Using Quantum-Chemical Parameters for Predicting Anti-Radical (Но∙) Activity of Related Structures Containing a Cinnamic Mold Fragment. I. Derivatives of Cinnamic Acid, Chalcon and Flavanon

2021

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The quantum-chemical parameters of 52 derivatives related to flavanones, flavanonoles, flavones and flavonoles with a phloroglucinic type of the A ring and containing electron-donating substituents in the B ring were studied.The aim is the analysis of the dynamics of changes in the electron density, bond numbers, free valence indices and unsaturation indices on carbon atoms C-7 → C-8 of the vinyl group of the main conjugation chain in relation to the position and number of substituents in the “B” ring and the type of the pharmacological activity.Materials and methods. The quantum-chemical parameters of the 4 analyzed groups of the compounds, have been calculated by the semi-empirical method PM7 (WinMopac 2016 program) on the workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.Results and discussion. When comparing the quantum chemical parameters of the analyzed compounds, it was established that when the C-7 → C-8 multiple bond is formed, the free valency and unsaturation indices increase on both carbon atoms of the vinylene group in flavones and flavonols compared to the corresponding flavanones and flavanonols. This is explained by the fact that the value of the bond numbers Nµ on these atoms, on the contrary, decreases (Fµ = 4.732-Nµ). The transition from flavanone to flavone is accompanied by the formation of a vinyl group C-7 → C-8, and therefore both atoms from the sp3-hybridized state go into the sp2-state. The consequence of this transformation is a change in the electronegativity value and an increase in the unsaturation index of C-7 and C-8 atoms: C sp3 = 2.5; Csp2 = 2.8. At the same time, the transition from flavanone to flavone leads to the formation of a conjugated system with the participation of π-electrons of the aromatic system “B”, C-7, C-8 atoms and the carbonyl group, which is commonly called the “main conjugation chain”. These structural changes, namely, the transition from a less oxidized flavanone to a more oxidized flavone, contribute to a decrease in the electron density on C-7 and C-8 atoms, and an increase in the total unsaturation of the molecules in general. Mulliken charges on C-7 of all groups of compounds are characterized by a positive value. As for the carbon atoms of the B fragment, the following features are revealed here: in the presence of one substituent -OH or -OCH3 on the carbon atom to which the substituent is bounded, the Mulliken charge is positive; if there are two substituents in the B ring -OH or -OCH3, as well as two -OCH3 groups, then the carbon atoms bonded to the indicated substituents also have a positive Mulliken charge; in the case of trihydroxy substituted in the C-2, C-3 and C-4 B ring, all three carbon atoms are characterized by a positive Mulliken charge; if there are methoxy groups in positions C-2, C-3 and C-4, then the positive Mulliken charge is concentrated only on C-2 and C-4 atoms, and on C-3 atom this charge has a negative value.Conclusion. The above data on the quantum-chemical parameters of the main conjugation chain indicate that the transition of C-7 and C-8 atoms to the sp2-hybrid state, leads to a decrease in the electron density and a decrease in the bond numbers, with a simultaneous increase in the indices of unsaturation and free valence on these atoms. Thus, the trigger mechanism of the anti-radical activity, primarily with respect to the HO • radical, is determined by the fact that this particle, electrophilic in its properties, will attach in the C-8 atom during an initial attack.

Section: заключениеunclassified

Using Quantum-Chemical Parameters for Predicting Antiradical (Ho•) Activity of Related Structures Containing a Cinnamoil Fragment. Iv. Structure-Activity Relationship Between Unsaturation Indices and Flavone Derivatives With Floroglucin Ring “A”

2021

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“…Малликеновские заряды (а.е) В нашем предыдущем сообщении [5] помимо коричной кислоты анализу были подвергнуты производные 2'-гидроксихалкона, не содержащие заместителей в кольце «А», и соответствующие им флаваноны. У 2'-гидроксихалкона и соответствующего ему флаванона [4] на атоме С-9 положительный малликеновский заряд соответственно равен примерно +0,4657 и +0,5222, а на атоме С-8 у всех проанализированных соединений без исключения он имеет отрицательное значение, равное, примерно, -0,300.…”

Section: результаты и их обсуждениеunclassified

“…У 2'-гидроксихалкона и соответствующего ему флаванона [4] на атоме С-9 положительный малликеновский заряд соответственно равен примерно +0,4657 и +0,5222, а на атоме С-8 у всех проанализированных соединений без исключения он имеет отрицательное значение, равное, примерно, -0,300. Это дало нам основание сделать вывод о том, что первичная атака радикала НО• происходит именно по положению С-8 как коричной кислоты, так и 2'-гидроксихалкона, а также соответствующего флаванона [5,6].…”

Section: результаты и их обсуждениеunclassified

“…Известные факты о взаимосвязи процессов свободнорадикального окисления с формированием патохимических процессов и возникающими при этом заболеваниями актуализирует проблему дальнейшего поиска новых производных флавоноидных соединений, проявляющих антирадикальные свойства [1][2][3]. В этой связи значительный интерес представляют структуры, содержащие три заместителя в положениях 2,3,4 ароматического ядра главной цепи сопряжения [4] (циннамоильный фрагмент): 2,3,4-тригидрокси-, 2,4-диметокси-3-гидрокси-и 2,4-дитретбутил-3-гидроксипроизводные [5]. При таком типе замещения фенольный гидроксил у С-3 находится в окружении двух орто-заместителей, благодаря экранирующему эффекту которых образующийся пространственно затрудненный феноксильный радикал характеризуется достаточной устойчивостью.…”

Section: Introductionunclassified

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Using Quantum-Chemical Parameters for Predicting Anti-Radical (Но∙) Activity of Related Structures Containing a Cinnamoyl Fragment Ii. Derivatives of 2’,4’-Dihydroxychalcone, Flavanone and Flavone, Containing a Hydroxy Group in Position 7

2020

42 derivatives of 2’,4’-dihydroxychalcone, flavanone and flavone, containing the hydroxy group in position 7 (ring "A"), as well as substituents in the ring "B", have been studied.The aim is to study the quantum-chemical parameters of 2',4'-dihydroxychalcone, flavanone and flavone derivatives containing a hydroxy group in position 7, in order to identify the effect of substituents on Mulliken charges (a.e) in the aromatic core "A", bond numbers (Nµ), the unsaturation index (IUA) and the electron density of the carbon atoms of the cinnamoyl fragment.Materials and methods. The listed above parameters have been calculated by the semi-empirical method PM7 (WinMopac 2016 program) on the workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.Results. The analysis of the values of quantum-chemical parameters, as well as their comparison with the corresponding indicators presented in Report I, revealed a number of important features associated with the influence of the hydroxy group in position 7 (ring "A") on the studied quantum-chemical parameters of molecules. It has been established that the hydroxy group in the ring “A” does not significantly affect the Mulliken charge and the electron density of the carbon atoms of the propenone unit C-7→C-8→C-9. On atom C-9 (carbonyl carbon), the Mulliken charge always has a positive value, and the electron density is about 3.4670-3.4840 for all three groups of compounds. The transition from 2’,4’-dihydroxychalcone to flavanone and flavone by the formation of the pyrone heterocycle, is accompanied by an increase in the negative charge on C-8, which can be explained by the involvement of the oxygen heteroatom in the transmission of electronic effects. The hydroxy group in the ring “A”, has practically no effect on the charge and electron density of atoms. An analysis of the values of bond numbers and unsaturation indices suggests that atoms C-1 of 2’,4’-dihydroxychalcone and 7-hydroxyflavanone derivatives, are characterized by the lowest Nµ value; the lowest bond numbers are characteristic for atom C-8 derivatives of 7-hydroxyflavone. Consequently, the primary attack of the HO·radical will be directed at C-1 (in chalcones and flavanones) and at C-8 in flavones.Conclusion. The performed quantum-chemical calculations make it possible to analyze the effect on the main quantum-chemical parameters of the molecule, which can be useful in predicting the biological activity of flavanoid compounds due to their antiradical effect on reactive oxygen intermediate species (ROIs).

“…В продолжение наших предыдущих сообщений [5,6] в настоящей работе представлена интерпретация квантово-химических характеристик произво-дных халкона, флаванона и флавона, характеризующихся флороглюциновым типом кольца (всего 42 соединения) и имеющих электронодонорные заместители в кольце «В».…”

Section: Introductionunclassified

Use of Quantum-Chemical Parameters for Forecasting Antiradical (Ho·) Activity of Related Structures Containing a Cinnamic Mold Fragment. Iii. Chalcones, Flavanones and Flavones With Phloroglucinic Type of Ring “A”

2021

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42 derivatives of chalcone, flavanone and flavone having a phloroglucinic type of ring “A” and containing the same electron-donating substituents on ring “B”, have been studied. Flavonoids with the phloroglucinic type of ring “A” are the most common in nature, which is due to the peculiarities of biogenetic formation with the participation of malonyl and acetyl fragments.The aim of the article is to determine the effect of the hydroxy group in position 6' of chalcones and in position 5 of flavanones and flavones on bond numbers (Nµ), free valence indices (Fµ), Mulliken charges (a.e), electron density, unsaturation indices (IUA) of the carbon atoms C-1 → C-6 → C-7 → C-8.Materials and methods. The calculations of the listed above parameters with the use of the semi-empirical method PM7 (WinMopac 2016 program) have been carried out on a workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.Results. The quantum-chemical characteristics of the considered derivatives having a phloroglucinic type of the “A” ring, indicate that the OH group in position 6' of chalcones (in the corresponding flavanones and flavones in position 5) has different effects: a slight increase occurs in chalcones negative charge (a.e.) and electron density, the bond numbers take different values, which depends on the position and number of substituents on the ring "B". In flavanones, Nµ practically remains at the same level of 3.822-3.829. For flavones, the binding numbers Nµ for C-8 are in the range of 3.700-3.706, and the Mulliken charges are in the range from -0.4120 to -0.4356. For position-substituted C-3 (6anone and 7anone), the charges are -0.4436 and -0.4479, respectively. The charge on C-7 of chalcones is negative for compounds 4x, 5x, 10x and 13x from -0.0204 to -0.0470. The remaining derivatives of the chalcone, as well as the corresponding flavanones and flavones, are characterized by a positive value of a.e. on C-7. Based on the bond numbers (Nµ), free valency indices (Fµ) have been found for the carbon atoms of the cinnamoyl fragment C-1 → C-6 → C-7 → C-8. When comparing the obtained data, it was found out that for chalcones on C-1 → C-8 atoms, the values of the free valence indices are in the range of 0.900-0.980 for compounds 12x, 13x, where Fµ> 1. For flavanones on C-1, C-3, and C-5 atoms (compounds 12anone and 13anone), the free valence indices are in the range of 0.984-1.024, and for the remaining atoms the value of Fµ is approximately the same as that of chalcones. On the C-8 atoms of all the derivatives, as well as on C-1, C-3 and C-5 (compounds 12one, 13one), Fµ ≥ 1.0. It can be assumed that at values of Fµ = 0.850-0.955 for all the analyzed compounds, coupling reactions on the double bond are possible, and if Fµ ≥1, the coupling will take place according to the free radical mechanism. The data obtained indicate that the OH group in position 6’ for the chalcone and 5 for the flavanones, does not significantly effect the Mulliken charge (a.e) and the electron density on C-8 atoms.Conclusion. It has been established that the OH group in position 6' of the "A" ring of chalcones (in position 5 of the "A" ring in flavones and flavanones) has a conflicting effect on the bond numbers: when passing from chalcone to flavanone, Nµ increases, and then, in flavone, sharply decreases. For C-8 of all flavone derivatives, Fµ ≥1. The following conclusion has been confirmed: at the initial stage of the reaction the electrophilic hydroxyl radical is attached at the C-8 position of the cinnamoyl fragment