Tailored Functionalization of Natural Phenols to Improve Biological Activity

Abstract

Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols' anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.

Keywords: carvacrol; curcumin; eugenol; hispolon; hydroxytyrosol; lipidic phenols; phenolic acids; polyphenols; resveratrol; thymol.

Scheme 1

Tyrosol esterification with phenolic acids (top) [80]; tyrosol hydroarylation with cinnamic esters (bottom) [81]. Abbreviations: DIAD = diisopropyl azodicarboxylate; DMC = dimethyl carbonate; DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene.

Scheme 2

Carvacrol and 4-bromocarvacrol esterification with heterocyclic acyl halides [99].

Scheme 3

Synthesis of carvacrol amino acid ester prodrugs CAR-1 and CAR-2 [102].

Scheme 4

Synthesis of sulfur containing amino acid ester prodrug CAR-3 [103]. Abbreviations: Ac₂O = acetic anhydride.

Scheme 5

Synthesis of carvacrol ester and ether with a -NH₂ terminal group [104]. Abbreviations: NHS = N-hydroxysuccinimide; EDAC = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; Azido-PEG-amine = O-(2-aminoethyl)-O′-(2-azidoethyl)triethylene glycol.

Scheme 6

Synthesis of a metronidazole carvacrol ether derivative [108].

Scheme 7

Synthesis of alkyl 4-oxobutanoate p-substituted carvacryl ethyl ethers [110].

Scheme 8

Synthesis of CAR-4 [111,112].

Scheme 9

Synthesis of oxypropanolamine carvacrol derivatives [113].

Scheme 10

Synthesis of CAR-5 [114] and CAR-6 [115].

Scheme 11

Synthesis of CAR-7 [122].

Scheme 12

Synthesis of thymol acrylate derivatives [136].

Scheme 13

Synthesis of thymol ketoprofen derivative [139].

Scheme 14

Synthesis of benzoic acids [141] and cinnamic acids [144], derivatives of thymol. Abbreviations: TBDMSCl = tert-butyldimethylsilyl chloride; DIEA = N,N-diisopropylethylamine; EDCI = 1-etil-3-(3-dimetilaminopropil)carbodiimide; HOBt = hydroxybenzotriazole.

Figure 1

Structure of the glucosides thymol derivatives THY-1, THY-2, THY-3 [149].

Scheme 15

Synthesis of heterocyclic sulfide thymol derivatives [150].

Scheme 16

Synthesis of thymol-based substituted pyrazolines and chalcones [162].

Figure 2

Eugenol structure.

Figure 3

Structure of eugenol phthalocyanine derivative (EUG-1) [185] and eugenol Pt(II) complexes EUG-2-4 [186].

Scheme 17

Eugenol derivatives obtained by epoxidation and ring opening reactions [200,201].

Figure 4

Structure of different eugenol triazole derivatives [203,204,205,206].

Scheme 18

Synthesis of different eugenol triazole derivatives [207]. Abbreviations: TIPSCl = triisopropylsilyl chloride; TBAF = tetrabutylammonium fluoride.

Scheme 19

Synthesis of EUG-5 [209].

Figure 5

Structure of selected resveratrol derivatives.

Scheme 20

Synthesis of hispolon and hispolon methyl ether pyrazole derivatives [241].

Scheme 21

Synthesis of Pd complexes with hispolon derivatives [243].

Scheme 22

Synthesis of HT-1 [261] and HT-2 [262].

Scheme 23

Synthesis hydroxytyrosyl phosphodiesters [264]. Abbreviations: MS = molecular sieves; DCI = 4,5-dicyanoimidazole; TBHP = tert-butyl hydroperoxide.

Scheme 24

Synthesis of hydroxytyrosol carbonates [272,273].

Figure 6

Bioactive phenolic acids widespread in plants.

Scheme 25

Synthesis of ester and amide derivatives of caffeic acid by artificial biosynthetic pathways [292].

Scheme 26

Derivatives of caffeic acid with a triazole moiety inhibitors of 5-lipoxygenase [302].

Figure 7

Amides of caffeic acid with antiviral effect against influenza virus [304].

Scheme 27

Synthesis of caffeic acid–tacrine hybrids [305].

Scheme 28

Enzymatic transterification with Arbutin [308].

Scheme 29

Esters and imides from ferulic acid [311].

Scheme 30

Example of amide from ferulic acid with antioxidant property [314].

Figure 8

Amides of ferulic acid with in vivo insecticidal activities and antiviral activities [315].

Scheme 31

Synthesis of biologically active amides of 3-(3,4-dimethoxy)phenylpropanoic acid [316].

Scheme 32

Synthesis of ferulic acid amides designed to be used as histone deacetylase inhibitors [321].

Scheme 33

Lipase-catalyzed transesterification of flaxseed oil with caffeic acid [338,339].

Scheme 34

Chemo-enzymatic synthesis of lipidic phenols from ferulic acid [346].

Scheme 35

Chemo-enzymatic synthesis of lipidic phenols from ferulic acid [346].

Scheme 36

Enzymatic esterification of tyrosol with α-lipoic acid [349].

Scheme 37

Chemo-enzymatic approach for the synthesis of 1-[11-(ferulyloxy)undecanoyl)]glycerol [351].

Scheme 38

Synthesis of isobenzofuranones from anacardic acid [360]. Abbreviation: m-CPBA = m-chloroperoxybenzoic acid.

Scheme 39

Synthesis of bioactive 5-alkylresorcinols with long alkyl chains, by modified Wittig reaction [363].

Figure 9

Structures of parent heterocyclic compounds and their phenyl derivatives present in polyphenols.

Figure 10

Synthetic derivatives of catechin with enhanced activity [371,372,373].

Figure 11

Selected examples of biologically active synthetic derivatives of brazilein [375] and heterocyclic analogues of brazilin [376].

Scheme 40

Synthesis of 1,4-thiazepine derivative from 4-hydroxycoumarin [379].

Scheme 41

Enzymatic esterification of rutin [388].

Scheme 42

MW-assisted prenylation of pinostribin [391].

Scheme 43

Prenylation of pinostribin [392].

Scheme 44

Astilbin from taxifolin by microbial fermentation [394].

Scheme 45

Keto-enol equilibrium of curcumin.

Figure 12

The 4-Substituted curcumins that inhibit the formation of large amyloid aggregates [434] and 4,4-disubstituted curcumin that binds amyloid oligomers [435].

Figure 13

Curcumins 4-substituted with acid or ester groups [436].

Scheme 46

Sulfonamido analogues of curcumin [437].

Scheme 47

Synthesis of monocarbonyl curcuminoids [439].

Scheme 48

One-pot synthesis of curcuminoids incorporating 4H-pyran [443].

Scheme 49

Synthesis of (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one [445].

Scheme 50

Synthesis of retro-curcuminoids and compounds with cytotoxic properties [448].

Scheme 51

Synthesis of a curcumin–resveratrol hybrid [449].

Figure 14

Cationic curcumin derivatives with interesting antimicrobial photodynamic activity [450].