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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2023 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                                Review Article 

Therapeutic aspects of biologically potent vanillin derivatives: A critical review

Senthil Kumar Raju*, Naveena Sundhararajan, Praveen Sekar, Yogadharshini Nagalingam

Department of Pharmaceutical Chemistry, Swamy Vivekanandha College of Pharmacy,  Tiruchengode – 637 205, Tamilnadu, India.

Introduction

Vanillin (4-hydroxy 3-methoxy benzaldehyde), a white monoclinic crystalline phenolic aldehyde, has three functional groups, an aldehyde, hydroxy and ether groups located around an arene. The organic modifications in vanillin moiety can be achieved by altering the reactive groups namely, phenol and aldehyde for a good safety impact^1,2. Vanillin can be synthesized naturally, synthetically and by means of biotechnological ways. Vanillin is obtained naturally from the seed pods of Vanilla planifolia orchid. Lignin, guaiacol, 4-hydroxybenzaldehyde and 3-methoxy-4-hydroxy benzyl alcohol are some of the substrates involved in the synthesis of vanillin. It acts as an intermediate substrate for the synthesis of various pharmaceuticals like papaverine, L-methyldopa and trimethoprim³. Vanillin can also be prepared by means of biotechnological ways using enzymes i.e., isoeugenol and 4-vinyl guaiacol were converted to vanillin by oxygenase which has a coenzyme-independent catalyst activity, while enoyl-CoA hydratase/aldose converts the ferulic acid to vanillin^4,5. In the food and cosmetic industries, ethyl vanillin has been employed as a preservative because it has a remarkable protective effect against both bacteria and fungi. It significantly affects the cytoplasmic membrane of food-related bacteria and fungi such as Escherichia coli, Lactobacillus plantarum, Listeria innocua, Pseudomonas aeruginosa and Aspergillus niger. In contrast to more effective phenolic antimicrobials, the vanillin derivatives were found to be highly bacteriostatic^6,7. Vanillin is a non-toxic and bioactive substance with a wide range of pharmacological activity including anticancer and antioxidant^6,8, antimicrobial⁹, antimycobacterial¹⁰, antiviral¹¹, antimalarial¹², anti-inflammatory¹³, anti-Alzheimer¹⁴, anti-sickling¹⁵ and antidiabetic¹⁶ activities.

Vanillin was highlighted as a very promising building block for the preparation of bio-based monomers, bio-based epoxy thermosets and cross-linked polymers. Eco-friendly, vanillin derivatives can be synthesized by various approaches such as one-pot multicomponent synthesis, oil bath-assisted synthesis, microwave-assisted synthesis, hot plate with magnetic stirring, grindstone method and solvent-free chemical reactions using a simple trituration technique^2,17. In Schiff base derivatives, vanillin is used as an aromatic aldehyde with a primary aromatic or aliphatic amine in the presence of a basic catalyst resulting in the formation of azomethine (C=N) linkage which is responsible for various bio-activities. Mannich base is a deamination process used to generate α, β-unsaturated ketone moiety by reaction of the secondary amine with aldehyde and ketone^3,18. Vanillin hybrids were synthesized by reacting vanillin with various organic compounds or with their derivatives. For consideration, the vanillin reacted with diaryl pyrazole and obtained a pyrazole-based hybrid compound that produced dual activity against oxidative stress and diabetes¹⁹. Through a conventional method, vanillin-based chalcones were formed by the Claisen-Schmidt condensation reaction by reacting vanillin with different acetophenone derivatives. The vanillin and isovanillin-based chalcones can be referred to as curcumin mimics^20,21. Vanillin can also act as a phase transfer catalyst in the conversion of peracetylated lactosyl bromide to vanillin-based lactoside²². The biologically potent vanillin Schiff base metal complexes were developed using various metals such as copper, cobalt, manganese, zinc, nickel and palladium^23-26.

In this review, various literature indexed in PubMed, Scopus, Web of Science, Google Scholar, ScienceDirect, Springer, Embase and ResearchGate databases were collected between the period of 2011 to 2023 by using the keywords vanillin and its derivatives, anticancer, antimicrobial, antioxidant and biological activities, individually and in combination. The collected literature was shortlisted and scrutinized based on their abstracts. Thus, this review focuses on the potential pharmacological applications of possible derivatives of vanillin and it will be useful for designing potent novel derivatives in the future.

Pharmacological Activity of Vanillin Derivatives

Anti-microbial activity

4-(((4-butylphenyl)amino)methyl)-2-methoxyphenol (1) was obtained by reacting vanillin with the aromatic amine. The synthesized compound tested against E. coli, Micrococcus luteus and Bacillus subtilis microorganisms, determined by the broth microdilution method. The better activity was due to the presence of butyl group and lengthy aliphatic chain, which enhanced the antimicrobial property of vanillin derivatives⁶. The novel acetyl vanillin derivatives, 4-(((4-Fluorobenzyl)-imino)-methyl)-2-methoxy-6-nitrophenyl acetate (2) and 2-Methoxy-6-nitro-4-(((2-(pyridin-2-yl)-ethyl)-imino)-methyl)-phenyl acetate (3) were synthesized by reacting acetyl nitro vanillin with various amines and found to be exhibiting potent antimicrobial agent against E. coli, evaluated by using well diffusion method. The presence of electron-withdrawing substituents at the para position of substituted amine in the compounds (2) and (3) were the reason for their potent antimicrobial effect⁷.

Pyridyl substituted (3-methoxy benzylidene)-5-fluoroindolin-2-one derivatives, 5-Fluoro-3-(3-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methoxy)benzylidene)indolin-2-one (4) and 5-Fluoro-3-(3-methoxy-4-((4-methoxy-3,5-dimethyl pyridine-2-yl)methoxy) benzylidene)indolin-2-one (5) were synthesized by reacting vanillin derivatives, 5-Fluoro-3-(2-hydroxy-3-methoxybenzylidene)indolin-2-one and 5-Fluoro-3-(4-hydroxy-3-methoxybenzylidene)indolin-2-one with 2-chloromethyl pyridine and they were screened for in vitro and in silico antimicrobial studies. The in vitro antimicrobial effect was analyzed through the agar well diffusion method against fungal (Candida albicans), gram-positive bacterial (Streptococcus pyogenes, Staphylococcus aureus) and gram-negative bacterial (P. aeruginosa, E. coli) species. Thus, the vanillin pyridyl-based derivatives showed broad-spectrum antimicrobial activity against bacterial and fungal species with better DNA gyrase inhibition⁹. Vanillin chalcone derivatives, (E)-1-(4-Chlorophenyl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)prop-2-en-1-one (6) and (E)-3-(4-(2-(Dimethylamino)ethoxy)-3-methoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (7) were synthesized by Claisen-Schmidt reaction and found to be having potent antifungal activity against three dermatophytes (Trichophyton rubrum, T. mentagrophytes and Microsporum gypseum). The potent activity was due to the presence of electron-withdrawing substituted chalcone with high electrophilic character²⁰. 

Vanillin-derived Schiff bases, (E)-2-(4-hydroxy-3-methoxybenzylideneamino)-4-methoxybenzoic acid (8) and (E)-4-(4-hydroxy-3-methoxybenzylideneamino) benzoic acid (9) were obtained by reacting vanillin with various aromatic amines such as 2-amino-4-methoxy benzoic acid and p-amino benzoic acid in presence triethyl amine as a basic catalyst. These compounds exhibited excellent antibacterial activity against both gram-positive and gram-negative bacterial species (B. subtilis, S. aureus, Klebsiella pneumonia and P. aeruginosa), determined by the disc diffusion method²⁷. Vanillin hydroxamic derivative, 2-[2-ethoxy-4-({[2-(pyridin-2-yl)ethyl]amino}methyl)phenoxy]-N-hydroxyacetamide (10) was synthesized by condensing vanillin derivative, ethyl 2-(2-ethoxy-4-(((2-(pyridin-2-yl)ethyl)amino)methyl)phenoxy) acetate with hydroxylamine and the obtained novel peptide deformylase inhibitor showed promising antibacterial activity against E. coli, S. aureus, A. oryzae and A. foetidus microorganisms, which was also utilized to treat drug-resistant pathogens²⁸. The structures of the above discussed compounds are given in figure 1.

A novel chalcone and pyrazoline derivatives bearing substituted vanillin nucleus were screened for antibacterial and antifungal activity against gram-positive (S. aureus and M. luteus), gram-negative bacteria (E. coli and Salmonella typhi) and C. albicans as a fungal organism. The chalcone derivative, 3-(3-Methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)phenyl)-1-arylprop-2-en-1-one (11) and the corresponding pyrazoline derivative, 1-(5-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy) phenyl)-3-aryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (12) were designed and synthesized by reacting vanillin derivatives, 3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl)methoxy) benzaldehyde and 3-(3-methoxy-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy) phenyl)-1-arylprop-2-en-1-one with corresponding acetophenone and hydrazine hydrate. The result indicated that the synthesized compounds were found to be exhibiting better antibacterial activity against the tested species. Thus, the replacement of phenyl ring with heterocyclic rings demonstrated significant antibacterial activity against commercial drugs²⁹. 3-chloro-4-(4-(dimethylamino)phenyl)-1-(5-(4-hydroxy-3-methoxyphenyl)-1,3,4-thiadiazol-2-yl)azetidin-2-one (13) and  2-(4-(dimethylamino)phenyl)-3-(5-(4-hydroxy-3-methoxyphenyl)-1,3,4-thiadiazol-2-yl)thiazolidin-4-one (14) were synthesized by reaction carried out between the obtained vanillin derivative, 4-(5-((4-(substituted)benzylidene)amino)-1,3,4-thiadiazol-2-yl)-2-methoxy phenol with chloroacetyl chloride and mercaptoacetic acid. Thus, both compounds showed potent antibacterial and antifungal activity, determined by the cup plate method against S. aureus, S. typhi, E. coli, K. pneumonia, C. albicans and A. niger³⁰.

Vanillin-derived piperidin-4-one oxime esters with phenyl ester as a substituent, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one O-(4-fluorobenzoyl) oxime (15) and  2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one O-(4-chlorobenzoyl) oxime (16) were synthesized by reacting a vanillin derivative, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one oxime with substituted benzoyl chlorides and found to be possessing considerable antimicrobial activity against bacterial and fungal species such as E. coli, S. aureus, P. aeruginosa, A. flavus, C. albicans and Chrysosporium keratinophilum. Hence, the presence of electron-withdrawing substituents such as fluoro and chloro group at the para position of aryl ester in both compounds has been found to be an essential part of the antimicrobial effect³¹.

Figure 1: Compounds with antimicrobial activity

Using click reaction, 1,2,3-triazoles and Bis-1,2,3-triazoles derivatives were synthesised by reacting vanillin derivative, 3-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde with 1-(3-azidopropoxy)-3-nitrobenzene and 1,3-bis(3-azidopropoxy) benzene yield two bioactive compounds 3-methoxy-4-((1-(3-(3-nitrophenoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy) benzaldehyde (17) and 4,4'-(((((1,3-phenylenebis(oxy)) bis(propane-3,1-diyl))bis(1H-1,2,3-triazole-1,4-diyl))bis (methylene))bis(oxy))bis(3-methoxybenzaldehyde) (18). Both of them were evaluated for antimicrobial activity by the agar well diffusion method. The compound (17) bearing propoxy phenyl ring offers antibacterial activity against gram-negative bacteria such as P. aeruginosa and Shigella dysenteriae and the compound (18) with a benzene ring as an aromatic linker between both triazoles also showed promising antibacterial activity against B. subtilis, Methicillin-resistant S. aureus, S. epidermidis, S. saprophyticus and Vancomycin-resistant Enterococcus organisms. The molecular docking studies were also correlated with the in vitro findings³².

Vanillin-based ferrocenyl chalcone derivatives, 1-Ferrocenyl-3-(4-ethoxy-3-methoxyphenyl)prop-2-en-1-one (19) and 1-Ferrocenyl-3-(3-methoxy-4-propoxyphenyl)prop-2-en-1-one (20) were designed and synthesized by reacting o-alkylated vanillin derivatives with acetyl ferrocene using Claisen-Schmidt reaction. The obtained novel derivative showed significant antibacterial activity against various bacterial species such as S. aureus, B. subtilis, B. cereus, E. coli and Proteus mirabilis with better MIC (minimum inhibitory concentration) values indicating the presence of active ferrocene moiety, determined by the broth microdilution method. 1-Ferrocenyl-3-(4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one (21) with the same active ferrocene moiety produced antifungal activity against five fungal species such as A. niger, C. albicans, Penicillium italicum, Mucor mucedo and Trichoderma viride³³. The structures of the anti-microbial compounds are given in figure 2.

Figure 2: Compounds possessing antimicrobial activity

The reaction between dimedone with aromatic aldehyde resulted in 1,8-dioxo-octahydroxanthene derivative, 9-(3-ethoxy-4-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (22) which had very strong antibacterial activity against S. epidermidis. Hence, the potent activity was due to the ethoxy substitution, determined by the agar well diffusion method³⁴. The coupling of vanillin hydrazone derivatives, 4-[2-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethoxy]-3-methoxybenzaldehyde and 4-[2-(4-(2,4,6-Trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)ethoxy]-3-methoxy benzaldehyde with substituted benzohydrazides produced (E)-3,4,5-Trimethoxy-N'-{3-methoxy-4-[2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethoxy]benzylidene}benzohydrazide (23) and (E)-3,4,5-Trimethoxy-N'-{3-methoxy-4-[2-{4-(2,4,6-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl}ethoxy]benzylidene} benzohydrazide (24) and they were screened for antibacterial activity using the agar well diffusion method. The presence of 3,4,5-trimethoxyphenyl and phenyl substituent in the compound (23) and 1,3,5-trimethoxyphenyl and 3,4,5-trimethoxyphenyl substituent in the compound (24) were responsible for increased activity against four bacterial strains such as E. coli, P. aeruginosa, S. pyogenes and S. aureus³⁵.

Vanillin derivatives with 1-Pyrimidin-2-yl piperidine-4-carboxylic acid hydrazide resulted in novel vanillin hydrazone derivatives, namely, 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid (4-butoxy-3-methoxy-benzylidene)-hydrazide (25) and 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid [3-methoxy-4-(2-methoxy-ethoxy)-benzylidene] hydrazide (26). The newly derived compounds were determined for antibacterial activity against both gram-positive and gram-negative bacterial strains (S. aureus and P. aeruginosa) by using the paper disc diffusion method and showed better antibacterial activity against the tested microorganisms. The better activity was due to the presence of butoxy, methoxy and methyl-ethoxy groups with a highly reactive azomethine group³⁶.

2-{[(4-fluorophenethyl)imino]methyl}-6-methoxyphenol (27) was derived simply by reacting ortho vanillin with aliphatic amine and examined for antifungal activity against C. albicans species. Due to the presence of azomethine moiety, it produced a good MIC value with a better radius of inhibition, determined by agar-well diffusion and broth microdilution techniques³⁷. Vanillin hybrid derivative, (Z)-3-methoxy-4-(2-(4-((4-(3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (28) was synthesized by hybridization of alkyne with azomethine moiety produced vanillin connected triazole moiety acted as a potent inhibitor of LasR (Intracellular receptor-type transcription factor) and PqsR (PQS‐binding response regulator) receptors by ameliorating the virulence of the gram-negative pathogen P. aeruginosa³⁸. The structures of the above discussed molecules are given in figure 3.

Figure 3: Compounds showed antimicrobial activity

Antitubercular activity

Tuberculosis was mainly due to Mycobacterium tuberculosis, a bacterial strain responsible for the leading cause of life-threatening lung infectious disease over a global population. Thus, a vanillin lipophilic amine derivative, 2-methoxy-4-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)methyl)phenol (29) was synthesized by reductive amination of vanillin with aromatic amine showed a promising degree of antimycobacterial activity against M. tuberculosis H37Ra strain, determined by the microplate resazurin assay. The range of bioactivity varied depending on the position of boron substitution in the aniline ring. Thus, the compound (29) bearing a boron moiety in the ortho position of the ring was responsible for the elevated potent activity¹⁰.

A novel thiadiazole-based vanillin derivative, 4-(5-amino-1,3,4-thiadiazol-2-yl)-2-methoxyphenol (30) was obtained by reacting vanillin derivative, 2-(4-hydroxy-3-methoxybenzylidene) hydrazinecarbothioamide with two leading active moiety vanillin and thiosemicarbazide possessed significant antitubercular activity against M. tuberculosis H37Rv strain in Middlebrook 7H9 broth base i.e., a liquid growth medium used for Mycobacterium species, especially for M. tuberculosis adaptive growth³⁰. A vanillin derivative, 7-methoxy-2-[4-(methoxy)phenyl)-l-benzofuran-5-carboxaldehyde undergoes reductive amination with 3-chloroaniline to form 3-Chloro-N-{[7-methoxy-2-(4-methoxyphenyl)-1-benzofuran-5-yl]methyl}aniline (31) which showed better antitubercular activity, determined by in silico molecular docking studies³⁹. The structures of the above discussed compounds are given in figure 4.

Antimalarial activity

The infectious disorder transmitted by female mosquitoes belong to the genus of Plasmodium parasite leads to severe pathological conditions in the secondary host. The researchers developed some vanillin derivatives as a formidable antimalarial drug against the active parasite. A novel aminoalkylated chalcone derivative, (E)-1-(4-chlorophenyl)-3-(4-hydroxy-3-methoxy-5-(piperidin-1-ylmethyl)phenyl)-prop-2-en-1-one (32) was synthesized by the reaction carried out between vanillin and chloroacetophenone through Claisen-Schmidt condensation and followed by addition of amine through Mannich base reaction. The obtained compound (32) showed significant antimalarial activity against chloroquine-resistant Plasmodium falciparum, determined by in vitro antimalarial studies and in silico docking studies. Hence, the addition of a secondary amine to this derivative resulted in increased antimalarial activity¹².

The in vitro study of vanillin containing 9H-fluoren sulfone derivatives, (9H-fluoren-9-yl)methyl((2S)-1-((1-(4-ethoxy-3-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)-1-oxopropan-2-yl)carbamate (33) and (9H-fluoren-9-yl)methyl ((2R)-1-((1-(4-ethoxy-3-methoxyphenyl)-2-(methylsulfonly) ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (34) showed better antimalarial activity against P. falciparum and both compounds were prepared by coupling 1-(4-ethoxy-3-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine with triethylamine and N, N-dimethylformamide. Thus, the compound containing methyl sulfone group, methoxy group at the third position and ethoxy group at the fourth position in the phenyl ring are responsible for the activity against P. falciparum⁴⁰. The structures of the above discussed compounds are given in figure 4.

Antiviral activity

1-(3-formyl-5-methoxyphenyl)guanidine (35) was obtained by reacting vanillin with the guanidine and acted as a potential H1N1 neuraminidase inhibitor with the lowest EC₅₀ (Half maximal effective concentration) value, determined by the enzymatic H1N1 neuraminidase inhibition assay. The antiviral activity was due to the presence of the guanidine group¹¹. 1,2,3-triazoles vanillin derivative, 4-((1-(4-isopropylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzaldehyde (36) was synthesized and found to be effective against Zika virus through in vitro and in silico docking studies⁴¹. The structures of the above discussed compounds are presented in figure 4.

Figure 4: Compounds possessing antitubercular (29-31), antimalarial (32-34) and antiviral (35-36) activities

Anti-cancer activity 

A vanillin derivative reacted with substituted sulfanilamide to synthesize in vitro cytotoxic potential compounds such as (E)-4-((4-hydroxy-3-methoxy-5-nitrobenzylidene)amino)-N-(pyridin-2-yl)benzenesulfonamide (37), (E)-2-methoxy-4-(((4-(N-(pyridin-2- yl)sulfamoyl)phenyl)imino)methyl)phenyl acetate (38) and (E)-2-methoxy-4-(((4-(N-(pyridin-2-yl) sulfamoyl)phenyl)imino)methyl)phenyl isobutyrate (39). Then, these compounds were found to be significantly active against MCF-7 human breast cancer cell line. The in silico studies also correlated with the experimental outcomes and resulted in better interactions between the receptor and ligands. From the outcomes, it indicated that the compound containing azomethine group with sulfomoyl moiety and phenyl carboxylate system showed potent anticancer activity³.  4-(1H-imidazo[4,5-f][1,10]-phenanthrolin-2-yl)-2-methoxyphenol (40) was synthesized by reacting vanillin with 1,10-phenanthroline-5,6-dione and evaluated against human colorectal carcinogenic cell lines such as HT29 and HCT116 cells. The tested compound was found to be highly active against colorectal cancer, determined by the inhibition of Wnt/β-catenin signaling pathway. The molecular docking studies with better interactions confirmed that this compound had a significant effect against the colorectal cancer target⁸. 

A vanillin derivative, 2-(4-hydroxy-3-methoxy benzylidene)indan-1-one reacted with a secondary amine to synthesize 2-(4-hydroxy-3-dipropylaminomethyl-5-methoxy benzylidene)indan-1-one (41) and the obtained compound was studied against four human oral squamous cell carcinoma cell lines in the gingiva (Ca9–22), the tongue (HSC-2, HSC-3, HSC-4) and human normal oral cells namely, gingival fibroblasts (HGF), periodontal ligament fibroblasts (HPLF) and human pulp cells (HPC). The presence of dipropilamino moiety possesses potent anticancer activity against tested carcinoma cell lines with a good CC^­₅₀ (50% Cytotoxicity concentrations) range¹⁸. (Z)-2-(4-hydroxy-3-methoxy benzylidene)hydrazinecarboxamide (42) showed prominent efficacy against Ehrlich-Lettre ascites carcinoma (EAC) cells in Swiss albino mice with an improved cell growth inhibition, tumour weight reduction and also resulted in the enhancement of survival time⁴². The structures of the above discussed compounds are given in figure 5.

Anti-oxidant activity

The spectrophotometric method was used for the determination of the antioxidant activity of vanillyl acetate (43) and o-methoxy-p-methyl cyclohexan-1-ol (44). Both compounds were synthesized by reacting vanillin with acetic anhydride and tetrahydrofuran. The results revealed that the reduction and acetylation process of vanillin enhanced the antioxidant activity¹. Vanillin reacted with aromatic amine and produced a potential antioxidant vanillin derivative, 4-(((4-butylphenyl)amino)methyl)-2-methoxyphenol (45), determined by DPPH (2,2-diphenylpicrylhydrazyl), (ABTS^•+) (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and FRAP (Ferric reducing antioxidant power) assay. The phenyl group linked to the NH group was responsible for the potential antioxidant activity⁶. The vanillin-derived piperidine-4-one oxime ester derivatives, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one o-(3,5-dihydroxy benzoyl) oxime (46) and 2,6-bis(4-hydroxy-3-methoxy phenyl)-1-methylpiperidin-4-one o-(3,4,5-trihydroxybenzoyl) oxime (47) were synthesized by reacting a vanillin derivative, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one oxime with substituted benzoyl chlorides and analyzed through DPPH and ABTS^•+ radical scavenging activity. The compounds with the presence of a hydroxy group on phenyl ester in their structure were responsible for potent anti-oxidant activity³¹. 3-((3,4-dihydroxyphenethyl)amino)-3-(4-hydroxy-3-methoxyphenyl)-N-phenylpropanamide (48) and N-(4-bromophenyl)-3-((3,4-dihydroxyphenethyl)amino)-3-(4-hydroxy-3-methoxyphenyl) propanamide (49)  were designed and synthesized by solvent-free method with simple trituration of reactive components such as dopamine, vanillin and N-methylacetamide. The obtained compounds were found to be better antioxidant potential with significant antityrosinase activity, determined by the ABTS, AAPH (2,2ʹ-azobis (2-amidinopropane) dihydrochloride) free-radical assay, Nitric oxide (NO) scavenging activity and H₂O₂ scavenging activity. Hence, both compounds were commonly bearing a dopamine-connected vanillin substituent in their structure and showed elevated antioxidant activity with a better IC₅₀ (Half-maximal inhibitory concentration) value⁴³. The structures of the above discussed compounds are given in figure 5.

The novel vanillin derivatives, 4,4'-(((3-hydroxypropyl) azanediyl)bis(methylene))bis(2-methoxyphenol) (50) and 4, 4',4'',4'''-((1,4-phenylenebis (azanetriyl))tetrakis(methylene)) tetrakis(2-methoxyphenol) (51) were obtained by reacting vanillin with 3-amino-1-propanol and p-phenylenediamine. Both compounds exhibited strong antioxidant activity in DPPH, FRAP and ORAC (Oxygen radical absorbance capacity) assay. The presence of a tertiary amino group along with vanillin moiety in the molecule contributed to produce potent antioxidant activity⁴⁴. Amino-alkylation of vanillin derivative, dehydrozingerone by Mannich base reaction produced 4-{3-[(dimethylamino)methyl]-4-hydroxy-5-methoxyphenyl}but-3-en-2-one (52) and the obtained novel compound was subjected to free-radical DPPH scavenging activity which has highest antioxidant activity due to the presence of tertiary amine, phenolic functionality, vanillin moiety and electronic delocalization⁴⁵. The structures of the above discussed compounds are given in figure 6.

Figure 5: Compounds with anticancer (37-42) and antioxidant (43-49) activities

Anti-inflammatory activity

Vanillin-triazine derivative, 4-(4-(4-formyl-3-methoxy phenoxy)-6-chloro-1,3,5-triazin-2-ylamino)benzonitrile (53) was synthesized by the reaction carried out between 4,6-dichloro-1,3,5-triazine-2-ylphenylamine derivative with vanillin showed a significant anti-inflammatory effect due to the presence of three active substance triazine, vanillin, and phenylpyrazole, determined through in vivo animal studies and in silico docking studies with cyclooxygenase-1 and cyclooxygenase-2 isoenzymes¹³. A vanillin derivative, dehydrozingerone undergoes amino-alkylation through Mannich base reaction produced 4-{4-hydroxy-3-methoxy-5-[(4-methylpiperazin-1yl)methyl]phenyl}but-3-en-2-one (54) which has N-methyl piperazine was a responsible moiety for potent anti-inflammatory effect, determined by the inhibitory of heat-induced albumin denaturation method with better IC_{50 ­­}range⁴⁵. 

The anti-inflammatory effect of the synthesized derivatives, (4-nitro-phenyl)-acetic acid [4-(4'-fluoro-biphenyl-4-yl methoxy)-3-methoxy-benzylidene]-hydrazide (55) and (2,3-dihydro-benzofuran-5-yl)-acetic acid [4-(4'-fluoro-biphenyl-4-ylmethoxy)-3-methoxy-benzylidene]-hydrazide (56) were evaluated by using carrageenan-induced mice model. These compounds were synthesized by coupling vanillin with biphenyl moiety in the presence of various intermediates. The results revealed that the presence of 2-phenylacetohydrazides moiety in both compounds showed significant anti-inflammatory activity⁴⁶. Vanillin derivative, 4-((5-nitrofuran-2-yl)methoxy)-3-iodo-5-methoxybenzaldehyde reacted with benzohydrazide derivative and yield a novel compound (E)-N'-(4-((5-nitrofuran-2-yl)methoxy)-3-iodo-5-methoxybenzylidene)-4-hydroxybenzohydrazide (57) which has a hydroxy group at the fourth position in its structure showed effective anti-inflammatory activity in a carrageenan-induced rat model study⁴⁷. Pyrazoline derivative of vanillin, 3-(4-aminophenyl)-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (58) was synthesized by reacting a vanillin chalcone derivative, (2E)-3-(3,4-dimethoxyphenyl)-1-phenylprop-2-en-1-one with thiosemicarbazide produced a potent anti-inflammatory compound through cyclooxygenase assay⁴⁸. The structures of the anti-inflammatory compounds are given in figure 6.

Figure 6: Compounds possessing antioxidant (50-52) and anti-inflammatory (53-58) activities

Anti-Alzheimer’s activity 

The accumulation of amyloid β peptide Aβ _(1–42) in the extracellular as a plaque was one of the main pathological conditions that lead to the cause of Alzheimer's disease. Thus, (2-(3-(bis(4-hydroxy-3-methoxybenzyl)amino)propyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione) (59) was obtained by reacting di-vanillin derivative with naphthalimide exhibited potent butyrylcholinesterase (BuChE) selective inhibition activity with a better IC₅₀ value, which was greater than the corresponding acetylcholinesterase (AChE) inhibitory activity. The synthesized compound was targeted to cross the BBB (Blood Brain Barrier) for potential activity. The computational study was carried out to predict the logP nature of the compound. Hence, the compound (59) with naphthalimide has a maximum ability to cross the BBB with a better logP range represented as a potential base for multi-target Alzheimer’s disease (AD) therapeutic activity¹⁴.

N1-(1,2,3,4-tetrahydroacridin-9-yl)benzene-1,4-diamin coupled with vanillin to form a new vanillin scaffold, 2-methoxy-4-(((4-((1,2,3,4-tetrahydroacridin-9-yl)amino) phenyl)amino)methyl)phenol (60) which inhibited the Aβ _(1–42) peptide aggregation due to the presence of phenolic moiety with tacrine in their structure, determined by Thioflavin T (ThT) dye fluorescence assay⁴⁹. Vanillin azomethine derivatives, 4-(4-Hydroxy-3-methoxybenzylideneamino) benzoic acid (61), 4-(4-Hydroxyphenylimino) methyl)-2-methoxyphenol (62) and 2-Methoxy-4-(phenylimino) methyl)phenol (63) were obtained by reacting vanillin with aromatic amines. The existence of potent azomethine moiety showed considerable in vitro acetylcholinesterase inhibitory activity through AChE inhibition assay with a better IC₅₀ range⁵⁰. The structures of the above discussed compounds are given in figure 7.

Anti-sickling activity 

Sickling is carried out when the hemoglobin inside the red blood cells clumps or sticks together and the cells lead to become fragile, rigid and sickle-shaped. These sickled cells are counteracted by a novel pyridyl vanillin derivative, 5-methoxy-2-[(pyridin-2-yl)methoxy]benzaldehyde (64) was synthesized by reacting vanillin derivative with 2-(bromomethyl)pyridine and exhibited a prominent antisickling activity due to the presence of methoxy group and also by stabilizing the R-state Hb complex by increasing O₂ affinity¹⁵. The structures of the above discussed compounds are given in figure 7.

Anti-diabetic activity

The morbid condition of the pancreas leads to the insufficiency of insulin production. Nowadays millions of populations were affected by diabetes mellitus. Thus, the vanillin-based acetohydrazide-hydrazone derivative, (2,3-dihydro-benzofuran-5-yl)-acetic acid [4-(4-cyano-benzyloxy)-3-methoxy-benzylidene]-hydrazide (65) was designed and synthesized by coupling a vanillin derivative, 4-((4-formyl-2-methoxyphenoxy)methyl)benzonitrile with 2-(2,3-dihydrobenzofuran-6-yl)acetohydrazide. The potent activity was due to the presence of 2,3-dihydrobenzofuran substituent in the synthesized compound, determined through in vivo study in alloxan-induced diabetic rats¹⁶. 

A vanillin hybrid, 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N'-[(Z)-(4-hydroxy-3-methoxyphenyl)methylidene]-4-methyl-1H-pyrazole-3-carbohydrazide (66) was synthesized by reacting 1,5-diarylpyrazole-3-carboxylic acids with vanillin and t-butyl carbazate. The hypoglycaemic activity was evaluated by using in vivo diabetes-induced rat model study. The presence of pyrazole moiety indicated a considerable anti-diabetic effect with a greater decrease in glycemia¹⁹. Thiazolidinedione vanillin derivative, (z)-5(4-hydroxy-3-methoxybenzylidine)-2,4-thiazolidinedione reacted in the presence of diazonium salt offered two novel compounds namely, 5-((E)-4-hydroxy-3-methoxy-5-((Z)-(4(methyl sulfonyl)phenyl)diazenyl)benzylidene) thiazolidine (67) and 5-((Z)-4-hydroxy-3-methoxy-5-((E)-(3,4,5-trimethoxyphenyl) diazenyl) benzylidene) thiazolidine-2,4-dione (68). Both compounds showed effective hypoglycaemic activity by in vivo antidiabetic assay⁵¹. The structures of the anti-diabetic compounds are presented in figure 7.

Radioprotective activity

Before radiation therapy radioprotective drugs are utilized in order to ensure high protection to prevent radiation-induced damage. The vanillin derivative, 4-hydroxy-3,5-dimethoxybenzaldehyde (69) improved the survival of lethally irradiated mice by promoting intestinal regeneration by significantly increasing the number of Lgr5⁺ intestinal stem cells (ISCs) with their daughter cells and the transient Ki67⁺ proliferating cells. The appropriate level of activated p53 gene was maintained which triggered the cell cycle arrest but it does not sufficient to induce NOXA-mediated apoptosis, thus it ensured the DNA damage repair in the irradiated small intestinal crypt cells. Further, it restored the intestinal bacterial flora structures altered by TBI (Traumatic brain injury) exposure. Thus, compound (69) had excellent radio-protective activity by modulating the p53/NOXA signaling pathway and also restoring the balance of gut microbiota⁵². The structures of the above discussed compounds are given in figure 7. 

Figure 7: Compounds showed anti-Alzheimer (59-63), anti-sickling (64),

 antidiabetic (65-68) and Radioproductive (69) activities

Conclusion

This review summarized the medicinally potent vanillin derivatives synthesized through recent development techniques. Hence, the researchers developed novel potential antimicrobial agents against various microbial species from vanillin moiety with a better inhibition rate. These derivatives can also act as an anticancer agent with high efficacy against various carcinoma cell lines resulting in induced cellular apoptosis. Apart from these activities, vanillin derivatives have a more prominent and extensive role against diverse diseases than the comparative standard drugs by easily modulating severe pathological conditions. Some recently developed vanillin derivatives are chalcone-based derivatives, hydrazone-based derivatives, azomethine Schiff base derivatives, Mannich-base derivatives, pyrazoline-based derivatives, triazole-based derivatives, vanillin-based hybrid molecules and metal complexes. Because of its massive therapeutic effect, it is continuously involved in the recent development techniques and also sustain in the field of medicinal chemistry as a leading scaffold.

Acknowledgement

We thank the Management and Dr. G. Murugananthan, the Principal of our college for giving constant support and encouragement for writing this review.

Author’s Contributions: All the authors have contributed equally. 

Funding: Nil.

Conflicts of Interests: The authors declare no conflict of interest.

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