A General Equation Correlating Intramolecular Rates With

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.

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