Schiff bases are compounds with an azomethine structure, which are formed as a result of the nucleophilic addition reaction of aldehydes and ketones to primary amines and which contain an azomethine group (–CH=N–) in their structure (R₁, R₂, and R₃ are alkyl or aryl substituents) (Fig. 1; Subasi 2022).

For the first time, azomethine derivatives were obtained by the German scientist Hugo Schiff in 1864 by condensation of a carbonyl group (aldehyde, ketone) with a primary aliphatic or aromatic amine. In the first step of the Schiff base synthesis, a carbinolamine intermediate is formed from the condensation of the carbonyl group with the primary amine, and in the second step, a Schiff base is obtained from the dehydration of the intermediate (Subasi 2022).

The types of amines that are condensed with carbonyl compounds are derivatives of hydroxylamine, hydrazine, phenylhydrazine, semicarbazide, thiosemicarbazide, and hydroxylamine. The names of the respective condensation products, depending on the type of amine, can be classified as hydrazones, phenylhydrazones, semicarbazones, thiosemicarbazones, and oximes (Raczuk et al. 2022).

The electron pairs on the nitrogen atom in the azomethine group determine basic properties. In Schiff compounds derived from aldehydes containing an ortho-hydroxy group, there are two tautomeric structures: phenol-imine and ketone-amine, which are identified by nuclear magnetic resonance (NMR), UV-VIS spectrophotometry, and X-ray crystallography. In studies with Schiff bases derived from 2-hydroxy-1-naphthaldehyde and some aromatic and aliphatic amines (ammonia, methylamine, and phenylamine), it has been observed that the keto form is dominant in polar solvents, while the enol form is predominant in nonpolar solvents (Subasi 2022).

The azomethine bond (–CH=N–) is a weak chromophore that absorbs in the ultraviolet region. Conjugation with phenyl groups causes a bathochromic shift of the absorption maximum of the –CH=N– chromophore to the visible region. In the presence of deactivating substituents in the aromatic ring, such as a halogen atom, the wavelength of the absorption maximum decreases due to the hypsochromic effect of the substituents. The infrared bands of the –CH=N– bond are observed in the interval 1610 cm⁻¹ – 1635 cm⁻¹ (Subasi 2022).

Over the past few decades, there has been great interest in Schiff derivatives (Al Zoubi et al. 2018; Aljamali et al. 2021). The presence of an azomethine group (Aljamali et al. 2021) has been found to be responsible for the following main important pharmacological activities of Schiff bases (Chaubey and Pandeya 2012): antitumor (Howsaui et al. 2021) and antibacterial (Chen et al. 2019; Gacitúa et al. 2022).

Compounds containing an azomethine moiety include hydrazones (Kulkarni et al. 2017), semicarbazones (Kulkarni et al. 2017), thiosemicarbazones (Güzel et al. 2008), and oximes (Dhuguru et al. 2022).

Hydrazones represent an important class of biologically active drug molecules containing an azomethine –CH=N–NH– group and are formed by the reaction of hydrazine or hydrazide with aldehydes and ketones. The azomethine structure determines a wide range of pharmacological properties of N-acylhydrazones (Thota et al. 2018; Dhuguru et al. 2022), which exhibit antitumor (Li et al. 2018; Aneja et al. 2019; Demurtas et al. 2019; Govindaiah et al. 2019; Banumathi et al. 2022; Shah et al. 2022; Vilková 2022; Kassab et al. 2023), antimicrobial (Guilherme 2019; Rezki et al. 2019; Yao et al. 2021), antituberculosis (Bonnett et al. 2018; Mandewale et al. 2019; Rohane et al. 2020), antiviral—including against Epstein-Barr virus (Reznichenko et al. 2019) and HIV (Yoneda et al. 2014)—fungicidal (Mali et al. 2021), antimalarial (dos Santos Filho et al. 2016), anti-Leishmanial (Jacomini et al. 2016; Visbal et al. 2023), anthelmintic, antiprotozoal, antischistosome (Socea et al. 2022), and trypanocidal (Serafim et al. 2014) effects.

Antitumor activity has been demonstrated for hydrazones of acridine (Vilková 2022), coumarin (Govindaiah et al. 2019), indole (Demurtas et al. 2019), isoniazid (Shah et al. 2022), α-carboline (Li et al. 2018), and azo-hydrazones (Banumathi et al. 2022). Isatin-triazole hydrazones have been developed as potential inhibitors of microtubule kinase and are promising agents for the treatment of cell proliferation and metastasis (Aneja et al. 2019). It has been reported that azo-hydrazone analogues exert activity against solid tumors by stimulating death signaling pathways (Banumathi et al. 2022). Some indole hydrazones can be used as multifunctional agents due to their antiproliferative and antioxidant effects (Demurtas et al. 2019).

Coumarin-hydrazone derivatives have been designed as compounds targeting tubulin and reducing cancer cell growth (Govindaiah et al. 2019). α-Carboline/acylhydrazone hybrids have been discovered as antitumor agents capable of overcoming cancer drug resistance (Li et al. 2018). Hydrazone derivatives of isonicotinic hydrazide exhibit cytotoxic and antibacterial potential (Shah et al. 2022). Acridine-based N-acylhydrazone analogues have been investigated as promising anticancer agents (Vilková et al. 2022).

By inducing apoptosis, the derivative 5-bromo-1-methyl-N’-[(E)-(1-methyl-1H-indol-3-yl)methylidene]-1H-indol-3-carbohydrazide possesses anticancer activity in breast and colon tumors. The compound 1-(4-methoxybenzyl)-N’-(7-methyl-2-oxoindolin-3-ylidene)-1H-1,2,3-triazole-4-carbohydrazide has shown antiproliferative effects (Aneja et al. 2019). The derivatives N’-(1-(4,7-dihydroxy-2-oxo-2H-chromen-3-yl)ethylidene)benzohydrazide and N’-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)benzohydrazide exert antiproliferative activity comparable to doxorubicin.

Acylhydrazones exhibit antimicrobial effects against Bacillus subtilis, Clostridium difficile, Enterococcus faecalis, Escherichia coli, Haemophilus influenzae, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Salmonella typhimurium, Staphylococcus aureus, and Streptococcus mutans, and possess antiparasitic activity toward Entamoeba histolytica, Leishmania amazonensis, and Trypanosoma cruzi (Socea et al. 2022).

Antibacterial effects are exhibited by hydrazones of isoniazid (Shah et al. 2022), pyridine (Rezki et al. 2019), and aminoguanine (Yao et al. 2021). Acylhydrazones derived from carbohydrates also demonstrate antimicrobial activity (Guilherme 2019). Pyridinium hydrazone-phenoxy conjugates have been evaluated for targeting resistant microbial strains due to their antibacterial potential (Rezki et al. 2019). Aminoguanidine derivatives containing an acylhydrazone moiety exert antimicrobial effects (Yao et al. 2021).

Hydrazones of quinoline (Mandewale et al. 2019) and eugenol (Rohane et al. 2020) are active against Mycobacterium tuberculosis (Bonnett et al. 2018). Zinc complexes of hydrazone derivatives of 3,4-dihydroquinolin-2-one have been studied for antitubercular properties (Mandewale et al. 2019). Hydrazones of eugenol have been developed as in vitro antimycobacterial agents (Rohane et al. 2020).

Bis(acylhydrazones) are modulators of Epstein–Barr virus immune evasion (Reznichenko et al. 2019). Oxoquinoline-acylhydrazone derivatives have been reported as inhibitors of HSV-1 DNA polymerase and may be used against HIV-1 (Yoneda et al. 2014).

Anti-leishmanial properties have been established for naphthylacylhydrazones (Visbal et al. 2023) and pyrazolohydrazones (Jacomini et al. 2016). Some antimalarial compounds have been obtained from conjugation of N-acylhydrazone and 1,2,4-oxadiazoles (dos Santos Filho et al. 2016). Zinc(II)-sterol hydrazone complexes exhibit antiparasitic action against Leishmania (Visbal et al. 2023).

Pyrazolo[3,4-d]pyridazinone-N-acylhydrazone-(bi)thiophene hybrids have been reported to possess activity against Leishmania amazonensis (Jacomini et al. 2016). Hybrid derivatives of N-acylhydrazone and furoxan groups exert selective anti-Trypanosoma cruzi effects (Serafim et al. 2014).

Hydrazone derivatives are potential antidiabetic (Tariq et al. 2019), anti-inflammatory (Cordeiro et al. 2016, 2020), analgesic (Marchev et al. 2019), antioxidant (Demurtas et al. 2019; El-Mekabaty et al. 2021), anti-acetylcholinesterase (Bozbey et al. 2020), and antiglaucoma (Bozbey et al. 2020) agents. Hydrazone derivatives have also been studied for anticonvulsant (Marchev et al. 2019; Nesterkina et al. 2020), antihypertensive, antiplatelet, cardiotonic (de Oliveira et al. 2020), and immunomodulatory effects (Meira et al. 2018).

Xanthenone-based hydrazones are α-glucosidase inhibitors and exhibit antidiabetic function (Tariq et al. 2019). The antidiabetic effect of flurbiprofen hydrazone Schiff bases has been studied (Alam et al. 2022).

Hydrazones possess anti-inflammatory activity. Tetrahydronaphthyl-N-acylhydrazones exhibit in vivo anti-TNF-α effects and can reduce inflammatory processes (Cordeiro et al. 2016). Anti-inflammatory potential has also been demonstrated for 2-aminopyridinyl-N-acylhydrazones (Cordeiro et al. 2020).

Analgesic activity has been confirmed for some hydrazones, including aryhydrazone-based hybrids (Marchev et al. 2019). Indole hydrazones with antioxidant effects have been designed (Demurtas et al. 2019). Benzenesulfonamide hydrazones have been found to inhibit carbonic anhydrase (Sharma et al. 2019). Verbenone hydrazones show anticonvulsant properties (Nesterkina et al. 2020).

Guanylhydrazones are widely studied molecules of great scientific interest due to their broad biological potential, including antitumor (Franca et al. 2016), antibacterial (Gadad et al. 2000), antimalarial, antihypertensive, antidiabetic, and trypanocidal activities (Azevedo de Brito et al. 2017).

Guanylhydrazones exhibit biological activity against lung, breast, and glioma tumors. The 3-nitrophenyl and 4-nitrophenyl moieties of guanylhydrazones are important pharmacophoric groups that enhance affinity for specific tumor receptors. The guanylhydrazone derivatives 2-[(3,5-di-tert-butyl-4-hydroxyphenyl)methylene]hydrazinecarboximidamide, 2-([1,10-biphenyl]-4-ylmethylene)hydrazinecarboximidamide, and 2-[(3,4-dichlorophenyl)methylene]hydrazinecarboximidamide possess pharmacological activity against neoplastic cell lines such as colon (HCT-8), melanoma (MDA-MB435), glioblastoma (SF-295), and promyelocytic leukemia (HL-60) (Franca et al. 2016).

A number of hydrazones have been found to exhibit a multitargeted mechanism of action against various diseases, thus making them useful drug candidates. The broad biological potential of hydrazones encourages their continued exploration for new pharmacological applications.

Thiosemicarbazones are condensation products of thiosemicarbazide with an aldehyde or ketone (Matesanz et al. 2021), and they exert antitumor (Shakya and Yadav 2020), antiviral (Moharana et al. 2020), fungicidal (Altıntop et al. 2016), antimalarial (Matsa et al. 2019; Anant et al. 2022), trypanocidal (Silva et al. 2019), anti-Alzheimer (Palanimuthu et al. 2017; Mavroidi et al. 2022), antioxidant (Yang et al. 2020), and antidiabetic (Shehzad et al. 2019) effects.

Thiosemicarbazones have demonstrated activity against Alzheimer’s disease in vitro (Mavroidi et al. 2022). The antioxidant properties of camphene-based thiosemicarbazones have been evaluated (Yang et al. 2020). The antidiabetic potential of adamantyl-thiosemicarbazones has been explored, and it has been shown that this effect results from the inhibition of aldose reductase (Shehzad et al. 2019).

Some thiosemicarbazones exhibit multitarget activity. Naphthalene-substituted thiosemicarbazone derivatives have been shown to be potent antifungal and anticancer agents (Altıntop et al. 2016). Thiosemicarbazones and semicarbazones containing the 1,2,3-1H-triazole–isatin scaffold possess cytotoxic and trypanocidal activity (Silva et al. 2019).

Pyridoxal 4-N-(1-benzylpiperidin-4-yl)thiosemicarbazone exhibits antiproliferative effects, inhibits amyloid-β aggregation, suppresses oxidative stress, and exerts moderate anti-acetylcholinesterase activity (Palanimuthu et al. 2017). A multitargeting effect is also demonstrated by a Zn(II) thiosemicarbazone complex, which is active against SARS-CoV-2 and exhibits anti-inflammatory properties (Arslan et al. 2023). Quinazolinone thiosemicarbazones and their metal complexes possess antitumor, antimicrobial, antiepileptic, and analgesic activities (Aly et al. 2010). The compound 4-(1-adamantyl)-3-thiosemicarbazone is effective against Gram-positive and Gram-negative bacteria, as well as Candida albicans (Pham et al. 2020).

Thiosemicarbazone derivatives exert anticancer activity against various cell lines, including cholangiocarcinoma (HuCCA-1), liver carcinoma (HepG2), and lung carcinoma (A549) (Shakya and Yadav 2020). Isatin-based thiosemicarbazones have been reported to exhibit antiproliferative activity against acute lymphoblastic leukemia (MOLT-3) cells (Saranya et al. 2019). Antitumor effects have also been demonstrated for thiosemicarbazone complexes with Au(I) (González-Barcia et al. 2019), bis(thiosemicarbazones) of Zn(II) (Palma et al. 2019), and Co(II), Ni(II), Zn(II), and Pd(II) complexes derived from 2-acetyl-5-chlorothiophene thiosemicarbazone (Şen et al. 2019).

The following thiosemicarbazones (de Siqueira et al. 2019; Heffeter et al. 2019) have shown promising antitumor properties:

It has been reported that N4-aryl-substituted thiosemicarbazones derived from 1-indanones (Sólimo et al. 2018) and gallium(III)–thiosemicarbazone complexes (Qi et al. 2018) are potential antitumor agents for breast cancer treatment.

Derivatives of 5-nitro-thiophene–thiosemicarbazone have demonstrated anticancer activity, with a mechanism of action involving the induction of apoptosis and stimulation of DNA intercalation (Roque-Marques et al. 2019). Bromophenol–thiosemicarbazone hybrids have been evaluated as potent, selective inhibitors of poly(ADP-ribose) polymerase-1, suggesting promising anticancer potential (Guo et al. 2019). The in vitro antitumor activity of copper and zinc bis(thiosemicarbazone) complexes has also been demonstrated (Anjum et al. 2019). Thiosemicarbazones derived from 2-acetyl-5-methylthiophene and cinnamaldehyde, along with their palladium(II) complexes, have been investigated for antiproliferative effects (Nyawade et al. 2021). In addition, biotin-conjugated anticancer thiosemicarbazones and their iron(III) and copper(II) complexes have been evaluated for their antitumor properties (Kallus et al. 2019). Thiosemicarbazone derivatives of indole have been observed to exert antiproliferative activity (He et al. 2019).

Thiosemicarbazones were among the first discovered antiviral agents and, like their parent thiosemicarbazides, display activity against various viruses, including herpes simplex virus types 1 and 2, dengue virus, hepatitis C virus, and influenza virus (Moharana et al. 2020). Thiosemicarbazones containing benzene, thiophene, or pyridine rings have shown activity against vaccinia virus infection, with the strongest effects observed for thiosemicarbazones of:

P-aminobenzaldehyde-3-thiosemicarbazones were first discovered in 1950 by Hamre, Bernstein, and Donovick and were shown to exhibit antiviral activity (Moharana et al. 2020). Antiviral effects have also been reported for 5-fluoro-1H-indole-2,3-dione 3-thiosemicarbazones (Sevinçli et al. 2020). (Thio)semicarbazone-based benzimidazole derivatives have demonstrated antiviral activity against human respiratory viruses (Francesconi et al. 2020).

Salicylaldehyde thiosemicarbazones have been found to inhibit influenza virus endonuclease activity (Rogolino et al. 2015). In addition, thiosemicarbazones derived from α-amino acids have been evaluated for their antiviral activity against dengue virus (Padmanabhan et al. 2017).

Currently, there is great relevance in the study of the potential activity of:

It has been shown that multitarget action of Schiff bases derived from 2-naphthaldehyde as compounds with antidiabetic and antioxidant potential (Oladipo et al. 2023). It has been observed that 1,4-bisphenylhydrazone derivatives exert antioxidant effects and are acetylcholinesterase inhibitors (Amine-Khodja and Boulebd 2023).

The fragment of the azomethine group is contained in the chemical structure of drugs, with possible applications in the treatment of various pathologies. Drugs—azomethine derivatives with the following pharmacological effects are used in therapy (Socea et al. 2022):