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2330 Current Medicinal Chemistry, 2024, 31, 2330-2344

REVIEW ARTICLE

Recent Advances on the Antimicrobial Activities of Schiff Bases and

their Metal Complexes: An Updated Overview
Juliana Jorge1,#, Kristiane Fanti Del Pino Santos1,#, Fernanda Timóteo1, Rafael Rodrigo Piva
Vasconcelos1, Osmar Ignacio Ayala Cáceres1, Isis Juliane Arantes Granja2, David Monteiro
de Souza Jr.1, Tiago Elias Allievi Frizon3, Giancarlo Di Vaccari Botteselle4, Antonio Luiz
Braga5, Sumbal Saba2,*, Haroon ur Rashid1,5,* and Jamal Rafique1,2,*
1
Instituto de Química, Universidade Federal do Mato Grosso do Sul, Campo Grande, 79074-460, MS, Brazil;
2
Instituto de Química, Universidade Federal de Goiás - UFG, Goiânia, 74690-900, GO, Brazil; 3Department
of Energy and Sustainability, Universidade Federal de Santa Catarina - UFSC, Campus Araranguá, Araran-
guá, 88905-120, SC, Brazil; 4Departamento de Química, Universidade Estadual do Centro-Oeste - UNI-
CENTRO, Guarapuava, 85819110, PR, Brazil; 5Departamento de Química, Universidade Federal de Santa
Catarina, 88040-970, Florianópolis, SC, Brazil

ARTICLE HISTORY
Received: August 03, 2022
Revised: December 12, 2022
Accepted: December 29, 2022
DOI:
10.2174/0929867330666230224092830
Keywords: Schiff base, antimicrobial activity, imine, azomethine, antibacterial, antifungal, antiviral, antimalarial.
Abstract: Schiff bases represent a valuable class of organic compounds, synthesized via
condensation of primary amines with ketones or aldehydes. They are renowned for pos-
sessing innumerable applications in agricultural chemistry, organic synthesis, chemical
and biological sensing, coating, polymer and resin industries, catalysis, coordination
chemistry, and drug designing. Schiff bases contain imine or azomethine (-C=N-) func-
tional groups which are important pharmacophores for the design and synthesis of lead
bioactive compounds. In medicinal chemistry, Schiff bases have attracted immense atten-
tion due to their diverse biological activities. This review aims to encompass the recent
developments on the antimicrobial activities of Schiff bases. The article summarizes the
antibacterial, antifungal, antiviral, antimalarial, and antileishmanial activities of Schiff ba-
ses reported since 2011.

1. INTRODUCTION In the literature, they are considered synonyms for

imines (>C=N-) and azomethines (or secondary al-
Schiff bases are a class of nitrogenous organic com-
dimines, -HC=N-), as they are also known [1, 4-8].
pounds that have a general structure R-CH=N-R',
They received this name because of Hugo Schiff
where R and R' can be an alkyl or aryl group, linear or
(1834-1915), an Italian-German chemist laureated with
cyclic, which can be substituted in many ways [1-3]
the Nobel Prize and brother of the physiologist Moritz
They can be considered a subclass of imines, being
Schiff [1, 2, 4]. Hugo Schiff also discovered other
secondary ketamines (when both R and R' are different
imines, in addition to studying aldehydes, which led to
from H) and secondary aldimines (when R or R' is an H
the development of the Schiff reagent, for the identifi-
atom), depending on the presented structure [1, 2, 4, 5].
cation of these compounds, which consists of a color-
*Address correspondence to these authors at the Instituto de Quími-
less solution containing an indicator produced by the
ca, Universidade Federal de Goiás - UFG, Goiânia, 74690-900, GO, reaction between pararosaniline with sulfite in an acid
Brazil; E-mail: sumbalsaba@ufg.br (S.S.); Departamento de Quí- medium [5, 6].
mica, Universidade Federal de Santa Catarina, 88040-970, Floria-
nópolis, SC, Brazil; E-mail: haroongold@gmail.com (H.R.); Insti- The formation reaction of a Schiff base is presented
tuto de Química, Universidade Federal do Mato Grosso do Sul, according to the Schiff methodology (Fig. 1). They can
Campo Grande, 79074-460, MS, Brazil; be synthesized from an aliphatic or aromatic primary
E-mails: jamal.rafique@ufms.br, jamal.chm@gmail.com (J.R.)
#
Both authors contributed equally to this work.
amine (of the type R-NH2 or Ar-NH2), with an active

0929-8673/24 $65.00+.00 © 2024 Bentham Science Publishers

Recent Advances on the Antimicrobial Activities
carbonyl compound (C=O) of an aldehyde or a ketone
group, through nucleophilic addition, forming a hemi-
aminal, followed by dehydration, then generating an
imine (Fig. 2) [1, 2, 4, 5, 8].
Fig. (1). Synthesis of a Schiff base.
Fig. (2). Conventional reaction of formation of a Schiff base.
Schiff bases can occur naturally, as is the case with
the macrocyclic Schiff base derived from the corrin,
which is related to a substituted derivative found in
vitamin B12 (cobalamin), however, most are synthe-
sized in the laboratory [1].
Schiff's bases attract a lot of attention in the chemi-
cal area, mainly in inorganic chemistry, because of
their ability to coordinate with almost all existing metal
ions [9] and, therefore, expand the range of application
of these compounds in all areas of research and devel-
opment. They are considered “privileged ligands” [6,
10], and are classic ligands for metal ions in p, d, and f
blocks, having contributed a lot to coordination chem-
istry, especially in catalysis (homogeneous and hetero-
geneous catalysis) [2, 7]. They are considered easy to
form complexes with metals, in addition to being stable
[6, 10-12]. Metal complexes with chiral Schiff base
ligands also exhibit stereoselectivity in organic trans-
formations [11].
Currently, there are countless applications of Schiff
bases, for example, in photovoltaic energy [12], chemi-
cal and biological sensing [9, 13], etc. In the last dec-
ade, its application as fluorescent probe to detect bio-
logically important species has been reported [14]. Be-
sides, they are also utilized as stimuli-responsive link-
ers in polymer chemistry [15].
It is believed that the C=N portion of the molecule
is responsible for the biological activities that these
bases present [1, 2, 5], therefore, Schiff's bases attract
uprising attention in the medical field because of their
antitumor, anticancer, antibacterial, antiviral, antifun-
gal, antiparasitic, antiproliferative, anti-inflammatory,
antipyretic, anti-tuberculosis, insecticide, anticonvul-
sant activities [2, 3, 5, 8, 10, 16-20]. Schiff's bases have
Current Medicinal Chemistry, 2024, Vol. 31, No. 17 2331
already shown excellent action against various organ-
isms, such as Plasmopora viticola, Candida albicans,
Trichophyton gypseum, Erysiphe graminis, Bacillus
polymxa, Mycobacteria, Escherichia coli, Staphylococ-
cus aureus. Schiff bases based on o-phenylenediamine
are considered the best for medical applications, and
those obtained from p-toluidine and fluoro glyoxal
have been reported for their excellent inhibitory action
against Bacillus subtilis, Escherichia coli, Staphylo-
coccus aureus, and Proteus vulgaris. Schiff bases of 4-
dimethylamine benzaldehyde are potent antibacterial
agents, and isatin Schiff bases have antiviral, antiproto-
zoal, anti-HIV, anticonvulsant, and anthelmintic activi-
ties [3]. Considering these and other applications of the
Schiff bases, several excellent books, chapters, and re-
views are recently available in the literature [21-31].
In this context, herein we present a comprehensive
and up-to-date overview, covering recent advances in
the antimicrobial activities (antifungal, antiviral, anti-
malarial, and anti-leishmanial) of Schiff bases. This
represents a continuation of our research lines, which
encompass the synthesis of nitrogenous compounds
and their biological application [32-41]. Accordingly,
the review presented herein covers scientific literature
(excluding the patent literature) since 2021 (after the
report by da Silva et al. [5]). The chemistry of Schiff
Bases, which do not involve antimicrobial activities has
not been included. Consequently, there are many rele-
vant publications reporting very interesting studies,
carried out by many groups, which have regrettably
been omitted from this review article.
2. BIOLOGICAL ACTIVITIES OF SCHIFF BA-
SES
2.1. Antimalaria Activity
Malaria is a serious global disease caused by para-
sitic protozoa of the genus Plasmodium, which has
been neglected causing serious public health problems.
According to data, it has already infected about 241
million people in 2018, with this figure being reduced
(cases per 1000 population at risk) from 81 in 2000 to
59 in 2015 and 56 in 2019, before increasing again to
59 in 2020 (during the COVID-19 pandemic) [27, 42].
Currently, five types of the disease are known to infect
humans: Plasmodium falciparum (P. falciparum) (re-
sponsible for most malaria deaths in the world), Plas-
modium vivax (P. vivax), Plasmodium ovale (P. ovale),
Plasmodium malarieae (P. malarieae), and Plasmodi-
um knowlesi (P. knowlesi) [42].
Schiff bases studied in the last decades have shown
efficacy in the treatment of malaria. In 2019, Fonkui
2332 Current Medicinal Chemistry, 2024, Vol. 31, No. 17
and colleagues studied the reaction of Oct-2-ynoicacid-
(1, 3-dihydrobenzoimidazole-2-ylidene) amide (1) with
aniline derivatives (2) in the presence of a hot ethanolic
solution under reflux for 4 hours (Fig. 3) [43]. The
Schiff bases formed (3) significantly reduced the
growth of P. falciparum, causing complete cell death in
the studied concentration.
Fig. (3). Synthesis of Schiff bases under reflux in ethanol.
In this study, Schiff bases increased the action of
antimalarial drugs, as an example, this effect is shown
by an ancistrocladidina Schiff base, which is a second-
ary metabolite produced by the Ancistrocladaceae and
Dioncophyllaceae plant family. Among the tested
Schiff bases, compound 4 presented the best antimalar-
ial response (4). The IC50 (lowest concentration of
compounds that reduced the growth of parasites by
50%) was observed to be 26.96 µg/mL for this com-
pound [43] (Fig. 4).
H
N
N
N C C C5H11
H N
N
(4)
Fig. (4). Schiff base derivative with antimalarial prop-
erties.
2.2. Antileishmanial Activity
Leishmaniasis is an important parasitic tropical dis-
ease in many countries and is commonly found in de-
veloping countries. Like malaria, it has been ignored in
terms of public health, resulting in a problem that caus-
es millions of new cases every year, and thousands of
deaths [44]. The Leishmania parasite is transmitted by
the bite of infected female sandflies. About 98 species
of the genera Phlebotomus and Lutzomyia have been
described as established or alleged vectors for human
leishmaniasis. Currently, there are almost 18 species of
Leishmania reported as pathogenic to humans [45].
Recently, Chander and colleagues synthesized three
Schiff bases; N’-benzylidene-2-(6, 7-dimethoxy-3, 4-
Jorge et al.
dihydroisoquinolin-2-(1H)-yl) acetohydrazide deriva-
tives. These compounds were then tested in vitro
against amastigote and promastigote forms of Leish-
mania infantum (L. infantum). Two of these com-
pounds exhibited moderate activity against pro-
mastigote L. infantum (IC50 > 25 to ≤ 50 µg/mL), and a
third compound showed weak activity against this
form. For the assay against the amastigote L. infantum,
one of the two best compounds significantly inhibited
its growth, showing an inhibitory effect IC50 6.84 ±2.50
µM, and selectivity index (SI) > 29, while the others
showed weak inhibitory potential (IC50 > 50 µg/mL)
[46].
Direkel et al. produced four Schiff bases and veri-
fied their cytotoxic activity in vitro against pro-
mastigote forms of L. infantum. According to the ob-
tained results, one compound had the highest minimum
inhibitory concentration (MIC) value (78 µg.mL-1),
indicating high antileishmanial activity, whereas two
other compounds showed the second-best MIC value
(156 µg/mL, both) [47].
Granato and collaborators synthesized two Schiff
bases and their antileishmanial activity was tested in
vitro against amastigotes and promastigotes of some
species of Leishmania sp., and it was verified that the
second one synthesized presented the best activity (IC50
~ 2 µg/mL) against promastigotes of Leishmania ama-
zonensis (L. amazonensis), Leishmania brasiliensis (L.
brasiliensis) and Leishmania major (L. major), and for
amastigote of L. amazonensis (IC50 = 35.45 µg/mL),
the SI of this compound was > 1 [48]. Likewise, Godoi
et al. produced two other Schiff bases, 2-((4-
chlorobenzylidene) amino)-N-(2-(2-(4-chlorobenzyli-
dene)hydrazinyl)-2-oxoethyl) benzamide and 2-((4-
chlorobenzylidene) amino)-N-(3-(2-(4-chlorobenzyli-
dene) hydrazinyl)-3-oxopropyl) benzamide, and deter-
mined its cytotoxic activity in vitro against pro-
mastigotes of Leishmania aethiopica (L. aethiopica)
[33]. The results were promising and the Schiff base 2-
((4-chlorobenzylidene) amino)-N-(2-(2-(4-chloroben-
zylidene) hydrazinyl)-2-oxoethyl) benzamide had a
better IC50 than the standard drug of choice, Miltefo-
sine, and its activity was comparable to that of Ampho-
tericin B deoxycholate, indicating a high level of an-
tileishmanial activity [49].
Also, Mangwegape and co-authors produced Schiff
bases from the condensation of commercial 2-amino
benzenesulfonamide with triethylorthoacetate/ben-
zoate. The Schiff bases resulting from this reaction
were tested in vitro against promastigote forms of some
species of Leishmania sp., and the results showed that
Recent Advances on the Antimicrobial Activities
there was significant activity and selectivity against L.
major (the most active compound had IC50 = 0.2
µg/mL) and moderately active or inactive against
Leishmania donovani (L. donovani) (the most potent
compound against this species had IC50 = 6.5 µg/mL)
[50].
Recently, Taha et al. synthesized 20 analogous
compounds of Schiff base disulfides, whose basic
structure is shown in Fig. (5). The obtained compounds
were tested in vitro to verify their antileishmanial activ-
ity. All compounds showed higher inhibitory potential
than standard Amphotericin B, and 22 of the 27 ana-
logs showed high inhibitory potential with IC50 values
ranging from 0.010 ± 0.00 to 0.096 ± 0.01 µg/mL, 5
compounds showed good inhibitory potential with IC50
values ranging from 0.010 ± 0.00 to 0.137 ± 0.01
µg/mL when compared to the standard Amphotericin B
[51].
R
N
S
S tate for a variety of reasons, whether through the envi-
N
R
Fig. (5). Structure of Schiff base disulfide.
Ünver and co-authors produced eight new Schiff
bases with chalcone derivatives and tested their an-
tileishmanial activities against promastigote forms of L.
infantum. The highest antileishmanial activity was de-
termined by a MIC value of 2500 µg/mL, and some
compounds exhibited a MIC of 10000 µg/mL [52]. In
another study, they also produced nine other Schiff ba-
ses, which were tested against promastigotes of L. in-
fantum. In this recent study, only one compound was
considered the most effective with a MIC of 1250
µg/mL, and the other 3 compounds showed antileish-
manial activity at different concentrations, with MIC
ranging between 5000 and 10000 µg/mL [53].
Suleymanoglu and colleagues synthesized a Schiff
base of 1, 2, 4-triazole thiol-thione derivative and as-
sessed its antileishmanial activity against promastigotes
of L. infantum. The MIC was recorded to be 1250
µg/mL, indicating its activity antiparasitic against this
form of L. infantum [54].
Schiff base ligands can also be used in complexes for
application against leishmaniasis, such as the one synthe-
sized by Tahir et al. (Fig. 6) [55]. In this work, the authors
synthesized a new Schiff base ligand, N-(3, 4, 5-
trimethoxybenzylidene)-2, 3-dimethylbenzenamine, and
assessed it against the promastigotes of Leishmania tropi-
Current Medicinal Chemistry, 2024, Vol. 31, No. 17 2333
ca (L. tropica). The new ligand was shown to be active
with an IC50 of 0.179 mg/mL compared to the standard
Glucantime (12.9 µg/mL). The authors believe that the
activity presented may be related to the interference in the
functioning of the parasite's mitochondria.
O
O
N
O
Fig. (6). Structure of the novel Schiff base ligand N-(3, 4, 5-
trimethoxybenzylidene)-2, 3-dimethylbenzenamine.
2.3. Antiviral Activity
One of the most used ways to eradicate viral patho-
gens is through vaccines. Throughout history, diseases
such as rubella, smallpox, and poliomyelitis have
somewhat been eradicated through them [5]. However,
there are still numerous viruses that do not have specif-
ic vaccines or drugs for their eradication, such as HIV
[56], dengue [57], and influenza [58]. Viruses can mu-
ronment, by joining other types of viruses, or by strains
of resistant antiviral drugs, making it a global concern
and increasing the demand for new viral agents for un-
explored drugs [59].
Molecules with antiviral properties with Schiff ba-
ses have been studied and gaining prominence for their
infinite applications [5, 8, 57-60]. Regarding the appli-
cation of Schiff bases as antivirals, it is known to have
activity in both RNA and DNA [58, 60].
Jarrahpour and co-authors reported computational
studies by using the PETRA software, which provides
empirical data for the calculation of the physical-
chemical properties of organic molecules [58]. These
studies have presented interesting results. In this study,
the Schiff bases (Fig. 7) were subjected to calculations
of delocalized load obtained from the partial pi-load of
heteroatoms. These molecules (5-16) have high stabil-
ity when coordinated favoring the antiviral activity of
the drug. These factors are possible thanks to the steric
and electronic factors of these ligands when they are
coordinated with transition metals. With this infor-
mation, it becomes possible to obtain, without many
changes’ new designs of antiviral drugs [58, 61].
In another similar study, Abbas et al. synthesized 5-
fluoro isatin derivatives of Schiff bases with anti-viral
properties (Fig. 8) [62].
Through the antiviral screening carried out on some
selected compounds. The inhibitory activity of antiviral
agents was observed against the replication of the
2334 Current Medicinal Chemistry, 2024, Vol. 31, No. 17 Jorge et al.

Fig. (7). Schiff bases with anti-viral properties.

vesicular stomatitis virus (VSV) and evaluation of cy- Table 1. Cytotoxicity & antiviral activity of compounds
totoxicity in cell lines Vero clone CCL-81. Among the- 17-22.
se compounds, the most reactive were compounds
shown in Fig. (9) with their IC50 values shown in Table IC50 Virus Titer Virus Titer
Compound
1 [62]. (µg/mL) Log10 Difference Log
H H
F N N
F O 17 24.8 5.40 0.88
O

N 18 24.9 5.49 0.76

N
HN HN N R
NH 19 1.0 5.38 0.90
NHR
S S
20 3.0 5.57 0.68
Fig. (8). 5-Fluoroisatin derivatives of Schiff bases.
21 12.2 6.00 0.28

22 12.6 6.11 0.17

Madni and colleagues showed significant results of

Fig. (9). 5-Fluoroisatin derivatives of Schiff bases.
The antiviral activity was determined by the differ-
ence between the treated and untreated cells, using the
drug interferon as a standard. Among synthesized 5-
fluoro isatin derivatives, compound (17) showed the
best antiviral activity. In contrast, compound (19), and
those that had less antiviral activity were compounds
(21) and (22). The compounds investigated in this
study demonstrate that they are indicated as promising
antiviral agents against VSV [62].
antiviral activity of compounds (23), (24), and (25a-x)
(Fig. 10) against HIV-1 (IIIB) and HIV-2 (ROD) [63].
These compounds showed excellent IC50 values and
selectivity index (SI) against the IIIB virus, but none of
the compounds showed activity against the ROD virus.
Among these, the most active analogs against IIIB were
(25n) (IC50 = 0.50 µg/mL, SI = 5) and (25r) (IC50 =
0.45 µg/mL, SI = 3), while compounds (25a) and (25i)
exhibited only activity (IC50 > 0.45 and > 0.47 µg/mL)
against IIIB, not being selective (SI < 1) [63].
Maryam and collaborators presented a study with S-
substituted dithiocarbazate (Fig. 11) containing mono-
terpene enantiomers with high antiviral potential
against a class of clinically isolated active DENV 2
compounds [57]. The antiviral activity against Vero
cells infected with DENV 2 was observed in com-
pounds (26 - 29), (32 - 33) after the second evaluation,
IC50 and SI values are shown in Table 2.
Recent Advances on the Antimicrobial Activities Current Medicinal Chemistry, 2024, Vol. 31, No. 17 2335

respectively, suggesting antiviral activity in the order

Co> Zn> Cu> Ni> ligand [64].

Fig. (10). Compounds (23), (24), and (25a - x).

Fig. (12). HPTP compound and its metal complexes.

Viral pathologies are diseases that affect not only

Fig. (11). S-Substituted dithiocarbazate Schiff bases.
humans but all living beings on this planet. Several
studies are using Schiff bases for the treatment of to-
bacco mosaic virus (TMV). Recently, Zhang and co-
authors used Schiff bases mechanisms Gossypol O2-
(Fig. 13) for the treatment of TMV [65]. The authors
reported that the accumulation of Schiff bases Gossy-
pol O2- can influence the anti-TMV activity, highlight-
ing the importance of observing not only the interaction
of the virus and the specific compound but also the in-
teraction of the compound and its host.
R'
NH O

Table 2. Selectivity index (SI) of compounds with anti- R OH R'

H OH
HN HO
dengue potential. O
OH
O
HN
OH
O
HO OH
H NH HO
R
Compound IC50 (µg/mL) (SI) (-)-gossypol Schiff base (+)-gossypol Schiff base

(26) 6.9 ± 1.2 12.8

(38) R = (39) R’ =

(27) 6.2 ± 3.2 14.3 F 3C F 3C

(40) R = (41) R’ =
(28) 7.8 ± 3.7 8.3
O Na + O Na +
(29) 6.8 ± 2.8 14.1 (42) R = S - (43) R’ = S -
O O
O O
(32) 7.8 ± 4.5 10.4
O Na + O Na +
(44) R = (45) R’ =
(33) 6.8 ± 2.3 12.8 O
S -
O
O
S -
O

(46) R = NO 2 (47) R’ = NO 2

In addition to the studies cited, Johnson and Yardily

studied the ligand 3-(2-hydroxyphenyl)-1-(thiazol-2-yl)
prop-2-en-1-one (HPTP) with some transition metals
(Fig. 12) and realized that with this metallic coordina-
tion, the properties of antiviral activity and non-linear
optics (NLO) were increased [64]. The reported exper-
imental results were striking with theoretical spectral
investigations, the values of the energies associated
with the HPTP, Co (II), Ni (II), Cu (II), and Zn (II)
complexes are 298, 446, 340, 347 and 435 kcal.mol-1,
Fig. (13). Gossypol compounds (+) and (-) some of their
Schiff bases.
2.4. Antibacterial Activity
In 1928, Alexander Fleming's discovery of penicil-
lin was a milestone in a new era of advances in the
medical field, and in 1941 his first clinical tests were
carried out [66, 67]. Strains of Staphylococcus aureus
resistant to penicillin were recorded in the 1940s when
2336 Current Medicinal Chemistry, 2024, Vol. 31, No. 17
the production of beta-lactamase enzymes by bacteria
was identified, this is the most commonly known peni-
cillin resistance mechanism [68]. After the end of
World War II, benzylpenicillin and records of resistant
strains of Staphylococcus pyogenes were registered in
1949 [69]. With the emergence of resistance to antibi-
otics with their base structure as beta-lactam rings,
there was a need to find other compounds from other
structural classes that also had antibiotic activity.
In this context, many Schiff bases are produced us-
ing the drug design principles associated with molecu-
lar docking to obtain more assertive results regarding
the antibacterial activity. Kumar and co-authors syn-
thesized twenty compounds trying to combine different
functional groups that are reported in the literature to
increase antimicrobial activity. The new compounds
obtained were tested against the Gram-positive bacte-
ria: Staphylococcus aureus (S. aureus), Bacillus subtilis
(B. subtilis), and the Gram-negative bacterium Esche-
richia coli (E. coli). The results pointed out that (48)
(MIC = 0.83 µmol.mL-1) and (50) (MIC = 0.36 µg/mL)
(Fig. 14) were the most potent against B. subtilis and S.
aureus, respectively. Compound (49) (MIC = 0.77
µg/mL) (Fig. 14) proved effective against E. coli. No
selectivity results were presented in this study [70].
Fig. (14). Antibacterial activity obtained for compounds
(48), (49), and (50) against B. subtilis, S. aureus and E. coli.
Duan and co-authors developed derivatives of Ber-
berine (Fig. 15) that are Schiff bases associated with a
triazole nucleus and organic ramifications used to im-
prove physicochemical characteristics, such as solubili-
ty [71]. The derivatives obtained showed better biolog-
ical activity than the precursor compared to most of the
tested bacteria, and the modifications of compound
(52) showed more activity than Berberine in the 10
strains tested, with a highlight in 4 of them that the
derivate was also more active than the standard chlo-
romycin, including Methicillin-Resistant Staphylococ-
Jorge et al.
cus aureus (MRSA). The evaluation of the develop-
ment of resistance to the compound (52) was per-
formed with MRSA strain and norfloxacin as a positive
control. Over 14 passages, MICs were calculated and it
was possible to identify that compound (52) did not
develop bacterial resistance, unlike norfloxacin which
showed an increase in MIC from the fifth pass.
Fig. (15). Antibacterial activity obtained for (51) and (52)
against S. aureus, Methicillin-Resistant S. aureus N315, Mi-
crococcus luteus (M. luteus) ATCC4698, and E. coli DH52.
A study developed the synthesis of Schiff base-
linked imidazole naphthalimides and derivatives found
promising derivatives that presented antibacterial activ-
ity and in particular, the compound 6 (Fig. 16) that pre-
sented low MIC (0.003 µg/mL) against an MRSA
strain and six times greater activity compared to the
Norfloxacin (MIC = 0.020 µmol.mL−1) standard. And
compound (53) did not present a propensity to induce
bacterial resistance, the tests were carried out until ten
passages, on the other hand, the MIC of Norfloxacin
increased considerably after six passages [72].
Fig. (16). Structure and antimicrobial activity against MRSA
of naphthalimide derivative (53).
These compounds are widely explored because they
have a wide spectrum of biological activity, and the evi-
dence points out that this improvement in antimicrobial
activity is related to the ability of electron donation pro-
vided by the formation of the Schiff bases [73]. In this
context, the condensation of coumarins with pyrazole
groups forming Schiff bases was investigated by Chavan
and Hosamani [74]. The study revealed that compounds
(54) and (55) (Fig. 17) presented antibacterial activity
against S. aureus (MIC = 0.78 µg/mL) and (MIC =
Recent Advances on the Antimicrobial Activities
1.562 µg/mL), respectively which means 8 and 4 more
activity compared to ciprofloxacin positive control.
Fig. (17). Chemical structure of (54) and (55), and their re-
spective biological activities against B. subtilis, S. aureus, E.
coli, and Pseudomonas aeruginosa (P. aeruginosa).
These results are promising and among the scaffolds
produced, there were more active compounds in bio-
logical and molecular docking simulation results. The
combination of coumarins and pyrazole resulted in en-
hanced biological activity due to its synergism effects.
Discovered in 2015, Teixobactin presented itself as
a strong alternative to be used as an antibiotic. A study
reveals that it works through the inhibition of cell wall
synthesis by binding to a precursor to peptidoglycan
and a precursor of the cell wall teichoic acid. The re-
sults of this study did not indicate the development of
bacterial resistance to this compound in strains of S.
aureus or Mycobacterium tuberculosis (M. tuberculo-
sis) [75]. On the other hand, vancomycin is used as the
first option against infections by methicillin-resistant S.
aureus (MRSA), but drug-resistant strains have also
emerged. To find an alternative, Ng, Kuehne, and Chan
proposed a synthesis of teixobactin derivatives using
amino acids [76], and one of them is characterized as a
Schiff base. The derivative (56) (Fig. 18) presented
activity against 5 different S. aureus strains and 3 dif-
ferent Propionibacterium acnes (P. acnes) strains (IC50
= 17.82 ± 3.42 µg/mL against S. aureus SH1000).
Fig. (18). Chemical structure of (56), and their respective
biological activities against different lineages of S. aureus, P.
acnes, and P. aeruginosa.
Current Medicinal Chemistry, 2024, Vol. 31, No. 17 2337
2.5. Antifungal Activity
In a study aiming at the development of new biolog-
ically active compounds, a research group synthesized
4-(6-substituted-1, 3-benzothiazol-2-yl)-amino-2-(4-
substituted-phenylmethylidene)amino-1, 3-thiazoles.
Different substitutes at position 6 of the benzothiazole
ring, and position 2 of the phenyl ring of the mentioned
compounds were incorporated. Five of the substituted
compounds showed interesting antifungal activity
compared with the standard used in the study (Flucona-
zole). They concluded that using electron-withdrawing
atoms like fluorine in position 6 of the benzothiazole
ring and even chlorine in position 2 of the phenyl ring
might be responsible for their reasonable activity
against two pathogenic fungal strains, Candida albi-
cans (C. albicans) and Aspergillus niger (A. niger),
compared with Fluconazole, the antifungal reference
[77]. The compound that showed maximum activity for
both strains is number 2: for C. Albicans it showed a
MIC of 2 µg/mL compared with 1 µg/mL of the stand-
ard; for A. niger the activity displayed was 4 µg/mL
compared with 2 µg/mL of Fluconazole. All the other
four compounds showed reasonable activity when
compared with the standard used. The main skeleton of
the chemical structure (Fig. 19) with the substituted
positions marked as R1 and R2, the substituents of each
of the five compounds are shown in the table below.
The antifungal activity of the substances is in Table 3,
with the standard antifungal drug used in the study.
Fig. (19). Chemical structure of the main skeleton and a ta-
ble below showing which substituents are in the marked po-
sition as R1 and R2.
In another study, researchers evaluated the antimi-
crobial activity (bacteria and fungi) of 5-substituted
Schiff base of isatin derivatives. They modified Ciprof-
loxacin methylene isatin derivatives in position 3, sub-
stituting with aromatic aldehydes. One of the com-
pounds (Fig. 20) exhibited the same activity compared
with the reference used (Ketoconazole) for two patho-
genic strains of fungi: A. niger and Aspergillus fumiga-
tus (A. fumigatus), responsible for food contamination
(black mold), especially apricots, grapes, onions, and
2338 Current Medicinal Chemistry, 2024, Vol. 31, No. 17 Jorge et al.

peanuts. They can also cause otomycosis (fungal ear
infection) and more rarely a serious disease called as-
pergillosis (lung infection). In addition, this compound
also exhibited good antimicrobial activity compared
with the standard used in the study Ciprofloxacin,
against S. aureus, a Gram-positive bacterium that can
cause a wide range of diseases, from minor skin infec-
tion to serious conditions such as meningitis [78]. The
antifungal and antibacterial activity of the mentioned
compound is shown in Table 4.
activity very close to 100% against Fusarium oxysporum
(F. oxysporum), an ascomycete fungus that could be
pathogenic to important crops, like soybean. The drug
used as standard in the tests was Nystatin. They attribut-
ed the good antifungal activity to the presence of elec-
tron-withdrawing groups (bromide and nitro respective-
ly) [79]. Both compounds only differ from the substitu-
ent in the benzene ring (Fig. 21) a comparative table of
percentage of inhibition against F. oxysporum using
Nystatin as reference is seen in Table 5.

Table 3. Minimum Inhibitory Concentration (MIC) for

antifungal activity of the compounds given in
µg/mL.

Compound Candida albicans Aspergillus niger

(57) 9 10
Fig. (21). Chemical structures of formamidine derivatives
(58) 2 4 with antifungal activity against F. oxysporum, (62a) and
(59) 3 5 (62b) only differ in the substitute of the benzene ring.
(60) 5 9
Table 5. In vitro antifungal activity of (62a) and (62b).
(61) 6 8
Fluconazole 1 2
Compound % Inhibition
- Fusarium oxysporum
(62a) 97.1
(62b) 96.9
Nystatin 100

In the interest of investigating Schiff bases that have

antifungal activity against fungi that causes diseases in
Fig. (20). Chemical structure of the 5-substituted Schiff base
important agricultural crops, another group of re-
of isatin derivative with an aromatic aldehyde in position 3.
searchers synthesized and tested inulin derivatives
modified with Schiff’s bases [80]. Inulin is a polysac-
charide made up of D-fructofuranose units linked by β2,
Table 4. Minimum Inhibitory Concentration (MIC) for
1-glycosidic bonds. Two derivatives could completely
antifungal and antibacterial activity of the
compound given in µg/mL. inhibit the test fungi, Botrytis cinerea (B. cinerea), F.
oxysporum, and Phomopsis asparagi (P. asparagi), at
Staphylococcus Aspergillus Aspergillus
1.0 mg/mL. Their structures are shown in Fig. (22).
Compound
aureus niger fumigatus
Proposed 7.81 15.62 7.81
Ciprofloxacin 15.62 -- --
Ketoconazole -- 15.62 7.81

Another path investigated by researchers is
formamidine derivatives, the group investigated (E)-
N’-(2-chloropyrimidin-4-yl)-N-(5-cyano-2-hydroxy-6-
phenylpyrimidin-4-yl) formamidine derivatives and
their Schiff bases. Two compounds exhibited antifungal
Fig. (22). Chemical structures of inulin derivatives with anti-
fungal activity against B. cinerea, F. oxysporum, and P. as-
paragi, compounds only differ in the substitute chloride of
the benzene ring in position 3.
Recent Advances on the Antimicrobial Activities
Using also inulin, another group attached pyridine
rings changing just the position of the bond between
the pyridine ring and 6-amino-6-deoxy-3, 4-acetyl inu-
lin(3). Their results suggest that the antifungal activity
resides on the substituents with no significant differ-
ences in the antifungal activity concerning the position
of the N atom on the pyridine ring. They tested these
compounds against B. cinerea, F. oxysporum, and P.
asparagi, too, but using as reference the drug Car-
bendazim, a broad-spectrum fungicide used in agricul-
ture to control botanical diseases, especially fruits. All
three substances have good activity at 2.0 mg/mL [81].
The chemical structures of these inulin derivatives are
shown in Fig. (23).
Fig. (23). Chemical structures of inulin derivatives named
(63), (64), and (65) with antifungal activity against Botrytis
cinerea, Fusarium oxysporum, and Phomopsis asparagi,
compounds only differ in the position of the N atom on the
pyridine ring.
(E)-2-{[(3-aminopyridin-4-yl)imino]-methyl}-4, 6-
di-tert-butyl-phenol (compound 66a¸ Fig. 24) also ex-
hibited antifungal activity against yeast (Cryptococcus
spp.) with MIC of 4.468 µg.mL-1 after 48 hours using
ketoconazole as reference [82]. A derivative of the
aforementioned compound: ((E)-2-{[(3-aminopyridin-
4-yl)imino]-methyl}-4, 6-di-chloro-phenol) (compound
66b, Fig. 24) showed some activity (25%) against B.
cinerea (mold) at 10 µg/mL compared with the refer-
ence used, fenhexamid fungicide used for the control of
gray mold in grapes [83].
Fig. (24). Antifungal active Schiff bases (66a-b).
In another approach, Sabaa and colleagues synthe-
sized Schiff bases modified chitosan-graft-
poly(acrylonitrile), using another polymer, derivate
from chitin. The compound (67) (Fig. 25) exhibited
satisfactory antifungal activity against A. fumigatus
(same MIC as the reference), C. albicans and Geotri-
Current Medicinal Chemistry, 2024, Vol. 31, No. 17 2339
cum candidum (G. candidum) (good activity compared
with reference drug), Table 6. The standard used is
Amphotericin B [84].
Fig. (25). Chitosan-graft-poly(acrylonitrile) modified Schiff
base (67).
Table 6. Minimum Inhibitory Concentration (MIC) for
antifungal activity of the compounds given in
µg/mL.
Aspergillus Candida Geotricum
Compound
fumigatus albicans candidum
Chitosan-graft-
0.98 3.90 0.98
poly(acrylonitrile)
Amphotericin B 0.98 0.49 0.49
Also using chitosan but with a slightly different ap-
proach, Anush and colleagues synthesized Schiff bases
of chitosan modifying the N-acetyl-D-glucosamine unit
of the chitosan with pyrazole-based compounds. 1-
Phenyl-3-methyl-5-o-cresyloxy 1H-pyrazole-4-carbal-
dehyde (68) (Fig. 26) showed antifungal activity
against C. albicans with a MIC of 12.5 µg/mL [85].
Fig. (26). Antifungal active Schiff bases (66a-b).
CONCLUSION
Schiff bases represent gifted organic compounds
that have been widely studied for their countless chem-
ical, medicinal, and industrial applications. They have
also attracted considerable attention in the pharmaceu-
tical industry due to the presence of a privileged func-
tional group (-C=N-). It has been known for a long
time that Schiff bases exhibit significant antimicrobial
activities. Due to the simplicity of their synthesis,
chemical stability, and diverse biological properties,
they are among the functionality of choice among the
scientific community.
2340 Current Medicinal Chemistry, 2024, Vol. 31, No. 17
In conclusion, this review reinforces recent advanc-
es in the antibacterial, antifungal, antiviral, antimalari-
al, and antileishmanial activities of Schiff bases since
2011. The progress described in this review highlighted
are envisioned to stimulate further research in Schiff
bases. Besides, several examples of Schiff bases with
transition metal complexes have also been discussed.
With these interesting features, in this area, challeng-
es, as well as new opportunities, need to be addressed.
Detailed analyses for thestructure-activity relationships
of the Schiff bases and mechanistic studies on their
mood of action need to be explored, to broaden the un-
derstanding of their biological activities. Furthermore,
molecular hybridization of Schiff bases with other bio-
logically relevant compounds and pharmaceuticals
would be of interest for the advancement of this area.
LIST OF ABBREVIATIONS
MIC = Minimum Inhibitory Concentration
VSV = Vesicular Stomatitis Virus
SI = Selectivity Index
NLO = Non-linear Optics
TMV = Tobacco Mosaic Virus
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
We gratefully acknowledge CAPES (Grant no. 001)
and CNPq. S.S., and J.R. are grateful to CNPq (Grant
nos. 315399/ 2020-1, 422645/2021-4, 309975/2022-0,
and 403210/ 2021-6), Fundação de Apoio a Pesquisa -
(FUNAPE - UFG) (Call No. 01/2022, No.: 210, and
Call No. 01/2022, No.: 223) and INCT-
Catálise/FAPESC/CNPq for funding.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial
or otherwise.
ACKNOWLEDGEMENTS
Declared none.
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