On the Chemistry of the Resveratrol Diastereomers

Table S1. Relationship of E-state contribution index (SssOE), augmented eccentricA C A connectivity topochemical index (  C ), molecular connectivity index (  ) and connective eccentricity topochemical index (C c ) with CDK4 inhibitory activity CDK4 inhibitory activityCpd C A Predicted using R SssOE A   C c No. C MAA models Reported SssOE Ac  C  A C cA1 H 24.16 18.71 12.63 5.27 - - - - -A 2 7- Br 24.43 18.04 12.45 4.66 - - - - -A 3 6-Br 24.41 18.56 12.45 4.84 - - - - -A 4 6-NO2 24.4 19.78 13.69 5.48 - ± - ± -A 5 6-I 24.42 18.18 12.31 4.53 - - - - -O A 6 37.16 19.94 14.67 5.56 - ± ± ± - C N(Me)2A 7 N 24.94 20.61 14.99 5.65 + + + + + OA 8 N C CH3 36.02 19.20 14.27 5.36 - - - - - HA 9 N 25.11 20.26 15.49 5.57 - ± - ± -A10 25.06 20.10 15.71 5.59 ± ± - ± -O A11 24.91 20.51 14.96 5.63 + + + ± -O A12 24.92 20.51 14.96 5.63 + + + ± +S A13 25.09 20.98 14.60 5.55 ± + ± ± +O A14 HC 36.11 19.67 16.45 5.42 - ± ± ± +A15 C C 25.11 19.05 16.58 5.42 - - ± - - H HA16 C C 25.07 19.05 16.58 5.42 ± - ± - -B1 - 24.15 17.97 12.83 5.24 - - - - - B 2 -Br 24.4 18.10 12.65 4.83 - - - - - B 3 -Cl 24.4 18.34 12.92 5.18 - - - - - B 4 -OMe 24.47 18.51 13.61 5.34 - - - - - B 5 -NO2 46.56 19.12 13.89 5.46 - - - ± - B 6 -I 24.41 17.77 12.51 4.51 - - - - - O B 7 37.15 19.34 14.87 5.54 - ± ± ± - C N(Me)2B8 N 24.93 20.01 15.2 5.63 + ± + + + OB 9 N C CH3 36.01 18.60 14.47 5.34 - - ± - - HB10 N 25.1 19.72 15.7 5.57 - ± - ± -1 B11 N O 25.1 19.93 15.53 5.55 - ± - ± -B12 N N Me 25.17 19.67 15.98 5.50 - ± - ± - B13 HN 25.05 19.02 16.22 5.47 ± - ± ± -B14 25.05 19.53 15.80 5.57 ± ± - ± -B15 O 24.91 19.92 15.16 5.61 + ± + ± +B16 25.02 19.65 15.72 5.59 + ± - ± + NB17 S 24.98 20.46 14.80 5.54 + - ± ± +B18 F 25.04 19.29 16.07 5.44 ± ± - ± -B 19 Cl 25.15 19.09 15.88 5.32 - - - - -B 20 25.08 19.93 16.12 5.64 ± ± ± + + OHB 21 OH 25.07 19.34 16.12 5.47 ± ± ± ± +B 22 25.21 19.82 16.57 5.59 - ± ± ± - OMeB 23 OMe 25.18 19.28 16.57 5.44 - ± ± ± +B 24 O 25.45 19.64 19.12 5.54 - ± ± ± -B 25 -CN 25.14 18.46 13.72 5.35 - - - - -N C1 N 24.49 19.90 12.81 4.70 - ± - - -C2 N NH 24.48 19.04 12.75 4.71 - - - - -C 3 N N CH3 24.53 18.98 13.14 4.70 - - - - -C 4 24.48 18.55 12.73 4.61 - - - - - N N CH3C 5 N N CH3 24.54 19.15 13.14 4.70 - - - - -N D 1 N N Me 24.89 20.74 14.89 5.66 + + + + + N D 2 N N Me 24.89 20.75 14.89 5.66 + + + + + N N D 3 N N Me 24.86 20.97 14.83 5.69 - + ± + - N N D 4 N N Me 24.91 22.04 15.26 5.85 + + + + + N D 5 N N Me 24.87 20.78 14.83 5.63 + + ± ± + N N D 6 N N Me 24.86 20.76 14.83 5.63 - + ± ± - NNote: (+) active compound, (-) inactive compound and (±) compound in transitional rangeTable S2. List of molecular descriptors employed for the study Code Descriptor References A1 Molecular connectivity topochemical index 32,33 A2 Eccentric adjacency topochemical index 34 A3 Augmented eccentric connectivity topochemical index 35 A4 Eccentric connectivity topochemical index 36 A5 Connective eccentricity topochemical index 35 A6 Zagreb topochemical index 37 A7 Wiener’s topochemical index 38 A8 Molecular connectivity index 39 A9 Eccentric adjacency index 402 A10 Augmented eccentric connectivity index 41 A11 Eccentric connectivity index 42 A12 Connective eccentricity index 43 A13 Zagreb index 44, 45 A14 Wiener’s index 46, 47 A15 Balaban mean square distance index 48 A16 Superpendentic index 49 A17 Rotatable bond count 50 A18 S log p 51 Alignment independent descriptors 52 A19 T_C_O_7 A20 T_2_O_3 A21 T_2_N_4 A22 T_C_C_1 A23 T_2_T_5 Estate contribution descriptors 53, 54 A24 SssOE-index A25 SssCH2E-index A26 SdsCHE-index A27 SaaCHE-index A28 SssNHE-index A29 SdOE-index A30 5PathCount 50 A31 Chi5chain descriptor 55 A32 chiV0 A33 chiV4 pathCluster A34 kappa1 56, 57 A35 k2alpha 58 A36 Polarizability AHP 59 A37 Polarizability AHC 59 A38 Molecular Weight, MW 50 A39 XlogP 60 A40 SMR 51 A41 Hydrogens count 50 A42 Carbons count 50 A43 Polar surface area excluding P and S 61, 62 A44 Superaugmented eccentric connectivity topochemical index 1 63 A45 Superaugmented eccentric connectivity distance sum topochemical index-2 64 A46 Super adjacency topochemical index 65Table S3. Reported and predicted activity of 4-Aminomethylene isoquinoline-1, 3- dione derivatives used in training set with CDK4 inhibitory activity by MLR S. No. Index # pIC50 * R IC50 (μM) Residual Reported Predicted 1 1a H 4.1 5.38 6.1262 -0.739 2 2a 7- Br 1.4 5.85 6.1262 -0.27233 3 3a 6-Br 11 4.95 5.6047 -0.6461 4 4a 6-NO2 0.14 6.85 6.3819 0.472 5 5a 6-I 11 4.95 5.1650 -0.20646 6a O 0.39 6.40 6.3819 0.027 C N(Me)2 7 7a N 0.33 6.48 6.0138 0.4677 8 8a O N C CH3 0.22 6.65 6.9340 -0.2764 H 9 9a N 0.13 6.88 6.2694 0.6167 10 10a 14.3 4.84 5.5332 -0.6885 11 11a O 2.3 5.63 5.5332 0.105112 12a O 10 5 5.2518 -0.2518 13 1b - 1.1 5.95 6.1262 -0.1676 14 2b -Br 2.5 5.60 5.3536 0.2485 15 3b -Cl 2 5.69 4.8577 0.8413 16 4b -OMe 15.1 4.82 5.6456 -0.8246 17 5b -NO2 0.3 6.52 6.1262 0.3967 18 6b -I 21.2 4.6737 4.2038 0.4699 19 7b O 0.14 6.8539 6.3819 0.472 C N(Me)2 20 8b N 1 6 5.6456 0.3544 21 9b O N C CH3 1.8 5.7447 5.5332 0.2115 H 22 10b N 0.32 6.4948 6.3819 0.112923 11b N O 0.05 7.3010 6.3819 0.9191 24 12b N N Me 0.13 6.8861 6.9340 -0.0479 25 13b HN 0.31 6.5086 6.3819 0.1267 26 14b 19.4 4.7122 4.8365 -0.1243 27 15b O 0.027 7.5686 7.4952 0.073428 16b 0.041 7.3872 7.4627 -0.0755 N29 1c N N 50 4.3010 4.8204 -0.5194 30 2c N NH 15.8 4.8013 5.9013 -1.131 3c N N CH3 2.7 5.5686 5.6456 -0.077 32 4c 3 5.5229 5.1650 0.3579 N N CH3N 33 1d N N Me 0.11 6.9586 6.7500 0.2086 N 34 2d N N Me 0.82 6.0862 6.7500 -0.6638 N N 35 3d N N Me 0.08 7.0969 6.9340 0.1629 N N 36 4d N N Me 0.25 6.602 6.5659 0.03614 * = Compound concentration in micro mole required to inhibit CDK4 activity by 50%.-6 # = -Log (IC50 *10 )Table S4. Reported and predicted activity of 4-Aminomethylene isoquinoline-1, 3- dione derivatives used in training set with CDK4 inhibitory activity by PLSR S. No. Index # pIC50 * R IC50 (μM) Residual Reported Predicted 1 1a H 4.1 5.38 5.34 0.04 2 2a 7- Br 1.4 5.85 5.7 0.15 3 3a 6-Br 11 4.95 4.63 0.32 4 4a 6-NO2 0.14 6.85 6.32 0.53 5 5a 6-I 11 4.955 4.958 -0.0036 6a O 0.39 6.40 6.17 0.23 C N(Me)2 7 7a N 0.33 6.48 6.92 -0.44 8 8a O N C CH3 0.22 6.65 6.924 -0.274 H5 9 9a N 0.13 6.88 6.22 0.66 10 10a 14.3 4.84 6.426 -1.586 11 11a O 2.3 5.63 6.04 -0.4112 12a O 10 5 4.51 0.49 13 1b - 1.1 5.95 5.9 0.05 14 2b -Br 2.5 5.60 6.02 -0.42 15 3b -Cl 2 5.69 5.7 -0.01 16 4b -OMe 15.1 4.82 5.29 -0.4717 5b -NO2 0.3 6.52 6.003 0.517 18 6b -I 21.2 4.6737 5.55 -0.8763 19 7b O 0.14 6.8539 6.6 0.2539 C N(Me)2 20 8b N 1 6 5.8 0.2 21 9b O N C CH3 1.8 5.7447 6.21 -0.4653 H 22 10b N 0.32 6.4948 6.53 -0.035223 11b N O 0.05 7.3010 7.08 0.22 24 12b N N Me 0.13 6.8861 6.081 0.8051 25 13b HN 0.31 6.5086 6.6 -0.0914 26 14b 19.4 4.7122 4.9 -0.1878 27 15b O 0.027 7.5686 6.68 0.88628 16b 0.041 7.3872 6.57 0.8172 N29 1c N N 50 4.3010 5.3 -0.999 30 2c N NH 15.8 4.8013 4.95 -0.1487 31 3c N N CH3 2.7 5.5686 5.836 -0.2674 32 4c 3 5.5229 5.317 0.2059 N N CH3 N 33 1d N N Me 0.11 6.9586 6.6 0.3586 N 34 2d N N Me 0.82 6.0862 5.9 0.1862 N N 35 3d N N Me 0.08 7.0969 6.99 0.1069 N N 36 4d N N Me 0.25 6.602 5.835 0.7676 Table S5. Reported and predicted activity of 4-Aminomethylene isoquinoline-1, 3- dione derivatives used in test set for CDK4 inhibitory activity by PLSR # pIC50 * S. No. Index R IC50 (μM) Residual Reported Predicted 1. 13a S 12.1 4.9172 5.72 -0.80282. O 14a HC 0.48 6.3188 5.64 0.67883. 15a C C 41 4.3872 5.188 -0.8008 H H 4. 16a C C 1.62 5.7905 5.47 0.32055. 18a F 0.1 7 7.03 -0.036. 18b Cl 29 4.5376 4.7 -0.16247. 19b 3.3 5.4815 5.699 -0.2175 OH 8. 20b OH 3.5 5.4559 5.317 0.13899. 21b 0.92 6.0362 5.835 0.2012 OMe 10. 22b OMe 34.7 4.4597 4.7 -0.240311. 23b O 0.037 7.4318 7.28 0.151812. 24b -CN 27.8 4.5560 5.24 0.697 13. 25b N N CH3 0.32 6.4948 6.98 -0.485214. 5c N N CH3 2.8 5.5528 6.03 -0.477215. N 5d N N Me 0.13 6.8862 6.25 0.636216. N 6d N N Me 1.25 5.9031 5.95 -0.0469 NTable S6. Reported and predicted activity of 4-Aminomethylene isoquinoline-1, 3- dione derivatives used in training set with CDK4 inhibitory activity by PCRS. No. Index # pIC50 * R IC50 (μM) Residual Reported Predicted 1 1a H 4.1 5.38 5.57 -0.19 2 2a 7- Br 1.4 5.85 5.43 0.42 3 3a 6-Br 11 4.95 5.3347 -0.3847 4 4a 6-NO2 0.14 6.85 6.9674 -0.1174 5 5a 6-I 11 4.955 5.954 -0.9996 6a O 0.39 6.40 6.354 0.046 C N(Me)2 7 7a N 0.33 6.48 6.55 -0.07 8 8a O N C CH3 0.22 6.65 6.7089 -0.0589 H 9 9a N 0.13 6.88 6.147 0.733 10 10a 14.3 4.84 6.355 -1.515 11 11a O 2.3 5.63 6.3016 -0.671612 12a O 10 5 5.09 -0.09 13 1b - 1.1 5.95 5.443 0.507 14 2b -Br 2.5 5.60 5.44 0.16 15 3b -Cl 2 5.69 5.3732 0.3168 16 4b -OMe 15.1 4.82 5.229 -0.40917 5b -NO2 0.3 6.52 5.44 1.088 18 6b -I 21.2 4.6737 5.3352 -0.6615 19 7b O 0.14 6.8539 6.9674 -0.1135 C N(Me)2 20 8b N 1 6 5.43 0.57 21 9b O N C CH3 1.8 5.7447 6.33 -0.5853 H 22 10b N 0.32 6.4948 6.367 0.127823 11b N O 0.05 7.3010 6.404 0.997 24 12b N N Me 0.13 6.8861 6.069 0.8171 25 13b HN 0.31 6.5086 5.6401 0.9685 26 14b 19.4 4.7122 6.23 -1.5178 27 15b O 0.027 7.5686 6.7457 0.822928 16b 0.041 7.3872 7.1471 0.2401 N29 1c N N 50 4.3010 5.0633 -0.7623 30 2c N NH 15.8 4.8013 5.229 -0.4277 31 3c N N CH3 2.7 5.5686 5.836 -0.2674 32 4c 3 5.5229 5.4436 0.0793 N N CH3 N 33 1d N N Me 0.11 6.9586 6.46 0.4986 N 34 2d N N Me 0.82 6.0862 6.278 -0.1918 N N 35 3d N N Me 0.08 7.0969 6.3781 0.7188 N N 36 4d N N Me 0.25 6.602 6.7089 -0.10699 Table S7. Reported and predicted activity of 4-Aminomethylene isoquinoline-1, 3- dione derivatives used in test set for CDK4 inhibitory activity by PCR # pIC50 * S. No. Index R IC50 (μM) Residual Reported Predicted 17. 13a S 12.1 4.9172 5.3347 -0.417518. O 14a HC 0.48 6.3188 5.437 0.881819. 15a C C 41 4.3872 5.32 -0.9328 H H 20. 16a C C 1.62 5.7905 5.4458 0.344721. 18a F 0.1 7 6.9422 0.057822. 18b Cl 29 4.5376 5.089 -0.551423. 19b 3.3 5.4815 5.571 -0.0895 OH 24. 20b OH 3.5 5.4559 5.3455 0.110425. 21b 0.92 6.0362 5.4566 0.5796 OMe 26. 22b OMe 34.7 4.4597 5.45 -0.990327. 23b O 0.037 7.4318 6.104 1.327828. 24b -CN 27.8 4.5560 5.45 -0.89429. 25b N N CH3 0.32 6.4948 6.367 0.127830. 5c N N CH3 2.8 5.5528 5.836 -0.283231. N 5d N N Me 0.13 6.8862 6.147 0.739210 32. N 6d N N Me 1.25 5.9031 6.2426 -0.3395 N11

On the Chemistry of the Resveratrol Diastereomers

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