Latin American Applied Research 44:137-140 (2014)

STUDY ON STRUCTURE-ACTIVITY RELATIONSHIP OF 2E-3- PHENYL PROPENYL ACYLOXY ALKYL PHOSPHONATE MOLECULAR DERIVATIVES

H.-M. BI†, P.-T. XIE†, J.-P. HU†, Y. LIU†, F.-Y. YOU† and L.-P. MENG‡

† key laboratory of organic small molecule materials, Handan College, Handan 056002, . [email protected] ‡ , Shijiazhuang, Hebei Province 050091, China

Abstract— The quantum chemistry calculation of obtained. Harmonic vibrational frequencies calculated at 2E-3-phenyl propenyl acyloxy alkyl phosphonate the same level were used for the characterization of sta- derivates was carried out to investigate the relation- tionary points as a minimum. All quantum calculations ship between the structure and plant regulator activ- were performed with the Gaussian 03 program. The ity of these compounds. All the compounds were logP, V, M, Sg and Rm were calculated by Hyperchem studied by HF method with 6-31G* basis set using using the optimized configuration from the result of the PCM model within the self-consistent reaction Gaussian 03. field method to assess solvent effects, and then we es- tablished mathematical correlation between the B. Results and discussions properties and bioactivity of these compounds. The Stability configurations and natural charge result showed that the bioactivity of these com- Figure 1 depicts the structure of compounds. The atom- pounds has a linear relationship with the frontier ic natural charges of compounds are given in Table 1. orbital energy and other properties. At the same These data show that the negative charge is mainly con- time, the active sites of these molecules were predict- centrated in the C (8), and O (10) of carbonyl, These at- ed. These compounds are electron acceptors. oms make the electronegative area of the compound and they could combine with positive area of receptor. The Keywords phosphonate derivatives; quantum positive charge is mainly concentrated in the C (9) of chemistry; quantitative structure-activity relation- carbonyl , P, and N of R in the compound. These atoms ships; solvent effects. are the positive area of the molecule, and they could I. INTRODUCTION combine with negative area of receptor. Phosphonate derivatives are important insecticides (Bai- The energy, main composition and proportion of the riki et al., 2012; Heinze et al., 2012; Chang et al., frontier molecules orbital 2011), have a wide activity about herbicidal sterilization According to the theory of molecular orbital (MO), the and plant growth regulating and so on (Shaekhov et al., highest occupied molecular orbital (HOMO) and the 2011; He, 2003). Wang Tao synthesized 2E-3-phenyl lowest unoccupied molecular orbital (LUMO) have the propenyl acyloxy alkyl phosphonate molecular deriva- greatest influence on the activity of compounds. The re- tives (Wang et al., 2011; He and Liu, 2001) and deter- action between active molecule and macromolecular re- mined the biological activity of these compounds. The ceptor operated on the frontier molecules orbital. EHOMO results showed that these compounds have good plant is the energy of HOMO, which relates to the molecular regulating activity to the plant root cells under certain electron donor abilities. ELUMO is the energy of LUMO, conditions. which relates to the molecular ability of electron ac- A theoretical study of 2E-3-phenyl propenyl acyloxy ceptance. For pesticide molecules, too low-ELUMO or too alkyl phosphonate derivatives was carried out. The high-EHOMO means that the intrinsic molecular activity study found a correlation between the antibacterial ac- is too strong and it is easy to be metabolized in organ- tivity of these compounds (Bittner et al., 2009; Gacitúa ism, The effect of pesticides is difficult to control, so the et al., 2009) and structural parameters. The main factors ELUMO or EHOMO of a pesticide molecule should be suit- affecting the biological activity were analyzed, the in- able to estimate an expected activity value (Wei et al., fluence in biological activity from the changes in the 2009; Yang et al., 1998). molecular structure was explained and the mechanism H 3C H 2C R and sites of action of compounds were discussed. O 3 2 P CH 9 8 7 4 1 O 12 O C H C H C II. METHODS 11 H 3C H 2C O 5 6 A. Method of Calculations 10 All the compounds were studied by HF method with 6- R=(4a) H; (4b)CH3; (4c)CH3CH2; (4d)CH3CH2CH2; 31G* basis set using the PCM model within the self- (4e)(CH3)2CH; (4f)Ph; (4g)4-CH3Ph; (4h)4-ClPh; consistent reaction field method to assess solvent ef- (4i)2-ClPh; (4j)2, 4-Cl2Ph; (4k)4-CH3OPh; fects. For these molecules, the solvation free energies (4l)3-NO2Ph; (4m)2-Furyl; Figure 1. The structure of compounds (ΔGsol) in water and the dipole moments in water were

137 Latin American Applied Research 44:137-140 (2014)

Table 1-The atomic natural charge of compounds Compd. P C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) O(10) R 4a 1.516 -0.206 -0.228 -0.188 -0.107 -0.187 -0.230 -0.072 -0.412 0.983 -0.706 — 4b 1.510 -0.211 -0.227 -0.193 -0.099 -0.192 -0.228 -0.092 -0.384 0.988 -0.702 — 4c 1.514 -0.211 -0.227 -0.193 -0.099 -0.192 -0.228 -0.092 -0.383 0.989 -0.702 — 4d 1.512 -0.210 -0.227 -0.191 -0.100 -0.191 -0.228 -0.092 -0.391 0.986 -0.708 — 4e 1.515 -0.210 -0.228 -0.191 -0.100 -0.191 -0.228 -0.092 -0.397 0.983 -0.700 — 4f 1.518 -0.216 -0.227 -0.197 -0.093 -0.197 -0.227 -0.109 -0.366 0.987 -0.706 — 4g 1.518 -0.216 -0.227 -0.197 -0.092 -0.197 -0.228 -0.110 -0.365 0.987 -0.707 — 4h 1.520 -0.214 -0.226 -0.196 -0.095 -0.196 -0.227 -0.104 -0.371 0.986 -0.702 — 4i 1.526 -0.212 -0.228 -0.193 -0.098 -0.193 -0.228 -0.095 -0.377 0.987 -0.696 — 4j 1.528 -0.210 -0.227 -0.191 -0.100 -0.192 -0.229 -0.090 -0.382 0.986 -0.692 — 4k 1.517 -0.216 -0.227 -0.197 -0.092 -0.197 -0.227 -0.110 -0.365 0.988 -0.707 — 4l 1.518 -0.212 -0.226 -0.195 -0.097 -0.194 -0.227 -0.098 -0.377 0.986 -0.696 N 0.666 C(1)0.301; 4m 1.539 -0.207 -0.228 -0.188 -0.105 -0.188 -0.230 -0.079 -0.408 0.984 -0.693 C(2)-0.326

Table 2. The energy of the molecular frontier orbitals (eV)

Compd EHOMO ELUMO ΔE Compd EHOMO ELUMO ΔE 4a -8.70554 1.887669 10.5932 4h -8.51778 2.174751 10.69253 4b -8.60322 2.093116 10.69634 4i -8.52621 2.082232 10.60844 4c -8.60131 2.093933 10.69525 4j -8.58608 1.989712 10.57579 4d -8.60921 2.040326 10.64953 4k -8.40757 2.284686 10.69225 4e -8.61274 2.032162 10.64491 4l -8.6073 1.423439 10.03074 4f -8.44594 2.271624 10.71756 4m -8.45737 1.92767 10.38504 4g -8.42607 2.278699 10.70477

Table 3. The main composition and proportion of molecular frontiers orbital Compd R HOMO LUMO C(1)20.39; C(2)3.73; C(3)7.25; C(4)22.02; C(1)14.93; C(3)9.44; C(4)7.81; C(5)6.00; 4a H C(5)7.46; C(6)4.74; C(7)5.92; C(8)23.17; C(6)3.08; C(7)22.51; C(8)17.97; C(9)5.79; O(10)4.85 O(10)5.64; C(1)19.89; C(2)3.61; C(3)7.29; C(4)21.06; C(1)15.52; C(3)9.70; C(4)9.45; C(5)6.03; 4b CH3 C(5)7.61; C(6)4.34; C(7)6.93; C(8)22.52; C(6)3.44; C(7)20.44; C(8)18.12; C(9)5.21; O(10)3.67 O(10)5.17; C(1)19.86; C(2)3.61; C(3)7.29; C(4)21.03; C(1)15.46; C(3)9.67; C(4)9.42; C(5)6.00; 4c CH2CH3 C(5)7.61; C(6)4.34; C(7)6.94; C(8)22.50; C(6)3.44; C(7)20.38; C(8)18.09; C(9)5.18; O(10)3.66 O(10)5.12; C(1)20.08; C(2)3.56; C(3)7.35; C(4)21.36; C(1)14.74; C(3)9.34; C(4)8.57; C(5)5.68; 4d CH2CH2CH3 C(5)7.63; C(6)4.48; C(7)6.96; C(8)22.73; C(6)3.30; C(7)20.32; C(8)17.56; C(9)5.18; O(10)4.40 O(10)5.00; C(1)20.15; C(2)3.55; C(3)7.39; C(4)21.44; C(1)14.82; C(3)9.35; C(4)8.59; C(5)5.76; 4e CH(CH3)2 C(5)7.62; C(6)4.53; C(7)6.94; C(8)22.78; C(6)3.28; C(7)20.66; C(8)17.60; C(9)5.37; O(10)4.54 O(10)5.31; C(1)14.48; C(3)8.87; C(4)9.43; C(5)5.65; C(1)9.32; C(2)3.35; C(3)7.45; C(4)21.21; C(5)7.58; 4f C(6)3.26; C(7)18.38; C(8)16.44; C(9)5.42; C(6)4.08; C(7)8.04; C(8)21.29; O(10)3.99 O(10)5.05; C(1)18.72; C(2)3.20; C(3)7.29; C(4)19.56; C(1)14.60; C(3)8.92; C(4)9.46; C(5)5.63;

4g C H 3 C(5)7.41; C(6)3.94; C(7)8.05; C(8)20.91; C(6)3.31; C(7)18.26; C(8)16.48; C(9)5.38; O(10)4.03 O(10)5.02; C(1)19.61; C(2)3.53; C(3)7.35; C(4)20.66; C(1)13.70; C(3)8.55; C(4)8.71; C(5)5.48; 4h C l C(5)7.58; C(6)4.19; C(7)7.60; C(8)21.29; C(6)3.02; C(7)18.53; C(8)16.12; C(9)5.37; O(10)3.94 O(10)4.98; C l C(1)19.45; C(2)3.37; C(3)7.37; C(4)20.49; C(1)14.52; C(3)8.88; C(4)8.42; C(5)5.73; 4i C(5)7.54; C(6)4.24; C(7)7.38; C(8)22.41; C(6)3.10; C(7)20.37; C(8)17.17; C(9)6.01; O(10)4.10 O(10)5.83; C l C(1)19.65; C(2)3.47; C(3)7.26; C(4)20.85; C(1)13.98; C(3)8.68; C(4)7.80; C(5)5.63; 4j C(5)7.50; C(6)4.36; C(7)7.38; C(8)22.45; C(6)2.90; C(7)20.72; C(8)16.95; C(9)6.02; C l O(10)4.15 O(10)5.86; C(1)13.27; C(2)2.29; C(3)5.27; C(4)13.93; C(1)14.50; C(3)8.87; C(4)9.47; C(5)5.60;

4k O C H 3 C(5)5.36; C(6)2.74; C(7)6.12; C(8)15.15; C(6)3.30; C(7)18.27; C(8)16.46; C(9)5.32; O(10)3.33; R-C 23.85; R-O 5.04 O(10)4.96; N O 2 C(1)20.02; C(2)3.70; C(3)7.32; C(4)21.20; C(7)1.57; C(8)1.35; P 2.01;R-C 52.33; R-N C(5)7.70; C(6)4.30; C(7)7.20; C(8)21.75; 4l 15.77; R-O 21.81 O(10)3.87 C(1)14.41; C(3)9.16; C(4)7.80; C(5)5.86; O C(1)3.29; C(4)3.55; C(8)4.83; C(12)6.59; R-C 4m C(6)3.01; C(7)21.98; C(8)17.75; C(9)5.74; 58.2; P 10.48 O(10)5.66;

138 H. -M. BI, P. -T. XIE, J. -P. HU, Y. LIU, F. -Y. YOU, L. -P. MENG

From Table 2, when the receptor is the root cells of a lected as independent variables and activity data as the monocotyledon (wheat), the data of promoted activity dependent variable (y) to perform multiple linear re- would be the best for compound 4l. The ELUMO of 4l is gression analysis. the lowest, so it has strong ability to accept electrons. The ELUMO and ΔE were selected as independent This may be the reason that these compounds promote variables, and y1 as the dependent variable. The curve growth for the plant root. The data of promoted activity fitting to model (1) resulted as follows: would be bad for compound 4k, where the ELUMO is y1  607.364 1001.185ELUMO 1332.844E (1) high. The E of compounds 4e and 4m is compara- LUMO with n=13; R=0.707; Se=0.913; F=4.989; Q=0.774, tively low, and the data of promoted activity of them where would be better than the one of 4k. We can conclude n - The number of samples in the model that the lower ELUMO of compound, the better the rela- tive promoted activity of the compound is. The conclu- R - Multiple correlation coefficient sion is consistent with the experimental values. Se - Standard deviation From the above discussion, the mechanism of action F - Sher’s statistics of 2E-3-phenyl propenyl acyloxy alkyl phosphonate Q - Quality factor (Q=R/Se) molecular derivatives on the root cells of monocotyle- The value of ELUMO was proportional to the inhibition ratio of root cells of monocotyledon, which is consistent don (wheat) is mediated by the ELUMO, the main factor affecting activity. When these compounds react with the with the previous discussion. receptors, they accept electrons. Table 4-Results of Calculation-Molecular Parameters From Table 3, the main composition and proportion compd μ EHOMO ELUMO ΔE ΔGsol 4a 3.7803 -0.3199 0.0694 0.3893 14.68 of ELUMO of 4l are in the R-C, R-N, and P, and for other compounds are in the C (1) − C (9) and O (10), the posi- 4b 4.2716 -0.3162 0.0769 0.3931 17.71 tive charge of them are mainly concentrated in the C 4c 4.1705 -0.3161 0.0770 0.3930 19.2 4d 4.4129 -0.3164 0.0750 0.3914 20.11 (9), and the charge of C (1) − C (8) are negative. The 4e 4.6872 -0.3165 0.0747 0.3912 20.88 electronic affinity has a major influence on the biologi- 4f 4.0896 -0.3104 0.0835 0.3939 19.62 cal activity. Some atoms could accept electrons from 4g 4.3201 -0.3096 0.0837 0.3934 23.22 receptor. The main composition and proportion of 4h 3.1375 -0.3130 0.0799 0.3929 20.1 EHOMO of these compounds are in the C (1) − C (8) and 4i 5.6633 -0.3133 0.0765 0.3898 19.85 O (10), the negative charge is mainly concentrated in 4j 4.1848 -0.3155 0.0731 0.3886 21.75 these atoms and they have strong ability to provide elec- 4k 5.3339 -0.3090 0.0840 0.3929 24.00 trons. 4l 7.5416 -0.3163 0.0523 0.3686 21.83 The main composition and proportion of E of 4l 4m 3.7292 -0.3108 0.0708 0.3816 18.64 LUMO logP V M Sg Rm is in the R-C, R-N, and P; the positive charge is mainly 4a 3.09 880.33 282.28 544.48 78.15 concentrated in this area. These atoms could accept 4b 3.10 903.17 296.30 542.10 82.99 electrons. The nitrobenzene group plays an important 4c 3.67 953.68 310.33 567.56 87.46 role because of the strong electron-withdrawing effects. 4d 4.07 999.23 324.36 589.58 92.06 So, when the receptor is the root cells of monocotyle- 4e 4.17 990.19 324.36 583.95 91.87 don, the growth of root cells will be promoted because 4f 4.84 1041.00 358.37 594.33 102.69 the phosphonate group accepts electrons from target 4g 5.30 1093.31 372.40 629.33 107.73 cells. The analysis of QSAR. 4h 4.46 1086.41 392.82 620.49 109.04 4i 5.33 1074.08 392.82 604.88 109.40 The parameters 4j 5.11 1119.02 427.26 625.97 114.12 The results of quantum calculation are included in Table 4k 4.58 1116.88 388.40 634.49 109.15 4. 4l 0.01 1102.77 403.37 631.70 109.53 4m 2.54 1024.66 348.34 612.93 97.14 Correlation analysis μ - Molecular dipole moment in water (D), The SPSS statistical software was used to correlation EHOMO or ELUMO – the energy of HOMO or LUMO (a.u.), ΔGsol– Solvation free energy in water (a.u.), analysis. The independent variables are the parameters LogP - The hydrophobic parameter, in Table 4, and the dependent variable was the rate of V – The molecular (volume bohr3·mol-1), inhibition. The correlation coefficients are presented in M - Relative molecular mass, 2 Table 5. Sg – The molecular surface area (nm ), Rm –Molecular molar refractive index, From Table 5, when the receptor is the root cells of monocotyledon, the y1 was significantly associated with Table 5-The correlation coefficients between the parameters ELUMO, ΔE and logP; when the receptor is the root cells and the rate of inhibition of dicotyledon, the y was significantly associated with 2 μ EHOMO ELUMO ΔE LogP V, Sg and ΔGsol. y1 -0.434 0.268 0.691 0.694 0.715 Regression analysis y2 0.526 0.105 -0.351 -0.467 -0.209 The QSAR results of 2E-3-phenyl propenyl acyloxy al- V M Sg Rm ΔGsol kyl phosphonate molecular derivatives were analyzed. y1 0.105 0.073 0.038 0.112 0.064 The higher correlation parameters of table 5 were se- y2 0.537 0.475 0.606 0.456 0.542

139 Latin American Applied Research 44:137-140 (2014)

The y2 was significantly associated with V, Sg and ant properties of triazine phosphonates derivative ΔGsol, but the ΔGsol was associated with V and Sg. The with cotton fabric,” Fibers and Polymers, 12, 334- ΔGsol was excluded because of their low association 339 (2011). with y2. V and Sg were selected as independent varia- Gacitúa, S.A., C.F. Valiente, K.P. Díaz, J.C. Hernández, bles, and y2 as the dependent variable being the curve M.M. Uribe and E.V. Sanfuentes, “Identification fitting to model (2) as follows: and Biological Characterization of Isolates with Activity Inhibitive Against Macrophomina (2) y2  143.747  0.151V  0.605Sg phaseolina (Tassi) Goid,” Chilean Journal of Agri- n=13; R=0.646; Se=0.913; F=3.589; Q=0.708 cultural Research, 69, 526-533 (2009). He, H.W., “Phosphorus chemistry, A field full of vitali- It could be concluded from model (2) that V shows ty and scientific opportunities,” Journal of Organ- the differences of the size of R, and the parameter Sg ometallic Chemistry, 23, 155-161 (2003). was the molecular factor to influence the activity of He, H.W. and Z.J. Liu, “ progresses in Research of compounds. These results give clues for further molecu- oxophosphonic Acid Derivatives with Herbicidal lar design. Activity,” Chinese Journal of Organic Chemistry, III. CONCLUSIONS 21, 878-883 (2001). (1) When the receptor is the root cells of Heinze, T., V. Sarbova, M.C. Vieira Nagel, “Simple monocotyledon, the ELUMO of phosphonates is the main synthesis of mixed cellulose acylate phosphonates factor to influence activities of these kinds of com- applying n-propyl phosphonic acid anhydride,” pounds. Cellulose, 19, 523-531 (2012). (2) The results indicate that C (9) of carbonyl and nitro- Shaekhov, T.R., E.M. Gibadullina, K. Voronina Yu, benzene group is the important active site for monocoty- V.V. Syakaev, D.R. Sharafutdinova, A.R. Burilov ledon root cells interactions. They promote growth. and M.A. Pudovik, “Synthesis of novel phospho- (3) The influence of molecular volume and surface area rus-containing sterically hindered phenols by the can not be ignored for the active site of dicotyledon. reaction of diphenyl (3,5-di-tert-butyl-4- oxocyclohexa-2,5-dienylidene) methylphosphonate ACKNOWLEDGEMENTS with phenols,” Russian Chemical Bulletin, 60, This project was supported by the Science and technol- 1999-2002 (2011). ogy projects of Hebei Province (Contract No. Wang, T., H.J. Huang, J. Luo and S.T. Zhou, “Synthesis 10273939). and Biological Activity of O,O-Diethyl-(2E-3- Phenacryloyloxy) Alkyl Phosphonates,” Journal of REFERENCES Bayrakci, M., Ş. Ertul and M. Yilmaz, “Synthesis of JiangXi Normal University (Natural Sciences Edi- new water-soluble phosphonate calixazacrowns tion), 35, 15-20 (2011). and their use as drug solubilizing agents,” Journal Wei, T.B., Y.L. Leng, Y.C. Wang, J.H. Zhang and Y.M. of Inclusion Phenomena and Macrocyclic Chemis- Zhang, “Biology Activity and Quantum Chemical try, 74, 293-303 (2012). Calculation of p-Toluene Sulfonylamido Bittner, M., M.A. Aguilera, V. Hernández, C. Arbert, J. Acetacylhydrazone Derivatives,” Chinese Journal Becerra and M.E. Casanueva, “Fungistatic activity of Organic Chemistry, 29, 216-221 (2009). of essential oils extracted from Peumus boldus Yang, G.F., H.Y. Liu, Y.H. Zheng and X.F. Yang, “De- Mol., Laureliopsis philippiana (Looser) Schodde sign, Syntheses and Biological Activity of Novel and Laurelia sempervirens (Ruiz & Pav.) Tul. Herbicides Targeted ALS () Studies on The Crystal (Chilean Monimiaceae),” Chilean Journal of Agri- Structure, Quantum Chemistry and Structure- cultural Research, 69, 30-37 (2009). Activity Relationship of 1,2,4-Triazolo[1,5-a] Py- Chang, S.C., B. Condon, E. Graves, M. Uchimiya, C. rimidine-2-sulfonamides Compounds,” Acta Fortier, M. Easson and P. Wakelyn, “Flame retard- Chimica Sinica, 56, 729-735 (1998).

Received: December 15, 2012 Accepted: August 18, 2013 Recommended by Subject Editor: María Luján Ferreira

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