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Structure Activity Relationship « Molecular Modelling and Natural Polyphenol Compounds

Structure Activity Relationship

III.1. Qualitative structure-antioxidant activity relationship

III.1.1. Number of OH groups

As the free radical action is mainly assigned to the HAT capacity from the OH groups, the number of OH groups is obviously an important descriptor. From a general overview, we can observe (Table 1) that active compounds have usually more than 2 or 3 OH groups. Regarding subclass by subclass, this is easily confirmed. E.g., for the benzoic acids, the hierarchy is 1 > 2 > 3 and 4, while the number OH groups are three, two, one and zero, respectively. Similar remarks can be observed for the other subclasses. Nonetheless this descriptor (number of OH groups) is not independent i.e., what is mandatory for the antioxidant activity is the number of active OH group(s). In other word the antioxidant activity correlates with the number of OH groups having a low BDE (i.e., high HAT capacity). E.g., for flavonols, the active OH groups are located in the B-ring and the hierarchy is 18 (no OH group in the B-ring) > 19 (one OH group in the B-ring) > 21 (two OH groups in the B-ring) ~ 22 (three OH groups in the B-ring). Compounds 21 and 22 does exactly fit with a linear dependence. Compound 20 (two OH groups in the B-ring) is less active 19 (one OH group in the B-ring). Therefore the number of OH groups strongly depends on the position and its chemical environement.

III.1.2. Position of OH groups

Over the past ten years numerous theoretical studies have confirmed the experimental structure antioxidant-activity relationship for polyphenols [7-10]. For flavonoids, the B-ring and the 3-OH group in the presence of the 2,3-double bond (flavonols) have been clearly identified as crucial OH positions to enhance the antioxidant capacity [5, 7]. The 3’- and 4’-OH  groups are the most active. This is clearly confirmed by the low BDEs 85.6, 78.8 and 76.4 kcal/mol obtained for the 3-, 3’- and 4’-OH groups. The A-ring has a minor role in the free radical scavenging capacity. This is also well-confirmed by the high BDE obtained for the 5-OH and 7-OH groups. The presence of a 6-OH group (3’-OH for chalcone numbering) decreases BDE and enhances the activity (compound 11) (Table 1) [10]. The high BDE obtained for the 5-OH group is partly attributed to the presence of a strong H-bond that exists with the keto group at C4. This demonstrates that the number of intra H-bonds can also be considered as a secondary and non-independent descriptor. The 7-OH group has also been demonstrated to indirectly participate in the antioxidant activity [5]. This is not clearly explained by the BDE values, which indicate the importance of other secondary parameters. Including acidity since 7-OH is the most acedic group (Table 2).

The 6’-OH group of chalcones also enhances the antioxidant activity [10], which is correlated with a relatively low BDE (83 kcal/mol).

The presence of a catechol moiety is particularly efficient whatever the subclass. Its role is slightly enhanced in the presence of the 2,3-double bond since p-electron delocalization helps to stabilize the subsequent ArO radical (BDE of the 4’-OH group is lower for 23 compare to 25) (Table 1) [5]. Again p-conjugation may appear as an important descriptor.

III.1.3. Double bonds and p-electron conjugation

The p-electron conjugation plays a crucial role in the antioxidant activity. For two compounds having the same number of OH groups at the same position, the compound with the 2,3-double bond exhibits a much better free radical scavenging activity e.g., i) 17 is more active than 15, ii) 23 is more active than 25 (Fig. 1 and Table 1). This comes from the extension of p-conjugation over a larger part of the molecule [5, 10] and subsequently a better stabilizati

on of the ArO radical formed after HAT, lower BDEs and better activities of the OH groups (Table 1 & 2). This criterion can simply be taken into account by the number of double bonds along the shortest path connecting the terminal groups of the molecule (Ntrack) as a descriptor.

III.1.4. Volume/size of the molecule

The size of the molecule is not a criterion by itself since the free radical scavenging capacity is mainly due to the capacity of the OH groups to release an H-atom, which is a relatively local property. If p-conjugation is favoured then the size may influence because the higher the p-electron delocalization, the higher the free radical scavenging capacity. Thus the volume/size of the molecule is a dependent descriptor; its role is indirect and depends on the number of double bonds.

III.1.5. Acidity of the OH groups

The capacity to remove a proton from the different OH groups is of importance if the free radical scavenging action occurs via the SPLET mechanism. Depending on the pH conditions of the environment in which the antioxidant action occurs, this mechanism maybe major [25-26]. The lowest DHdeprot is obtained for the 7-OH group (Table 2). This partly explains the importance of this group that has been observed by certain authors [27]. DHdeprot should be a major descriptor.

Compounds

1: Galic acid (R3=R4=R5=OH)

2: 3,4-dihydroxybenzoic acid (R3=R4=OH)

3: Vanilic acid (R3=OCH3, R4=OH)

4: 3,4-dimethoxybenzoic (R3=R4=OCH3)

Cinnamic acids

5: 3,5-dimethoxy-4-hydroxybenzoic acid (R5=OCH3)

6: Ferulic acid (R5=H)

Chalcones

7: 4-hydroxychalcone (R4=OH)

8: 2′-hydroxychalcone (R2’=OH)

9: 4′-hydroxychalcone (R4’=OH)

10: 2′,4-dihydroxychalcone (R4=R2’=OH)

11: 2′,3′,4′-trihydroxychalcone (R2’=R3’=R4’=OH)

12: 2′,4,4’-trihydroxychalcone (R2’=R4’=R4=OH)

13: 3-methoxy-2′,4′,4-trihydroxychalcone (R3=OCH3, R4’=R3’=R4=OH)

14: 2′,3,4,4’-tetrahydroxychalcone (R3=R4=R2’=R4’=OH)

15: 2′,4,4′,6′-tetrahydroxychalcone (R4=R2’=R4’=R6’=OH)

16 : 2′, 3,4,4′,6′-pentahydroxychalcone (R3=R4=R2’=R4’=R6’=OH)

Flavonols

18: Galangin (R2’=R3’=R4’=R5’=H)

19: Keampferol (R4’=OH)

20: Morin (R2’=R4’=OH)

21: Quercetin (R3’=R4’=OH)

22: Myricetin (R3’=R4’=R5’=OH)

Flavone

23: Luteolin

Flavananone

24: Naringenin (R7=R4’=OH)

25: Eriodictyol (R7=R3’=R4’=OH)

26: Hespertin (R7=R4’=OH, R3’=OCH3)

27: Narirutin (R7=OSugar, R4’=OH)

28: Didymin (R7=OSugar, R4’=OCH3)

29: Eriocitrine (R7=OSugar, R3’=R4’=OH)