6.520523
H 0.515356 0.930987 6.221182
H 1.702224 -0.357149 6.439902
H 5.034086 3.309208 4.275989
O 5.784067 3.797548 3.896164
H 5.996708 3.272715 3.114750
2TS2
O 0.000000 0.000000 0.000000
C 0.000000 0.000000 2.300000
C 1.496568 0.000000 2.247634
C 2.123883 0.083670 1.059712
C 1.254346 0.170338 -0.201085
O 1.824404 0.382991 -1.280611
C 3.606759 0.083979 0.848143
C 2.136108 -0.159065 3.611027
O -0.711033 -1.124202 2.205319
H -0.464264 -1.473780 1.323139
N -0.616560 1.028683 2.848957
H -0.045687 1.850615 2.997524
C -2.062461 1.166501 3.016957
H -2.437585 1.943883 2.345924
H -2.291225 1.433877 4.051478
H -2.533707 0.217594 2.772588
H 0.409505 0.512199 -2.560938
O -0.345667 0.583837 -3.175805
H -1.083369 0.381805 -2.586717
H 3.220541 -0.234621 3.530060
H 1.903570 0.679988 4.278959
H 1.772117 -1.067700 4.105821
H 3.847349 0.810828 0.069263
H 4.180642 0.302688 1.751011
H 3.929862 -0.889907 0.460644
2TS3
N 0.000000 0.000000 0.000000
C 0.000000 0.000000 1.842000
C 1.438062 0.000000 2.275903
C 1.706813 -1.232352 2.755529
C 0.492205 -2.069763 2.593856
O -0.555653 -1.218964 2.115120
O 0.299756 -3.242695 2.721380
O -0.723819 1.064291 2.198270
C -1.308526 0.419039 -0.556633
H -1.255035 0.424271 -1.647478
H -1.555779 1.419394 -0.200502
H -2.063964 -0.303305 -0.245299
H 0.191849 -0.981853 -0.290820
C 2.281690 1.227603 2.212763
C 2.946853 -1.809759 3.349993
H -1.656704 0.819057 2.319610
H 1.808228 2.039116 2.776198
H 3.273307 1.048045 2.629024
H 2.410060 1.587549 1.184548
H 2.785976 -2.048207 4.406977
H 3.206628 -2.748780 2.851326
H 3.791018 -1.123515 3.274095
H -0.047379 -2.939051 0.511236
O -0.182541 -2.760683 -0.428711
H 0.248816 -3.481688 -0.905686
H 0.749435 0.615822 -0.316331
3GM
O 0.000000 0.000000 0.000000
H 0.000000 0.000000 0.972014
O 0.104098 0.000000 2.958331
C 1.263380 0.047795 3.344066
O 2.270047 0.089585 2.495301
H 3.173477 0.127724 2.955407
O 4.406319 0.179672 3.805423
C 4.080260 0.165379 5.008280
C 2.687326 0.107324 5.513296
C 1.510143 0.057751 4.849466
C 0.226688 0.003375 5.635639
H 0.942477 0.032532 -0.205012
H 2.614352 0.104361 6.599528
N 5.022497 0.203970 5.981189
H 4.719777 0.189843 6.943288
C 6.449484 0.262872 5.707622
H 6.888742 1.169469 6.135778
H 6.960587 -0.611074 6.123920
H 6.583320 0.275298 4.626839
H -0.414711 0.848805 5.369961
H -0.339838 -0.894470 5.371751
H 0.412139 0.012410 6.711832
3TS2
O 0.000000 0.000000 0.000000
C 0.000000 0.000000 2.300000
C 1.482013 0.000000 2.188697
C 2.126426 -0.005807 1.013083
C 1.258679 0.031759 -0.246345
O 1.827232 0.081270 -1.343744
C 3.611710 -0.037038 0.856806
H 2.009307 0.002003 3.141370
O -0.760175 -1.067468 2.087074
H -0.546897 -1.278595 1.141330
N -0.562842 0.978224 2.985111
H 0.043855 1.746320 3.240904
C -1.989695 1.104459 3.276390
H -2.336635 2.090150 2.958469
H -2.171559 0.982829 4.347992
H -2.524614 0.331784 2.728861
H 0.400205 0.130602 -2.632731
O -0.356867 0.155072 -3.247759
H -1.099221 0.161304 -2.630614
H 3.939118 0.824853 0.267417
H 4.136445 -0.049086 1.815422
H 3.900356 -0.918554 0.274914
3TS3
N 0.000000 0.000000 0.000000
C 0.000000 0.000000 1.842000
C 1.427018 0.000000 2.270615
C 1.724616 -1.208466 2.772444
C 0.509357 -2.065374 2.618934
O -0.538535 -1.230579 2.124778
O 0.336372 -3.238386 2.759601
O -0.734950 1.053602 2.200362
C -1.300849 0.437253 -0.560501
H -1.236120 0.461807 -1.650491
H -1.544944 1.432935 -0.189341
H -2.064034 -0.285627 -0.269640
H 0.185559 -0.982045 -0.295910
H 2.056070 0.879197 2.210209
C 2.975735 -1.747230 3.373373
H -1.666796 0.800137 2.313453
H -0.044727 -2.925378 0.499629
O -0.182898 -2.748880 -0.439618
H 0.239972 -3.473766 -0.918416
H 3.276459 -2.669162 2.865167
H 3.789423 -1.023138 3.318313
H 2.805879 -2.009111 4.423468
H 0.758179 0.610857 -0.306540
4GM
C 0.000000 0.000000 0.000000
C 0.000000 0.000000 1.357189
C 1.425731 0.000000 1.896212
C 2.277527 0.390309 0.668866
C 1.411384 0.000537 -0.543891
C -1.176126 -0.054040 2.265570
O -2.358882 0.048277 1.883740
C -1.106899 -0.064870 -1.020915
O -2.369221 0.024416 -0.644427
N -0.907206 -0.205968 3.582781
O -0.793978 -0.189083 -2.197526
H 1.688412 -1.002111 2.268087
H 1.563196 0.698167 2.730746
H 2.440054 1.472863 0.671938
H 3.259448 -0.088710 0.667947
H 1.647930 -1.002838 -0.923178
H 1.513629 0.672724 -1.398950
H -2.454055 0.082200 0.361218
H -2.349885 -0.246787 -3.406891
O -3.092329 -0.309007 -4.032180
H -3.861676 -0.253980 -3.452281
C -1.969906 -0.303617 4.573415
H 0.044856 -0.356620 3.875469
H -1.551532 -0.105255 5.561446
H -2.742477 0.433052 4.348607
H -2.433850 -1.296238 4.571374
4TS2
O 0.000000 0.000000 0.000000
C 0.000000 0.000000 2.300000
C 1.471872 0.000000 2.263514
C 2.086464 0.062955 1.074481
C 1.258107 0.138526 -0.196547
C 3.580059 0.002370 1.225819
C 3.789417 0.205366 2.751689
C 2.434547 -0.170164 3.422728
O -0.583981 -1.150570 2.583908
N -0.678686 1.146376 2.414534
C -2.113753 1.223642 2.135608
O 1.846912 0.340046 -1.272109
H 2.423978 -1.209152 3.780187
H 2.201236 0.463146 4.286437
H 4.001594 1.261328 2.949425
H 4.625216 -0.373428 3.153363
H 3.941539 -0.976373 0.882346
H 4.087290 0.748277 0.606975
H -2.419407 2.268128 2.188713
H -2.688866 0.678667 2.891981
H -2.320446 0.836911 1.131576
H -1.550935 -1.086094 2.541916
H 0.818667 1.132699 -2.598814
O 0.236629 1.521939 -3.283708
H -0.174471 0.742292 -3.675447
H -0.142705 1.939820 2.086658
4TS3
N 0.000000 0.000000 0.000000
C 0.000000 0.000000 1.842000
O 1.343539 0.000000 2.134620
C 1.692771 1.285140 2.728646
C 0.423194 2.019698 2.836344
C -0.562587 1.305238 2.283365
C -1.902237 1.968836 2.376182
C -1.510342 3.399109 2.887721
C -0.040525 3.323356 3.412651
C 0.233781 -1.356128 -0.557810
H -0.538858 -2.035733 -0.197404
H 0.198219 -1.310372 -1.648256
H 1.228466 -1.680989 -0.250714
H -0.895225 0.376336 -0.314297
O -0.672024 -1.099393 2.192244
H -2.449994 1.997181 1.427929
H -2.539790 1.425201 3.085105
H -2.198375 3.751794 3.657241
H -1.564194 4.107162 2.057053
H 0.568023 4.173676 3.091765
H 0.012746 3.292846 4.507156
H -0.057256 -1.842719 2.316671
O 2.835698 1.550220 2.943025
H 2.629953 1.242479 0.549885
O 2.551654 1.070103 -0.395813
H 3.092786 1.730888 -0.845859
H 0.772172 0.615113 -0.311555
5GM
O 0.000000 0.000000 0.000000
H 0.000000 0.000000 0.972781
O 0.103006 0.000000 2.938247
C -0.932711 0.375391 3.471222
O -1.918732 0.879793 2.753362
H -2.746654 1.034423 3.307020
O -3.906285 0.973136 4.282339
C -3.561157 0.366568 5.314494
N -4.505210 -0.215427 6.091507
H -4.213364 -0.798981 6.859202
C -5.914399 -0.208393 5.724150
H -6.153774 0.749767 5.263418
H -6.152195 -1.003015 5.007576
H -6.517834 -0.344742 6.623565
H -0.747974 0.571869 -0.211150
C -1.038918 0.278871 4.984640
C -2.142517 0.249162 5.781024
C 0.295718 0.096465 5.676940
C 0.454607 1.042886 6.887085
C -0.818559 1.083799 7.764907
C -1.883456 0.078278 7.271136
H 0.365806 -0.944784 6.024995
H 1.102648 0.231880 4.958368
H 1.319641 0.716069 7.472561
H 0.689223 2.047317 6.521694
H -0.584464 0.864842 8.811696
H -1.261067 2.084849 7.746079
H -2.794744 0.219541 7.857252
H -1.526279 -0.943146 7.469580
5TS2
O 0.000000 0.000000 0.000000
C 0.000000 0.000000 2.300000
C 1.494092 0.000000 2.266381
C 2.103394 0.142867 1.072298
C 1.256054 0.193955 -0.191493
O 1.837036 0.371811 -1.271552
C 3.590708 0.282008 0.920866
C 2.205397 -0.239444 3.586304
O -0.725204 -1.111184 2.159854
H -0.497025 -1.386201 1.240821
N -0.610322 1.027959 2.856241
H -0.025572 1.825067 3.070662
C -2.054013 1.171590 3.033154
H -2.370875 2.135971 2.630087
H -2.317595 1.115508 4.093319
H -2.548738 0.367533 2.493196
H 0.428437 0.477805 -2.562659
O -0.323201 0.538741 -3.182924
H -1.064365 0.351026 -2.593466
C 3.717074 -0.435387 3.379195
H 2.038310 0.620655 4.253874
H 1.753966 -1.097359 4.100701
H 3.772556 1.094639 0.209666
C 4.283368 0.497860 2.274005
H 3.992150 -0.614215 0.429940
H 4.232236 -0.269067 4.332821
H 3.912289 -1.478942 3.089459
H 5.363246 0.345521 2.168231
H 4.143989 1.540506 2.597909
5TS3
N 0.000000 0.000000 0.000000
C 0.000000 0.000000 1.842000
O 1.329720 0.000000 2.133969
C 1.651865 1.272103 2.730090
O 2.786095 1.536740 2.989770
H 3.539615 0.945557 1.106638
O 3.929060 0.666507 0.267196
H 4.524478 -0.055330 0.507013
H -0.969890 0.167895 -0.274196
C 0.945758 0.937541 -0.665881
H 1.975141 0.654359 -0.417954
H 0.800271 0.887456 -1.747474
H 0.732542 1.951686 -0.324380
C 0.385143 2.023922 2.840397
C -0.602448 1.294431 2.281318
C -2.038350 1.706078 2.213825
C -2.167431 3.211459 2.535394
C -1.292756 3.626796 3.731114
C 0.206689 3.364532 3.476824
H 0.636003 4.130737 2.816952
H 0.785463 3.414052 4.405354
H -1.606681 3.071766 4.623304
H -2.606813 1.098603 2.932042
H -3.216076 3.446109 2.735391
H -1.878008 3.792605 1.651242
H -2.474397 1.479887 1.231791
H -1.443458 4.686524 3.952146
O -0.678528 -1.112480 2.148378
H -0.067282 -1.853234 2.302355
H 0.218151 -0.968722 -0.242393
6GM
O 0.000000 0.000000 0.000000
H 0.000000 0.000000 0.971926
O 0.104584 0.000000 2.967515
C 0.067683 1.151524 3.379921
O 0.028106 2.171698 2.547179
H -0.026373 3.075040 3.004244
O -0.292376 4.268200 3.893264
C -0.401747 3.897809 5.077893
C -0.128091 2.524790 5.566835
C 0.076486 1.372766 4.890540
C 0.352451 0.103220 5.664553
H -0.001983 0.942830 -0.205778
H -0.108281 2.441338 6.652564
N -0.768971 4.771180 6.046676
H -0.857335 4.429253 6.991586
C -1.072581 6.169127 5.786106
H -2.108004 6.399122 6.056849
H -0.402190 6.822451 6.353340
H -0.932667 6.348203 4.720979
H -0.306384 -0.681291 5.282040
C 1.810423 -0.364497 5.513645
H 0.115046 0.261115 6.721755
H 1.962316 -1.300419 6.058905
H 2.047634 -0.541181 4.462270
H 2.507341 0.379522 5.912537
6TS2
O 0.000000 0.000000 0.000000
C 0.000000 0.000000 2.300000
C 1.481589 0.000000 2.190705
C 2.127810 -0.003022 1.015529
C 1.258446 0.032194 -0.244830
O 1.825660 0.079207 -1.343475
C 3.616280 -0.029283 0.840529
H 2.003061 0.002178 3.145524
O -0.760135 -1.067811 2.087646