Accepted Manuscript

Isatin derivatives and their anti-bacterial activities

Hua Guo

PII: S0223-5234(18)31054-7
DOI: https://doi.org/10.1016/j.ejmech.2018.12.017
Reference: EJMECH 10950

To appear in: European Journal of Medicinal Chemistry

Received Date: 30 October 2018

Revised Date: 6 December 2018
Accepted Date: 8 December 2018

Please cite this article as: H. Guo, Isatin derivatives and their anti-bacterial activities, European Journal
of Medicinal Chemistry (2019), doi: https://doi.org/10.1016/j.ejmech.2018.12.017.

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 ACCEPTED MANUSCRIPT
Graphical Abstract

Isatin derivatives and their anti-bacterial activities

Hua Guo*

School of Chemistry and Life Science, Anshan Normal University, Liaoning Anshan, P R China

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The isatin moiety is ubiquitous in nature, and its derivatives possess diverse
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pharmacological properties. As “privileged building blocks”, almost all positions of
isatin moiety can be modified. The broad spectrum of biological activities combined
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with a wide range of structural modifications have inspired more researchers to study
isatins and create a large number of structurally diverse derivatives.
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In recent years, various isatin derivatives have been screened for their anti-bacterial
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activities, and some of them demonstrated promising in vitro and in vivo potency.
This review covers the recent advances of isatin derivatives as potential anti-bacterial
agents, and the structure-activity relationship is also discussed to provide an insight
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for further rational designs of more active candidates.

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 ACCEPTED MANUSCRIPT

Isatin derivatives and their anti-bacterial activities

Hua Guo*

School of Chemistry and Life Science, Anshan Normal University, Liaoning Anshan, P R China

Abstract: Bacterial infections are account for the majority of hospital-acquired and

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community-acquired infections. The emergency and widespread of drug-resistant pathogens has

further worsened the situation. In recent years, various isatin derivatives have been screened for

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their anti-bacterial activities, and some of them demonstrated promising in vitro and in vivo

potency. This review covers the recent advances of isatin derivatives including isatin-azole,

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isatin-quinoline/quinolone, isatin-furan/coumarin, isatin-hydrazone/(thio)semicarbazone, isatin

dimers and isatin-indole hybrids as potential anti-bacterial agents. The enriched structure-activity

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relationship may pave the way for further rational development of isatin derivatives with broader
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spectrum, higher potency, lower toxicity and multiple mechanisms of action.

Keywords: isatin; hybrid compounds; anti-bacterial; structure-activity relationship

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1. Introduction
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Bacterial infections, caused by Gram-positive (such as Staphylococcus aureus/S.

aureus, Staphylococcus epidermidis/S. epidermidis, Streptococcus pneumoniae/S.
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pneumoniae, Bacillus subtilis/B. subtilis, Enterococcus faecalis/E. faecalis and

Enterococcus faecium/E. faecium) and Gram-negative (such as Escherichia coli/E.
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coli and Pseudomonas aeruginosa/P. aeruginosa) pathogens, are account for the
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majority of hospital-acquired and community-acquired infections [1,2]. Moreover,

bacteria have already developed resistance to almost all currently used antibiotics due
to the long-term, broad, inappropriate use and even abuse of antibiotics, and this has
further worsened the situation [3,4]. Approximately 0.7 million deaths occurred

*
Corresponding author: m13704127672@163.com
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globally every year which is attributed to the drug-resistant pathogens, and the
number may increase to 10 million in the year of 2050 if current trends continue [5].
Thus, it’s urgent to develop new antibacterials with excellent activity against both
drug-sensitive and drug-resistant pathogens.

The exploration of medicinally privileged heterocyclic scaffolds is one of the most

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important areas in drug discovery. The isatin (1H-indole-2,3-dione, Figure 1) moiety
is ubiquitous in nature, and its derivatives possess diverse pharmacological properties

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such as anti-cancer [6,7], anti-tubercular [8,9], anti-HIV [10,11], anti-malarial [12,13]
and anti-bacterial [14,15] activities. As “privileged building blocks”, almost all

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positions of isatin moiety can be modified, and the N-1, C-3, and C-5 positions are the
major domains of the chemical variation [16]. Moreover, some isatin-based

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compounds such as semaxanib and indirubin have already used in clinics or under
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clinical trials for the treatment various diseases [17,18]. The broad spectrum of
biological activities combined with a wide range of structural modifications as well as
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successful applications in clinical practice have inspired more researchers to study

isatins and create a large number of structurally diverse derivatives.
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Figure 1 Chemical structures isatin, semaxanib and indirubin

In recent years, various isatin derivatives have been screened for their anti-bacterial
activities, and some of them demonstrated promising in vitro and in vivo potency.
This review summarized the recent advances of isatin derivatives as potential
anti-bacterial agents, and the structure-activity relationship (SAR) was also discussed
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to provide an insight for further rational designs of more active candidates.

2. Isatin hybrids

Incorporation of two or more pharmacophores into a single hybrid compound,

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represents a promising strategy in the development of new drugs with the potential to
overcome cross resistance and enhance potency compared to the parent drugs [19,20].

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Moreover, several hybrids such as Ro 23-9424 and TD-1792 are under clinical trials
for fight against various diseases. Thus, hybridization of isatin with other

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anti-bacterial pharmacophores may provide new candidates with great potency against
both drug-sensitive and drug-resistant Gram-positive and Gram-negative organisms.

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2.1 Isatin-azole hybrids
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Azoles are one of the most important classes of nitrogen containing heterocycles with
various biological activities, which may be attributed to their abilities to exert
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non-covalent interactions such as hydrogen bonding and dipole interaction that can
improve the solubility and the ability of binding to bimolecular targets [21-23]. Thus,
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it’s rationale to screen the anti-bacterial activities of isatin-azole hybrids.

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The isatin-1,2,4-triazole hybrids 1 (Figure 2) showed weak to moderate anti-bacterial

activities with minimum inhibitory concentration (MIC) values of 8-500 µg/mL
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against Gram-positive S. aureus, B. subtilis and Gram-negative E. coli and P.

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aeruginosa pathogens, and were no superior to the reference ampicillin (MIC: 0.8-1.6
µg/mL) [24]. The SAR indicated that the hybrids with -NO2 at C-5 position of isatin
moiety were more potent than the corresponding unsubstituted analogs generally, and
replacement of alkyl groups with phenyl or (substituted) benzyl groups couldn’t
improve the anti-bacterial activity apparently. Conjugate 1g (MIC: 8 and 16 µg/mL)
was found to be most active against Gram-positive S. aureus and B. subtilis, worth to
be further optimized.
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The 5-(morpholinosulfonyl)isatin 2 and its thiazole hybrids 3 and 4 exhibited

potential anti-bacterial activities against S. aureus, S. pyogenes, B. subtilis, Proteous
vulgaris/P. vulgaris, Klebsiella pneumonia/K. pneumonia and Shigella flexneri/S.
flexneri, but the majority of them were inactive against P. aeruginosa and S.
epidermidis [25]. The SAR revealed that all hybrids 3 and 4 were less active than the

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parent 2, and compounds 3 were less potent than derivatives 4. For conjugates 4,
introduction of -Me at R1 position reduced the activity slightly, while incorporation of

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-Ph could improve the activity. The most active hybrid 4h (MIC: 0.03-3.9 µg/mL)
was comparable to ampicillin (MIC: 0.007-1.95 µg/mL), but was less potent than the

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parent 2 (MIC: 0.007-0.49 µg/mL) against all tested pathogens.

Isatin-2,3-dihydrooxazole hybrids 5 and 6 (Figure 2) showed considerable activity

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with MIC and minimum bactericidal concentration (MBC) values ranging from 25 to
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100 µg/mL against Gram-positive B. subtilis, Gram-negative Enterobacter and K.
pneumonia, but all of them were less potent than the reference ciprofloxacin (MIC:
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6.25-10.25 µg/mL, MBC: 12.5-25 µg/mL) [26]. The isatin-azole hybrids 7a-e
displayed promising anti-bacterial activities with MIC values in a range of 1 to 15
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µg/mL against Gram-positive S. aureus and B. cereus, and Gram-negative E. coli and
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S. dysenterie, but were slightly lower than the references sulphamethoxazole (MIC:
2.5 µg/mL) against the majority of the tested strains [27]. The most active hybrid 7b
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with MIC of 5 µg/mL against S. aureus, B. cereus and E. coli and 1 µg/mL against S.
dysenterie, was comparable to sulphamethoxazole against S. aureus, B. cereus and E.
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coli, and 2.5-fold more potent than sulphamethoxazole against S. dysenterie.

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 ACCEPTED MANUSCRIPT
O O
NH R1
N R N R2 N
N N S S
R1 O O
R2 O N N O
S N N
O N S
N S
N O O N
H O O O O O
N O O
H N N
H H
1
2
3 4

1a: R1 = H, R2 = Me; 1b: R1 = H, R2 = Et;

1c: R1 = H, R2 = Ph; 1d: R1 = H, R2 = Bn; 4a: R1 = H, R2 = H; 4b: R1 = H, R2 = Me;
3a: R = H; 3b: R = Me; 4c: R1 = H, R2 = Et; 4d: R1 = H, R2 = Ph;
1e: R1 = H, R2 = 4-ClBn; 1f: R1 = H, R2 = 4-MeBn; 3c: R = Et; 3d: R = Ph;
1g: R1 = H, R2 = 4-OMeBn; 1h: R1 = NO2, R2 = Me; 4e: R1 = Me, R2 = H; 4f: R1 = Me, R2 = Me;
1i: R1 = NO2, R2 = Et; 1j: R1 = NO2, R2 = Ph; 4g: R1 = Me, R2 = Et; 4h: R1 = Me, R2 = Ph.
1k: R1 = NO2, R2 = Bn; 1l: R1 = NO2, R2 = 4-ClBn;
1m: R1 = NO2, R2 = 4-MeBn; 1n: R1 = NO2, R2 = 4-OMeBn.

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R R
O Ph O
N

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Ph S
O O Ph
HN N Ph N N O N O
O N H N
HN N H R2
O O O O
N O N N
H H
N R1
H

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5 6 7a 7b-d

5a: R = H; 5b: R = 2-OH; 6a: R = H; 6b: R = 2-Me; 7b: R1 = H, R2 = Me;

5c: R = 4-OH; 5d: R = 2-Cl; 6c: R = 3-Me; 6d: R = 4-Me; 7c: R1 = H, R2 = Cl;
5e: R = 4-Cl; 5f: R = 4-OMe; 6e: R = 2-Cl; 6f: R = 4-Cl; 7d: R1 = CH2OH, R2 = H.
5g: R = 4-NO2. 6g: R = 2,4-diCl.

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H H H
X N N N
MeO O
AN
N N N
H2N N3 O HN
HO N N NH
N N
N N N R S OO Ph
NH O HN
O N X R
O Ar O N H
N H 10
H
7e 8 9
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10a: X = O, R = H; 10b: X = O, R = 5-F;

9a: X = O, R = H; 9b: X = O, R = Br; 10c: X = O, R = 7-F; 10d: X = O, R = 5-Cl;
8a: Ar = 4-OMePh;
9c: X = O, R = NO2; 9d: X = O, R = F; 10e: X = O, R = 5-Br; 10f: X = O, R = 5-I;
8b: Ar = 4-FPh; 10g: X = O, R = 5-OMe; 10h: X = O, R = 5-NO2;
8c: Ar = 4-ClPh; 9e: X = O, R = I; 9f: X = O, R = Cl;
9g: X = S, R = H; 9h: X = S, R = Br; 10i: X = S, R = H; 10j: X = S, R = 5-F;
8d: Ar = 4-NO2Ph; 10k: X = S, R = 7-F; 10l: X = S, R = 5-Cl;
9i: X = S, R = NO2; 9j: X = S, R = F;
8e: Ar = furan-2-yl. 10m: X = S, R = 5-Br; 10n: X = S, R = 5-I;
9k: X = S, R = I; 9l: X = S, R = Cl.
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10o: X = S, R = 5-OMe; 10p: X = S, R = 5-NO2.

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Figure 2 Chemical structures isatin-azole hybrids 1-10

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The SAR for azide-containing isatin-pyrazoline hybrids 8 indicated that hybrids with
halogen atoms -F (8b) and -Cl (8c) at phenyl ring were more active than the
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corresponding analogs with -NO2 (8d) and -OMe (8a), and substituted phenyl groups
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were more favorable than furan-2-yl [28]. Compound 8b (MIC: 6.25-50 µg/mL) was
found to be most active against the tested S. aureus, B. subtilis, E. coli and P.
aeruginosa, but was less active than ciprofloxacin (MIC: <5 µg/mL).

The isatin-1,3,4-thiadiazole hybrids 9 (MIC: 62.5-500 µg/mL) displayed weak to

moderate anti-bacterial activities against a panel of Gram-positive and Gram-negative
pathogens, and were less active than the references gentamycin (MIC: 0.05-1 µg/mL),
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norfloxacin (MIC: 10 µg/mL), ciprofloxacin (MIC: 25-50 µg/mL) and

chloramphenicol (MIC: 50 µg/mL) [29]. The SAR revealed that the thione-conaining
(X = S) hybrids were generally more active than the ketone (X = O) analogs. Halogen
atoms -F, -Cl, -Br and -I at C-5 position of isatin motif were favorable to the activity,
while -NO2 was disfavored. Three hybrids 9f, 9j and 9l with MIC of 62.5-100 µg/mL

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were comparable to or more potent than ampicillin (MIC: 100-250 µg/mL) against all
tested seven organisms.

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For the isatin-pyrazole hybrids 10, conjugates with -F and -NO2 at isatin motif
showed no anti-bacterial activity against the tested ten pathogenic bacteria, whereas

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hybrids with -I and -OMe showed some anti-bacterial activities, and the contribution
order was as follows: -Cl ≥ -Br > -OMe > -I [30].

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2.2 Isatin-quinoline/quinolone hybrids
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Quinoline and quinolone derivatives exhibit a variety of biological activities, and

many of them which are exemplified by fluoroquinolones are one of the most
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common antibiotics in clinical practice [31-35]. Some isatin-quinoline/-quinolone

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hybrids demonstrated excellent anti-mycobacterial properties [36-40], and the SAR

indicated that the linker between the isatin and quinoline/quinolone plays an
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important role in exertion of the biological activities [41-44]. Thus,

isatin-quinoline/-quinolone hybrids represent important classes of bioactive
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heterocyclic compounds in the field of pharmaceuticals.

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The SAR of isatin-ciprofloxacin-/lomefloxacin hybrids 11 (Figure 3) showed that the

anti-bacterial activity was influenced greatly by the fluoroquinolone fragment and
ciprofloxacin hybrids were more potent than the corresponding lomefloxacin analogs
[45]. Compared with the unsubstituted hybrids, conjugates with -Me at C-5 position
of isatin moiety decreased the activity slightly. The ciprofloxacin-isatin hybrids 11a,b
(MIC: 0.10-0.50 µg/mL) were as potent as the parent ciprofloxacin (MIC: 0.10-0.25

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µg/mL), and were more potent than lomefloxacin (MIC: 0.25-2.50 µg/mL) against
Salmonella typhi, E. coli, Vibrio cholera, S. aureus, S. epidermidis, K. pneumonia, P.
aeruginosa, S. flexnari and Citrobactor ferundi.

Introduction of trimethoprim into isatin-fluoroquinolone (norfloxacin, ciprofloxacin,

gatifloxacin and lomefloxacin) hybrids could enhance the anti-bacterial activity which

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may be attributed to these hybrids may act at both the folate reductase (target for
trimethoprim) and DNA gyrase enzymes (target for fluoroquinolones). All

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isatin-fluoroquinolone hybrids 12 have broad-spectrum anti-bacterial activities against
all tested pathogens, and the SAR revealed that fluoroquinolone moieties influenced

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the in vitro anti-bacterial activities greatly [46-50]. The relative contribution order for
fluoroquinolone moieties was lomefloxacin > ciprofloxacin > gatifloxacin >

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norfloxacin against Gram-positive bacteria, and ciprofloxacin > gatifloxacin >
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norfloxacin > lomefloxacin against Gram-negative pathogens. In an E. coli NCTC
10418 infected mice model, three isatin-ciproflocacin hybrids 12b, 12e and 12h with
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ED50 of 0.62 mg/kg, were >2 folds more potent than the references norfloxacin,
ciprofloxacin and lomefloxacin (ED50: 6.0, 1.25 and 1.87 mg/kg, respectively) in vivo.
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The 5-bromoisatin-ciprofloxacin hybrid 12l with MIC of 0.00003-0.0290 µM against

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all tested twenty-four pathogens was more potent than the parent ciprofloxacin (MIC:
0.00037-0.4727 µM) against seventeen strains [50]. Moreover, compound 12l (ED50:
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0.46 mg/kg, respectively) also highly potent in vivo in the E. coli NCTC 10418
infected mice model, which was 2.7 and 4.0 folds more active than ciprofloxacin and
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lomefloxacin.
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Twenty-four norfloxacin-isatin hybrids 13 with substituents at C-3, C-4, C-5, C-6 and
C-7 position of isatin motifs were screened for their in vitro anti-bacterial activities
against twenty-eight Gram-positive and Gram-negative organisms by Pandeya et al.,
but no significant improvements were observed when compared with the parent
norfloxacin [51-53]. The SAR revealed that installation of isoniazid, semicarbazone,
thiosemicarbazone, trimethoprim, sulfadiazine and sulfadoxine at C-3 position of

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isatin moiety could improve the anti-bacterial activity when compared with the ketone
alalogs, and trimethoprim was optimal. Halogen atoms -Cl and -Br were favorable to
the activity, and -Cl > -Br > -H at C-5 position. The position of halogen atoms also
has great influence on the activity, and C-6 position was more favorable than C-4. In
an E. coli NCTC 10418 infected mice in vivo model, hybrids 13s and 13x (MIC: <1

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µg/mL against the majority of the tested strains, ED50: 1.25 and 1.62 mg/kg)
were >3.7 folds more potent than the parent norfloxacin (ED50: 6.0 mg/kg) [52]. The

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acute oral toxicity of the most active conjugate 13s (LD50: >4,000 mg/kg) was also
lower than norfloxacin (LD50: 4,000 mg/kg). The promising in vitro and in vivo

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anti-bacterial potency and excellent safety profile of hybrid 13s make it a potential
lead for further modification.

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The SAR for 5-flurorisatin-ciprofloxacin hybrids 14 demonstrated that substitutents at
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para-position of phenyl ring were more favorable than orth-position, and
electron-donating groups -OH and -OMe at phenyl ring could improve the
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anti-bacterial activity, whereas electron-withdrawing groups -Cl and -NO2 were

detrimental to the activity [54]. The majority of hybrids with MIC of 7.81-125 µg/mL
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were less active than the parent ciprofloxacin (MIC: 3.9-15.62 µg/mL) against the
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tested S. aureus, S. epidermidis, M. luteus, E. coli, P. aeruginosa, and K. pneumonia,

but the most active hybrid 14c (MIC: 7.81-15.62 µg/mL) was comparable to
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ciprofloxacin against S. aureus, S. epidermidis, M. luteus, E. coli and P. aeruginosa.

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O O

O O
F COOH
O R2
O
F COOH N O N N
NH2
O N F COOH R1 N N
O
N N N
O
N N R2 R1 N N
13
R N N R2 R1
R3
R
R3 13a: R1 = H, R2 = O; 13b: R1 = 4-Cl, R2 = O;
11 13c: R1 = 6-Cl, R2 = O; 13d: R1 = 5-NO2, R2 = O;
12 13e: R1 = 4-Cl, R2 = NNHCOpyridin-4-yl;
11a: R = H, R1 = c-Pr, R2 = H, R3 = H; 13f: R1 = 6-Cl, R2 = NNHCOpyridin-4-yl;
12a: R = Cl, R1 = c-Pr, R2 = OMe, R3 = Me;
11b: R = Me, R1 = c-Pr, R2 = H, R3 = H; 13g: R1 = 5-NO2, R2 = NNHCOpyridin-4-yl;
12b: R = Cl, R1 = c-Pr, R2 = H, R3 = H;
11c: R = H, R1 = Et, R2 = F, R3 = Me; 13h: R1 = 5-Cl, R2 = O; 13i: R1 = 5-Br, R2 = O;
12c: R = Cl, R1 = Et, R2 = F, R3 = Me; 13j: R1 = H, R2 = NNHCONH2; 13k: R1 = 5-Cl, R2 = NNHCONH2;
11d: R = Me, R1 = Et, R2 = F, R3 = Me. 12d: R = F, R1 = Et, R2 = H, R3 = H; 13l: R1 = 5-Br, R2 = NNHCONH2; 13m: R1 = H, R2 = NNHCSNH2;
12e: R = F, R1 = c-Pr, R2 = H, R3 = H; 13n: R1 = 5-Cl, R2 = NNHCSNH2; 13o: R1 = 5-Br, R2 = NNHCSNH2;

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12f: R = F, R1 = Et, R2 = F, R3 = Me; 13p: R1 = H, R2 = sulfadiazine; 13q: R1 = 5-Cl, R2 = sulfadoxine;
12g: R = F, R1 = c-Pr, R2 = OMe, R3 = Me;
13r: R1 = 5-Br, R2 = trimethoprim; 13s: R1 = H, R2 = sulfadiazine;
12h: R = Me, R1 = c-Pr, R2 = H, R3 = H;
13t: R1 = 5-Cl, R2 = sulfadoxine; 13u: R1 = 5-Br, R2 = trimethoprim;
12i: R = Me, R1 = Et, R2 = F, R3 = Me; 13v: R1 = H, R2 = sulfadiazine; 13w: R1 = 5-Cl, R2 = sulfadoxine;
12j: R = Me, R1 = c-Pr, R2 = OMe, R3 = Me;
13x: R1 = 5-Br, R2 = trimethoprim.
12k: R = Br, R1 = c-Pr, R2 = OMe, R3 = Me;
12l: R = Br, R1 = c-Pr, R2 = H, R3 = H;
12m: R = Br, R1 = Et, R2 = F, R3 = Me;

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12k: R = F, R1 = c-Pr, R2 = H, R3 = Me.

O O O
O R1
F COOH F
N F COOH O N

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N R2
O R2 O
O N N O
R N N N N R2
N N N N R
N N R
F R1
R1

14 16
15

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14a: R = H; 14b: R = 4-Cl; 14b: R = 4-OH; a: R = H, R1 = H, R2 = O; b: R = H, R1 = Me, R2 = O; c: R = H, R1 = H, R2 = NOMe;
14b: R = 4-OMe; 14e: R = 2-OH; 14f: R = 4-NO2; d: R = H, R1 = Me, R2 = NOMe; e: R = H, R1 = H, R2 = NOEt; f: R = H, R1 = Me, R2 = NOEt;
14g: R = 4-Me; 14h: R = 3-NO2; 14i: R = 3,4,5-triOMe; g: R = OMe, R1 = H, R2 = O; h: R = OMe, R1 = Me, R2 = O; i: R = OMe, R1 = H, R2 = NOMe;
14j: R = 3-OMe-4-OH; 14k: R = 4-NMe2. j: R = OMe, R1 = Me, R2 = NOMe; k: R = OMe, R1 = H, R2 = NOEt; l: R =OMe, R1 = Me, R2 = NOEt.
AN
O O O
R1
F COOH F
O N
R2 R2
M

O O
N N N N O
R2
N N OMe N N OMe
R1 R1

17 18
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a: R1 = H, R2 = O; b: R1 = F, R2 = O; c: R1 = Br, R2 = O;
d: R1 = H, R2 = NOEt; e: R1 = F, R2 = NOEt; f: R1 = Br, R2 = NOEt.
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Figure 3. Chemical structures of isatin-fluoroquinolone hybrids 11-18

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Since the linker between isatin and fluoroquinolone motif plays a pivotal role in the
exertion of the biological activities, so it’s rationale to optimize the linker [54]. The
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propylene-tethered isatin-ciprofloxacin/-8-OMe ciprofloxacin hybrids 15 and

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isatin-gatifloxacin hybrids 17 as well as their bis-isatin analogs 16 and 18 (Figure 3)

were screened for their in vitro anti-bacterial activities against a panel of clinically
important pathogens including drug-resistant bacteria, and the SAR indicated that all
isatin-ciprofloxacin/-8-OMe ciprofloxacin/-gatifloxacin hybrids were far more potent
than the corresponding bis-isatin analogs, suggesting carboxylic acid at C-3 position
of fluoroquinolones is crucial for the high activity [56-58]. As previous,

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fluoroquinolone moieties have significant influence on the in vitro anti-bacterial

activities, and the relative contribution order for fluoroquinolone moieties was
ciprofloxacin > gatifloxacin > 8-OMe ciprofloxacin. Introduction of alkyloxyimine at
C-3 position and -Me at C-5 position of isatin moiety could improve the activity. All
isatin-ciprofloxacin/-8-OMe ciprofloxacin hybrids 15 and isatin-gatifloxacin hybrids

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17 were highly active against Gram-positive E. faecalis, methicillin-sensitive S.
epidermidis (MSSE), methicillin-sensitive S. aureus (MSSA), methicillin-resistant S.

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aureus (MRSA) and Gram-negative E. coli, K. pneumonia, P. aeruginosa,
Acinetobacter calcoacetious, E. cloacae, E. aerogenes, Serratia marcescens,

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Morganella morganii, Providentia rettgeri, Proteus vulgaris, Proteus mirabilis,
Stenotrophomonas maltophilia, Citrobacter freundii with MIC values ≤1 µg/mL, and

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also showed moderate activities against Gram-positive methicillin-resistant
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Staphylococcus epidermidis (MRSE) and E. faecium with MIC values of 2-64 µg/mL.
In particular, isatin-ciprofloxacin hybrid 15d (MIC: ≤0.03-8 µg/mL) was highly
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potent against all tested Gram-positive and Gram-negative strains, and it was
comparable to or more potent than the parent ciprofloxacin and reference levofloxacin
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(MIC: ≤0.03-128 µg/mL). The metabolic stability and in vivo pharmacokinetic (PK)
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properties of hybrid 15d were evaluated in mice after oral administration 50 mg/kg,
and the results showed that hybrid 15d reached a maximum concentration (Tmax) in
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plasma at 1.2 h, its elimination half-life (t1/2) was 3.3 h, the peak serum concentration
(Cmax) was 832 ng/mL and the area under curve (AUC) was 2,865 ng•h/mL. However,
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the metabolic stability and in vivo PK profiles of hybrid 15d were inferior to the
parent ciprofloxacin (Tmax: 1.8 h, t1/2: 5.2 h, Cmax: 3,129 ng/mL and AUC: 17,835
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ng•h/mL), so it still needs to be modified.

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 ACCEPTED MANUSCRIPT

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Figure 4. Chemical structures of isatin-quinoline hybrids 19-21

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The isatin-quinoline hybrids 19-21 (Figure 4) showed moderate anti-bacterial
activities with inhibition zone 6-19 mm at 100 µg/mL against E. coli, P. aeruginosa, S.

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aureus and B. Cereus, and were less active than the references cefaclor, amoxycillin
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and gentamycin (inhibition zone: 19-27 mm at 100 µg/mL) [59-61].
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2.3 Isatin-hydrazone/(thio)semicarbazone hybrids

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Hydrazone, semicarbazone and thiosemicarbazone possess a wide spectrum of

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medicinal properties, and represent important pharmacophores in the development of

new drugs [62,63]. Isatin-derived hydrazone, semicarbazone and thiosemicarbazone
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hybrids also exhibited a variety of physiological properties including anti-bacterial

activity, and the anti-viral drug methisazone belongs to isatin-thiosemicarbazone
hybrid, so isatin-hydrazone/-(thio)semicarbazone hybrids have caused great interests
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in recent years [64-66].

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Vancomycin-resistant Enterococcus (VRE) and MRSA have caused an increasing

mortality rate, to fight against VRE and MRSA, a series of isatin-β-thiosemicarbazone
hybrids 22 (Figure 5) were tested for their activities against a panel of pathogens
including S. aureus, B. subtilis, E. faecalis, P. aeruginosa, K. pneumonia, VRE and
various MRSA isolates [67]. All hybrids (MIC: >100 µg/mL) were inactive against

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Gram-negative P. aeruginosa and K. pneumonia, but the majority of them (MIC:

0.39-6.25 µg/mL) demonstrated excellent activity against all tested Gram-positive
bacteria including VRE and MRSA. Substituents at both isatin moiety (R1) and
phenyl ring (R2) influenced the anti-bacterial activity significantly, and a halogen
substitution at C-7 of isatin was essential for hybirds possessed good anti-MRSA

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activity, while hybrids 23 without substituents at isatin motif or -OMe at orth-position
of phenyl ring or replacement of phenyl ring with cyclohexyl (24) or alkyl (25) such

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as -Et, -allyl and -Bu led to great loss of activity [67-70]. Hybrid 22u (MIC: 0.39-1.56
µg/mL) was found to be most active against the tested Gram-positive E. faecalis, VRE

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and MRSA isolates, and was more potent than Vancomycin (MIC: 1->8 µg/mL)
against E. faecalis, VRE and most of MRSA isolates [67]. Obviously, hybrid 22u can

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be considered as potential lead compound to discover anti-bacterial inhibitors to
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combat drug resistance.
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S H
S H N
N S H
N
H2N N NH
S N NH
R2 N NH R
R O
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N NH R1 O
O N
N
O H N N
H X
N
22
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23 24
methisazone 22a: R1 = 7-F, R2 = H; 22b: R1 = 7-Cl, R2 = H; 23a: R = H; 23b: R = 2-Me; 24a: X = O, R = Cl;
22c: R1 = 5-Cl, R2 = 4-F; 22d: R1 = 5-Br, R2 = H; 23c: R = 3-Me; 23d: R = 4-Me; 24b: X = O, R = Br;
22e: R1 = 5-NO2-7-Br, R2 = 4-F; 22f: R1 = 5-F, R2 = 4-F; 23e: R = 2-OMe; 23f: R = 3-OMe; 24c: X = O, R = NO2;
S 22g: R1 = H, R2 = H; 22h: R1 = H, R2 = 4-F; 23g: R = 4-OMe; 23h: R = 2-Br; 24d: X = O, R = OMe;
NHR 22i: R1 = 5-Br-7-Br, R2 = 4-F; 22j: R1 = 5-NO2, R2 = 4-F; 23i: R = 3-Br; 23j: R = 4-Br; 24e: X = CH2, R = Cl;
22k: R1 = 7-Cl, R2 = 4-Cl; 22l: R1 = 7-Cl, R2 = 4-Me; 23k: R = 2-Cl; 23l: R = 3-Cl; 24f: X = CH2, R = Br;
N NH 22m: R1 = 7-Cl, R2 = 2-Me; 22n: R1 = 7-Br, R2 = 4-F; 23m: R = 4-Cl; 23n: R = 3-NO2; 24g: X = CH2, R = NO2.
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22o: R1 = 7-Br, R2 = 4-Cl; 22p: R1 = 7-Me, R2 = 4-F; 23o: R = 4-NO2.

O 22q: R1 = 7-Me, R2 = 4-Cl; 22r: R1 = 7-F, R2 = 3-Me;
N 22s: R1 = 7-Cl, R2 = 3-Cl; 22t: R1 = 7-F, R2 = 3-F;
OAc 22u: R1 = 7-F, R2 = 3-Cl; 22v: R1 = 7-Cl, R2 = 3-F;
O 22w: R1 = 7-Br, R2 = 2-OMe; 22x: R1 = 7-Br, R2 = 3-F;
OAc 22y: R1 = 7-Br, R2 = 3-Cl; 22z: R1 = 7-Br, R2 = 4-Br;
22z1: R1 = 7-F, R2 = 2-OMe; 22z2: R1 = 7-I, R2 = 2-OMe.
OAc
C

25

25a: R = Et;
O
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25b: R = Bu; O R N
25c: R = Allyl. O
N NH N NH
R
O R2
OH N NH R O N N
O O
N R2 N
N NH N
R3 O O
O N N N
R2 O H H
N
N 30
R1 27 29 31
R1 28
R1
26 31a: R = H;
27a: R1= H, R2 = H; 28a: R = H; 28b: R = 2-F; 29a: R1 = H, R2 = Cl; 31b: R = Me;
27b: R1= Me, R2 = H; 28c: R = 3-Cl; 28d: R = 3-Br; 29b: R1 = H, R2 = Me; 31c: R = Ph.
R1 = H, CH2NPh2; R2 = 27c: R1= H, R2 = 5-Cl; 28e: R = 3-Me; 28f: R = 2-Br; 29c: R1 = H, R2 = H;
NHCSNH2, 4-ClPh, 4-MePh, 27d: R1= H, R2 = 5-Br; 28g: R = 3-F. 29d: R1 = Cl, R2 = Cl;
4-OMePh, NHPh, 4-BrPh, 27e: R1= H, R2 = 6-Cl; 29e: R1 = Cl, R2 = Me;
NH(2,4-diNO2)Ph; R3 = H, 27f: R1= H, R2 = 5-Fl; 29f: R1 = Cl, R2 = H;
Cl, Br, Me, NO2. 27g: R1= Me, R2 = 5-Cl. 29g: R1 = Me, R2 = Cl;
29h: R1 = Me, R2 = Me;
29i: R1 = Me, R2 = H.

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Figure 5. Chemical structures of isatin-thiosemicarbazone drug methisazone and

isatin-hydrazone/(thio)semicarbazone hybrids 22-31

Thirteen-five Schiff bases of isatins 26 (Figure 5) including isatin-thiosemicarbazone

hybrids were examined for their in vitro anti-bacterial activities by Sridhar et al. [71].

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All derivatives showed weak to moderate anti-bacterial activities with MIC values in
a range of 32 to 402 µg/mL, and were far less active than the reference norfloxacin

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(MIC: <2-20 µg/mL).

The isatin-carbohydrazides 27 showed moderate activity against the tested seven

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organisms with MIC of 12.5-100 µg/mL, and were less potent than azithromycin
(MIC: 6.25-12.5 µg/mL) against all tested bacteria [72]. The majority of hybrids 28

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also displayed moderate anti-bacterial activity against S. aureus, E. coli and P.
aeruginosa with IC50 values ranging from 0.03 to 0.830 mM, and compounds 28c and
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28d (IC50: 0.03 and 0.05 mM) exhibited higher anti-bacterial activity than penicillin
(IC50: 0.631 mM) [73]. Introduction of substituted benzyl groups (29) [74] or
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piperidin-1-ylmethyl (30) [75] at N-1 position of isatin motif couldn’t improve the
anti-bacterial activity apparently, and the similar results were also observed for
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isatin-hydrazone hybrids 31 [76].

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2.4 Isatin-furan/coumarin hybrids

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Furan and coumarin, the oxygen-conatining heterocycles, exhibited various biological

properties including anti-bacterial activity [77,78]. Some furan and coumarin based
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compounds such as furazolidone, nitrofurantoin, and coumermycin (Figure 6) have

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already used as anti-bacterial agents in clinical practice, so the combination of these

pharmacophores in the same molecule is meaningful for the development of new
anti-bacterial candidates.

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Figure 6. Chemical structures of furazolidone, nitrofurantoin, and coumermycin

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The isatin-furan hybrids 32 (Figure 7) showed moderate in vitro anti-bacterial
activity with inhibition zone ranging from 8.5 to 14 mm at the concentration of 20

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mg/mL against E. coli, P. aeruginosa, S. aureus and B. Subtilis, and were less potent
than gentamicin and chlorampheniol (inhibition zone: 15.6-26 mm at the

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concentration of 20 mg/mL) [79]. The SAR indicated that furan fragment at C-3
position of isatin (32c-e) was more favorable than at N-1 position (32a), while
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introduction of the second furan fragment was detrimental to the activity (32b).
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t-BuHN
O
t-Bu t-BuHN
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N O
MeO2C t-Bu
MeO2C O N
R3O2C
N S R3O2C O
O
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O S
S N
O
O S
N O
O R2
N
O O
O NHt-Bu
N O N
NHt-Bu
t-Bu N
R1
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COOt-Bu t-Bu
t-BuO2C
t-BuO2C COOt-Bu
32c: R1 = CO2Et, R2 = H, R3 = Et;
32a 32d: R1 = CO2Et, R2 = Cl, R3 = Me;
32b 32e: R1 = Oh, R2 = H, R3 = Et.
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O
R2
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N O O O
R2 N N N
O n
COOEt
N O
R1
R1 n R3 34
O
34a: n = 1, R1 = Br, R2= NOH;
n = 1, 2, 3, 4. 34b: n = 1,R1 = Br, R2 = NOMe;
33 34c: n = 1,R1 = Me,R2 = NOH;
34d: n = 1, R1= OMe, R2= NOH;
R1 = H, F, OMe; R2 = O, NOH, NOMe, 34e: n = 1, R1 = OMe, R2 = NOMe;
NOEt, NNHCSNH2; R3 = H, F, OMe. 34f : n = 2, R1= Me, R2= NOH;
34g: n = 2, R1= Me, R2= NOMe;
33a: n = 2, R1 = H, R2 = NOMe, R3 = OMe. 34h: n = 2, R1= OMe, R2 = NOH;
34i: n = 2, R1= OMe,R2 = NOMe;
34j: n = 1, R1= OMe, R2 = NOEt.

Figure 7. Chemical structures of isatin-furans 32,33 and isatin-coumarins 34

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The isatin-benzofuran hybrids 33 tethered through different length alkyl linkers

displayed promising anti-bacterial activities against a panel of Gram-positive and
Gram-negative pathogens including drug-resistant MRSA and MRSE with MIC
values in a range of 0.06-64 µg/mL [80-82]. The SAR revealed that this kind of
hybrids were more potent against Gram-negative bacteria than against Gram-positive

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strains. Alkyloxyimine at C-3 position of isatin motif could boost up the anti-bacterial
activity against both Gram-positive and Gram-negative organisms, while

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hydroxylamine and thiosemicarbazide were detrimental to the activity when
compared with the ketone analogs. In particular, the most active hybrid 33a with MIC

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values of ≤1 µg/mL against the majority of the tested Gram-negative and
Gram-positive pathogens, was comparable to cancomycin (MIC: 0.5-4 µg/mL) and

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ciprofloxacin (MIC: 0.125-8 µg/mL) against Gram-positive bacteria, and slightly less
potent than ciprofloxacin (MIC: ≤0.03-0.5 µg/mL) against Gram-negative pathogens.
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The 1,2,3-triazole tethered isatin-coumarin hybrids 34 (Figure 7) only exhibited weak
to moderate in vitro anti-bacterial activities against both Gram-positive and
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Gram-negative strains with MIC values ranging from 16 to >200 µg/mL, and were far
less active than the reference ciprofloxacin (MIC: 0.015-0.5 µg/mL) against the
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majority strains [83].

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2.5 Isatin dimers and isatin-indole hybrids

The dimer compounds usually exhibit some unique properties such as enhanced
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biological activities, so dimers are potential candidates for the development of new
drugs [1]. The isatin dimers 35 (Figure 8) showed promising anti-bacterial activities
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with inhibition zone of 12-20 mm at the concentration of 100 µg/mL against

Gram-positive S. aureus, B. subtilis, S. epidermis and Gram-negative E. coli, P.
aeruginosa, S. typhi and K. pneumonia, and were comparable to ciprofloxacin
(inhibition zone: 16-20 mm at 100 µg/mL) [84]. The SAR showed that -F at C-5
position (R1 and R2 positions) of isatin moiety was favorable to the activity, while
-Me was harmful to the activity, and the contribution order was -F > -H > -Me. The
most active dimer 35e (inhibition zone: 16-20 mm at 100 µg/mL) was no inferior to
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 ACCEPTED MANUSCRIPT
ciprofloxacin against all tested strains, worth to be further investigated.

The majority of hydrazone tethered isatin dimers only exhibited weak anti-bacterial
activity [85,86], but the carbohydrazone tethered isatin dimers 36 (MIC: 6.25-100
µg/mL) showed considerable activity against E. coli, P. aeruginosa, S. aureus and B.
Subtilis [87]. The SAR suggested that for isatin dimers 36, introduction of -Bn at N-1
position of isatin core could increase the anti-bacterial activity. Halogen atoms -F, -Cl

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and -Br at C-5 position of isatin preferred, while -Me, -NO2 and -COOH have little
influence on the activity.

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Ph O O
N NH R2
N N
O R2 N NH N
Ph
R1 O N
N O N OAc N
N N N
R1 R1 Cr3+

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S N N
O R2 H N N H
N
N 36
(AcO-)2
O O Ph
35 36a: R1 = H, R2 = H;
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36b: R1 = F, R2 = H;
36c: R1 = Cl, R2 = H; 37
35a: R1 = H, R2 = H; 35b: R1 = H, R2 = F; 36d: R1 = Br, R2 = H;
35c: R1 = H, R2 = Me; 35d: R1 = F, R2 = H; 36e: R1 = Me, R2 = H;
35e: R1 = F, R2 = F; 35f: R1 = F, R2 = Me; 36f: R1 = NO2, R2 = H;
35g: R1 = Me, R2 = H; 35h: R1 = Me, R2 = F; 36g: R1 = COOH, R2 = H;
35i: R1 = Me, R2 = Me. 36h: R1 = H, R2 = Bn;
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36i: R1 = Cl, R2 = Bn;

36j: R1 = Me, R2 = Bn.

Figure 8. Chemical structures of isatin dimers 35-37

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Compared with free form, metal-chelated derivatives may have profound effects on
biological activities, and some metal chelating agents which are exemplified by
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ferroquine are potential drugs or have already used in clinical practice [88,89]. Thus,
metal chelating complexes have caused great attention in recent years.
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Comparing to mono-isatin metal complexes which usually displayed weak

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anti-bacterial activity [90-101], bis-isatin metal complexes often showed higher

activity [102-110]. The cyclic bis-isatin-Cr3+ complex 37 (Figure 8) displayed great
potency with MIC values of 4-8 µg/mL against S. aureus, B. pumilus, B. megaterium,
P. aeruginosa and S. epidermidis, and was comparable to linezolid (MIC: 4-8 µg/mL)
and cefaclor (MIC: 2-8 µg/mL) [111]. Further investigations indicated that
replacement of Cr3+ by Co2+, Cu2+, Ni2+ and Zn2+ couldn’t improve the anti-bacterial
activity [112,113].

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Figure 9. Chemical structures of isatin-indole hybrids 38 and 39

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Thirteen isatin-bisindole hybrids 38 (Figure 9) were screened for their in vitro

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anti-bacterial activities against E. coli and S. aureus by Praveen et al., and all hybrids
exhibited potential activity with inhibition zone of 10-17 mm at 20 µg/mL [114]. The
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most active three hybrids 38a-c (inhibition zone: 15-17 mm at 20 µg/mL) were
comparable to the reference amikacin (inhibition zone: 17-18 mm at 20 µg/mL)
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against the tested two strains, so they could act as leads for further optimization.
However, the isatin-indole hybrids 39 only showed weak to moderate anti-bacterial
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activities, still need to be modified [115].

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3. Miscellaneous isatin derivatives

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The isatin-imine derivatives possessed considerable in vitro anti-bacterial activity, and

some of them were in micromolar level [116-124]. The isatin-imines 40 (Figure 10)
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were highly active against S. aureus, B. Subtilis, K. Pneumonia, E. coli, P. aeruginosa,

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and S. typhi with MIC ranging from 0.003 to 0.324 µM [123]. The SAR indicated that
introduction of 2,5-dimethyl at R2 position was favorable to the activity. For R1
position, -Me preferred, while -OMe was disfavored. Compounds 40l and 40n (MIC:
0.003-0.015 µM) were found to be most active against the tested strains, and were
comparable to ciprofloxacin (MIC: 0.002 µM).

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Figure 10. Chemical structures of isatin derivatives 40-42

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AN
Thirteen isatin-imines 41 also demonstrated excellent anti-bacterial activity against B.
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subtilis, S. aureus, S. epidermis, P. aeruginosa, E. coli and P. vulgaris, and MIC

values were in a range of 10-30 µg/mL [124]. Compounds 41i-m bearing alkyl or aryl
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substituents at N-1 position isatin moiety were less active than derivatives 41a-h
bearing -H or sulfonyl group at the same position. Derivatives 41a-h were as potent as
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ciprofloxacin (MIC: 10 µg/mL) against the majority of the tested strains, worth to be
further studied.
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Besides the above mentioned isatin derivatives, various other isatin derivatives also
displayed some anti-bacterial activities against both Gram-positive and
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Gram-negative pathogens [125-132]. All isatin-azetidines 42 showed promising

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anti-bacterial activity with MIC of 6.25-25 µg/mL against S. aureus, P. aeruginosa

and E. coli, and SAR demonstrated that 5,7-dibromo at isatin moiety was essential for
the high activity as evidenced by compounds 42a-e (MIC: 6.25-12.5 µg/mL) were
more potent than the corresponding unsubstituted 42f-j (MIC: 12.5-25 µg/mL) [125].
Among them, three compounds 42b-d (MIC: 6.25 µg/mL) were comparable to
amoxicillin, gentamycine and streptomycin (MIC: 6.25 µg/mL) against all tested

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pathogens.

4. Conclusion

The antibiotics have contributed enormously to treat bacterial infections, but bacterial
resistance appeared gradually due to the long-term, broad, inappropriate use and even

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abuse of antibiotics. Therefore, new anti-bacterial agents are needed urgently. Isatin
derivatives possess a variety of pharmacological properties including anti-bacterial

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activity, and some of isatin-based compounds have already used for clinical

SC
deployment in the control and eradication of various diseases. Thus, isatin derivatives
are reasonable choice for the development of new anti-bacterial agents.

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This review summarized the recent advances of isatin derivatives including
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isatin-azole, isatin-quinoline/quinolone, isatin-furan/coumarin,
isatin-hydrazone/(thio)semicarbazone, isatin dimers and isatin-indole hybrids as
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potential anti-bacterial agents. The enriched SAR may pave the way for further
rational development of isatin derivatives with broader spectrum, higher potency,
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lower toxicity and multiple mechanisms of action.

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Acknowledgement
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This study was supported by grant from the Natural Science Fund of Liaoning
Province (grant No. 2015020680).
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1. Isatin derivatives possess diverse pharmacological properties

2. As “privileged building blocks”, almost all positions of isatin moiety can be

modified.

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3. Various isatin derivatives have been screened for their anti-bacterial activities, and

some of them demonstrated promising in vitro and in vivo potency

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4. The structure-activity relationship was enriched.

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