A RECENT SURVEY ON CHEMICAL AND BIOLOGICAL SIGNIFICANCE OF ISATIN DERIVATIVES

A RECENT SURVEY ON CHEMICAL AND BIOLOGICAL SIGNIFICANCE OF ISATIN DERIVATIVES

Sowmiya * and K. Girija

Department of Pharmaceutical Chemistry, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Govt. of Puducherry Institution), Puducherry, India.

ABSTRACT: Isatin, a heterocyclic moiety, is a significant scaffold in medicinal chemistry. Isatin contains a nitrogen atom at position 1 and two ketone groups at positions 2 and 3. It consists of two cyclic rings, one of which is a six-membered ring, and the other is a five-membered ring. It is a resourceful nucleus for the synthesis of several pharmacologically active molecules. Isatin itself acquires an extensive range of biological activities. Currently, the design of unique isatin derivatives as potent drugs is the key role of the researchers. The focus of this present study is to overview the recent literature published on isatin derivatives. In this review, some of the pharmacological activities of isatin derivatives such as anticancer, antibacterial, antiviral, antifungal, antioxidant, antitubercular, anti-malarial, antidiabetic, anticonvulsant, analgesic, and anti-inflammatory activities were reported. From these studies, isatin has been established as the more promising candidate for further research and investigations in many fields.

Keywords: Isatin derivatives, Anticancer, Antibacterial, Antitubercular, Anti-inflammatory

INTRODUCTION: To design and develop safe and effective drugs is very much essential in order to overcome the various diseases emerging day by day. Synthesis of novel medicinal compounds with diverse biological activities is the prerequisite for medicinal chemists. Isatin, a heterocyclic moiety, is regarded AS a significant scaffold in medicinal chemistry to achieve a wide range of pharmacological activities. Isatin contains a nitrogen atom at position one and two ketone groups at positions 2 and 3 Fig. 1. It consists of two cyclic rings, one of which is a six-membered ring, and the other is a five-membered ring.

FIG. 1: STRUCTURE OF ISATIN

Isatin (1H-indole-2,3-dione) was obtained by Erdman and Laurent in 1841 as an oxidation product of indigo by nitric acids and chromic acids ¹. It also occurs naturally in plants. It is also found in humans as a metabolic derivative of the hormone adrenaline. An extensive literature survey pinpointed that is a tin derivative is a promising precursor for the development of novel drugs. Isatin derivatives have acquired a prominent interest in recent years because of their medicinal properties like anticancer, antibacterial, antiviral, antifungal, antioxidant, antitubercular, antimalarial, antidiabetic, anticonvulsant, analgesic, and anti-inflammatory. In this present study, some of the biological activities of isatin derivatives published in past two decades were discussed.

1. Anticancer Activity: A set of novel Schiff bases of Isatin derivatives (1) were synthesized by reaction of Isatin with various aromatic or heterocyclic primary amines. The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR spectroscopy and elemental analysis. Cytotoxic activities for some of the synthesized compounds were evaluated by MTT assay in three human cancer cell lines (HeLa, LS180 and Raji). Among the tested compounds, 3-(2-(4-nitrophenyl) hydrazono) indolin-2-one (1b) was found to be the most potent molecule (IC₃₀ =12.2 ± 3.1 µM in HeLa cells). Docking studies of 3-substituted indolin-2-one scaffolds on vascular endothelial growth factor receptor 2 (VEGFR-2) involved in cell proliferation and angiogenesis was performed (PDB Code: 2OH4). 3-(naphthalen-1-ylimino) indolin-2-one (1j) and 3-(2-(4-nitrophenyl) hydra-zono)indolin-2-one (1b) exhibited higher docking binding energies such as -9.20 and -7.89 kcal/mol among other synthesised compounds. The compound 1b interacts with amino acids Glu915, Asn921 and Arg1049 to obtain key hydrogen bonds with the receptor ².

A novel series of 3-(2-oxo-2-phenylethylidene) indolin-2-ones (2) incorporating pharmacophoric elements of isatins and chalcones were designed and synthesised by one pot sequential addition of isatin and substituted acetophenones in the presence of dimethylamine, glacial acetic acid, and concentrated HCl. The compounds were evaluated for anticancer activity against three breast cancer cell lines MDA-MB468 (EGFR positive breast adenocarcinoma cell line), MDA-MB321 (estrogen receptor-negative, basal-like breast cancer), and MCF7 (invasive ductal breast carcinoma). Compound 2m containing 5-chloro substituents in the benzo ring of the isatin moiety and 3,4-dimethoxy substituents in the phenyl ring was reported as the most active in the series with GI₅₀ values of 8.54, 4.76, and 3.59 against MDA-MB231, MDA-MB468 and MCF7 cells, respectively ³.

R: 1a = 2-phenylhydrazone, 1b = 2-(4-nitrophenylhydrazone), 1c = phenyl, 1d = p-tolyl, 1e = o-tolyl, 1f = 4-chlorophenyl, 1g = 4 hydroxyphenyl, 1h = 4-nitrophenyl, 1i = 4-chloro-2-methylphenyl, 1j = naphthyl, 1k = 6-chloro-2-methyl-pyrimidine, 1l = dihydrothiazole, 1m = 5-chloropyridine, 1n = benzimidazole, 1o = benzothiazole, 1p = 4-chlorothiazole, 1q = 4-methylisoxazole, 1r = 5-methylisoxazole.

In a recent study, a series of isatin-dehydro-epiandrosterone hybrids (3) were synthesized via the condensation of dehydroepianderosterone and isatin through the =N-N= bridge and which were evaluated for their potential anticancer activities against HepG2 (Human hepatocellular liver carcinoma), Huh-7 (human hepatoma), A875 (human melanoma) and BEL-7402 (5-fluorouracil resistant human hepatocellular carcinoma) cell lines by MTT assay.

R¹: 2a = H, 2b = H, 2c = H, 2d = H, 2e = H, 2f = H3-NO₂2m = Cl, 2g = H; R²: H, 2h = H, 2-OCH₃, 4-F2i = H, 3,4-OCH₃, 4-Cl, 2j = H, 4-CH_3, 4-Br, 2k = Cl, H_, 4-NO₂2l = Cl, 4-F_, 3,4-OCH_3, 4-OCH₃2n = Br, H

Results showed that all the target compounds displayed good antitumor activities when compared to 5-flurouracil (positive control). Especially compound 3d exhibited significant inhibition activities (IC₅₀= 5.97 ± 2.67 µM) against BEL-7402/5-FU cell lines that resistant to 5-FU, which might be developed as a novel lead scaffold for anticancer agents ⁴.

In another study, the development of novel carbonic anhydrase inhibitors based on the isatin moiety, reported the synthesis and biological evaluation of novel sulfonamides (4a-h, 5a-g and 6a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro inhibitory activity against the following human carbonic anhydrase (hCA) isoforms- hCA I, II, IX, and XII. Human CA isozymes IX and XII are two tumor-associated proteins being overexpressed in many tumors and involved in serious processes related to cancer progression and response to therapy. These two CA isozymes had been the recent target for anticancer drugs. The results revealed that compound 5b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2 nM, respectively). Molecular docking studies were carried out for compound 5b within the hCA II, IX, and XII active sites, allowed to rationalize the obtained inhibition results ⁵

Synthesis of N-phenethyl (7a-e) and N-(1-and 2-naphthylmethyl) derivatives (8a-b) of 5,7-dibromoisatin by N-alkylation reactions were reported ⁶. Their activity against human monocyte-like histiocytic lymphoma (U937), leukemia (Jurkat) and breast carcinoma (MDA-MB-231) cell lines were assessed. The results allowed further development of structure-activity relationships. The compound 5,7-dibromo-N-(1-naphthylmethyl)-1H-indole-2,3-dione (8a) was the most potent against U937 cells with an IC₅₀ value of 0.19 µM.

In a recent study, a series of eighteen symmetrical bis-Schiff base derivatives of isatin (9) were synthesized by condensation of the isatins with hydrazine and were evaluated for their in vitro and in-vivo antitumor activities. More than half of the obtained compounds showed potent cytotoxicity according to the MTT assay on five different human cancer cell lines such as HeLa, SGC-7901, HepG2, U251, and A549. The results showed that 3,3´-(hydrazine-1,2diylidene)bis (5-methylindolin-2-one) (9b) was the most potent compound on HepG2 (IC₅₀ = 4.23 µM). 3b was also found to be able to inhibit the tumor growth substantially on the HepS-bearing mice at a dose of 40 mg/kg. The real-time live-cell imaging and tracking in the H2B labelled HeLa cells revealed that 3b could induce mitosis interference and apoptosis-associated cell death ⁷.

Design and synthesis of a novel series of compounds with isatin-based caps and o-phenylenediamine-based zinc-binding groups (10) as Histone deacetylases (HDAC) inhibitors were reported recently⁸. HDACs as novel targets for the discovery of anticancer agents is a series of enzymes that regulate histone deacetylation, which may be the best-understood type of epigenetic modifications. All synthesized target compounds were evaluated for their HDAC inhibition using HeLa nuclear extract. Among these compounds, the most potent compound 10n exhibited better HDAC inhibition and antiproliferative activities against multiple tumor cell lines with IC₅₀ values of 0.032, 0.256, and 0.311 μM for HDAC 1, 2, and 3 respectively when compared with the positive control entinostat (MS-275). Compounds 10h and 10n were docked into the active site of HDAC1 (PDB code 5ICN), and hence the binding modes of these compounds in HDACs were explored.

2. Antitubercular Activity: A series of novel balofloxacin ethylene isatin derivatives (11) with remarkable improvement in lipophilicity as compared to the parent compound balofloxacin were designed and synthesized. All of the synthesized compounds were less active than balofloxacin against M. phlei CMCC 93201 and M. smegmatis CMCC 93202, but compounds 11g-j (MIC: <0.5e8 mg/mL) were more potent than balofloxacin (MIC:16 mg/mL) against MTB09710. In particular, compound 11h (MIC =< 0.5 mg/mL) was found to be comparable to moxifloxacin and ≥32 fold more potent than balofloxacin against MTB09710 and MTBH37Rv ATCC27294 ⁹.

In another study, the synthesis of a novel series of lamivudine prodrugs involving Schiff and Mannich reaction with isatin derivatives (12) was reported¹⁰. The synthesized compounds were screened against Mycobacterium tuberculosis strain H37Rv, and all the Mannich bases (12a–h) were found to be most active with 92–100% inhibition. In particular, the compound 12c showed 100% inhibition against Mycobacterium tuberculosis and concluded as a beneficial candidate for the treatment of tuberculosis.

A class of novel amide tethered ciprofloxacin-1,2,3-triazole-isatin hybrids (13) were designed, synthesised and the in-vitro anti-mycobacterial activity against both drug-susceptible MTB H37Rv and MDR-MTB strains. The result revealed that the most active hybrid 13a (MIC MTB H37Rv = 0.5 μg/mL and MIC MDR-MTB = 0.12μg/mL) had the activity in the same level with the first-line anti-tubercular agents isoniazid (MIC = 0.12 μg/mL) and rifampicin (MIC = 0.25 μg/mL) and it was 2-fold more active than the parent ciprofloxacin (MIC = 1.0 μg/mL) against MTB H37Rv and ≥16 folds more potent than ciprofloxacin (MIC = 2.0 μg/mL), isoniazid (MIC= >64 μg/mL) and rifampicin (MIC =>64 μg/mL) against MDRMTB ¹¹.

In another work, a set of novel analogs of isatin-quinoline hybrids (15) were designed and synthesized by a hybrid pharmacophore approach. The preliminary antitubercular screening of the test compounds was predicted against enoyl-ACP reductase enzyme (PDB ID: 4TZK) by using molecular docking studies. The compound 15h has the highest binding affinity with a binding energy of -9.08 kcal/mol, and the predicted inhibition constant is 221.75 nanomolar. This compound exhibited well-established hydrophobic bonds with amino acid Tyr 158 and the cofactor NAD 500 in the receptor active pocket. Further, in-vitro antitubercular activity was performed for all the hybrids against drug-resistant strains of Mycobacterium tuberculosis using microdilution assay, and their minimum inhibitory concentration was determined. Compound 15h has the good inhibitory (0.09 μM) activity as compared to the reference drug, isoniazid (0.03 μM) ¹³.A series of new Baylis–Hillman adduct-derived N-cinnamyl-substituted isatin derivatives (14) were synthesized from a starting material 5-halo isatin in a simple and efficient manner. All the synthesized compounds were evaluated for their in-vitro antitubercular activity against Mycobacterium tuberculosis H37RV strain ATCC 27294, which is susceptible to control drugs (Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide) using the agar dilution method. These compounds have inhibited Mycobacterium strains, especially compounds 14j–l have shown overall good activity with MIC = 1.56 µg/mL on M. tuberculosis H37Rv strain ATCC27294 ¹².

3. Antibacterial Activity: Synthesis of new 1-alkyl/cyclohexyl- 3, 3- diaryl- 10- methylspiro [azetidine-2, 30-indoline]-20,4-diones (16) from the reactions of the 2-diazo-1,2-diarylethanones with 1-methyl-3-(alkyl/ cyclohexylimino)indolin-2-ones were reported ¹⁴. All the synthesized compounds were screened for their antibacterial activity against the bacterial strains Gram-(+) Bacillus subtilis, Staphylococcus aureus and Gram-(-) Escherichia coli and Pseudomonas aeruginosa. The results revealed that four compounds showed activity on E. coli (16d: MIC =100 µgmL^-1, 16e: MIC =10 µgmL^-1, 16h: MIC =100 µgmL^-1, 16j: MIC =50 µgmL^-1) whereas only one compound showed activity on P. aeruginosa (16e: MIC =50 µgmL^-1).

In another study, Mannich bases of norfloxacin (17) were synthesized by reacting them with formaldehyde and several isatin derivatives.  The synthesized compounds were investigated for in vitro antimicrobial activity by the agar dilution method against many pathogenic bacteria. Among them, compounds 17d (3.7 times) and 17i (4.8 times) were more active (MIC:0.018 and 0.61μg/ml respectively) to than of norfloxacin (MIC: 1.22 μg/ml) against B. subtilis ¹⁵.

Synthesis of benzylimino isatin Mannich bases (18) by the simple Mannich reaction was reported¹⁶. The in-vitro antibacterial activities were screened with gram +ve as well as gram -ve bacteria by disc diffusion method. Especially, compound 18d showed better activity with 19, 17, 17 and 11mm zone of inhibition against S. aureus, B. subtilis, P. eruginosa, and E. Coli, respectively, compared to standard fluoroquinolone antibacterial Ciprofloxacin (30 mm zone of inhibition in B. subtilus and P. eruginosa). Molecular docking studies were carried out for the better active compound 19d with DNA gyrase enzyme (PDB Code: 1kzn) protein in order to determine the probable binding model into the active site of 1kzn with the compound 18d.

In another work, a series of novel Schiff bases of isatin were synthesized by refluxing isatin with p-aminoethyl benzoate. Further Mannich bases of isatin (19) were synthesized via Mannich reaction with various secondary amines. All the synthesized compounds were screened for antimicrobial activities by turbidity method using Ampicillin as standard against gram-positive and gram-negative bacteria. The results revealed that all compounds showed significant activity against Bacillus subtilis, Staphylococcus aureus, Proteus vulgaris and Escherichia coli. Notably Compound 19a showed excellent activity against all gram-positive organisms (Bacillus subtilis MIC =12.5 µg/mL and Staphylococcus aureus MIC = 12.5 µg/mL) and gram-negative organisms (Escherichia coli MIC =12.5 µg/mL and Proteus vulgaris MIC =25 µg/mL) ¹⁷.

4. Antiviral Activity: A series of 5-sulfonyl isatin derivatives (20) as SARS-CoV chymotrypsin-like protease inhibitors (3CL^pro) were designed, synthesized, and evaluated by in-vitro protease assay using fluorogenic substrate peptide, in which several compounds showed potent inhibition against the 3CL^pro. Structure-activity relationship was analyzed and possible binding interaction modes were proposed by molecular docking studies (PDB Code: 1uk4). Among all compounds, 20j showed the most potent inhibitory activity against 3CL^pro (IC₅₀ = 1.04 μM). These results indicated that these inhibitors could be potentially developed as anti-SARS drugs¹⁸.

In another study, a series of N-substituted isatin derivatives (21) were synthesized and tested against SARS CoV 3C-like protease using a colorimetric assay and confirmed by HPLC. The compounds were shown to be noncovalent, reversible inhibitors of SARS CoV 3C-like protease. The C-5 position was found to favor a carboxamide group and the N-1 position to favor large hydrophobic substituents. The results showed that compound 21f shows significant inhibition with an IC₅₀ of 0.37 µM ¹⁹.

A series of N-substituted isatin derivatives (22) were synthesized from isatin, sodium hydride and various bromide derivatives. The inhibition activities of these compounds against SARS CoV 3CL^pro were assessed by fluorescence resonance energy transfer (FRET) method and confirmed via HPLC analysis. The IC₅₀ values demonstrated that these isatin derivatives inhibited SARS CoV 3CL^pro in low micromolar range (0.95–17.50 µM). In particular, compound 22f with IC₅₀ = 0.95 µM was reportedasone of the most potent and selective SARS CoV 3CL^proinhibitors ²⁰.

R1	R2	R3	R4
22a = H	CN	H
22b = H	I	H
22c = H	H	NO2
22d = H	H	Br
22e = H	F	H
22f = H	I	H
22g = H	I	H

Synthesis of new 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines(23) using bromoethylisatin and 6-(2-bromoethyl)- 6H- indolo[2, 3-b]quinoxaline as starting materials were reported ²¹. These compounds were screened for antiviral activity against vesicular stomatitis virus (VSV). It was shown that compounds 23d and 23f demonstrate the maximal antiviral activity against L929 cells (-lg IC₅₀= 5.65 and -lg IC₅₀= 5.72, respectively).

5. Antifungal Activity: Some novel series of isatin N-(2, 3, 4, 6-tetra-O-acetyl-b-Dglucopyranosyl) thiosemicarbazones (24) with different substituents at 1-, 5- and 7-positions of isatin ring were synthesized by reaction of N-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)thiosemicarbazide with substituted isatins. All the compounds were evaluated for their in-vitro antifungal activity against Aspergillus niger (439), Candida albicans (ATCC 7754), Fusarium oxysporum (M42) and Saccharomyces cerevisiae (SH20). The results revealed that compound 24e with two bromine atoms at 5^th and 7^th positions is most active amongst these thiosemicarbazones with MIC = 3.12 µM and MIC = 6.25µM against Aspergillus niger and Candida albicans, respectively ²².

The minimum fungicidal concentration (MFC) was determined for the test compounds against Pyricularia oryzae, Pseudo-perenospora cubensis, Sphaerotheca fuliginea and Phytophthora infestans through the disc diffusion method. The results showed that compounds 25f have displayed better antifungal activity with MIC = 8 µg/mL against S. fuliginea ²³.In another study, two series of new 2,3-dihydrooxazole-spirooxindole derivatives (25) were efficiently synthesized and screened for antifungal activity against different pathogenic strain of fungi.

6. Antimalarial Activity: The synthesis of 1H-1, 2,3-triazole tethered isatin-7-chloroquinoline hybrids (26) along with evaluation of their anti-plasmodial activity against the CQ resistant W2 strain of P. falciparum were reported ²⁴. The activity profiles showed dependence on the substituents at the C-5 position of isatin as well as the length of the alkyl chain. Especially, Compound 26 h containing longer alkyl chain length and a chloro substituent at the C-5 position of the isatin ring, with IC₅₀ =1.21µM, displayed the best activity among the test compounds when compared to Chloroquine (IC₅₀ =0.099 µM).

In another study, 1H-1,2,3-triazole tethered isatin-ferrocene conjugates (27) were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The results showed that compound 27f and 27h with an optimum combination of electron withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent among the series with IC₅₀ values of 3.76µM and 4.58 µM against 3D7 and W2 strains respectively ²⁵.

7. Anti-Inflammatory and Analgesic Activity: In recent study, synthesis of some new Mannich bases of isatin derivatives (28) was reported. These compounds were evaluated for their in-vivo anti-inflammatory activities by Cotton pellet-induced granuloma method. The results showed that compounds 28c, 28e, and 28f were the most potent derivatives with percentage inhibition values of 55.44%, 52.58%, and 55.36%, respectively as compared to reference drug Indomethacin (56.82%) ²⁶.

In another work, a series of new Schiff bases (29) by condensations of isatins with the nalidixic acid-L-amino acid hydrazides through a peptide linkage were synthesized. The anti-inflammatory activity of these Schiff bases was evaluated via measurement of the expressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells model. The Schiff bases (29g and 29h) exhibited a significant dual inhibitory effect against the induction of the pro-inflammatory iNOS and COX-2 proteins. Notably, they strongly down-regulated the iNOS expression to the level of 16.5% - 42.2% compared to the effect on COX-2 expression (<56.4% inhibition) at the same concentration (10 µM) ²⁷.

A series of novel Schiff bases of isatin (30) were synthesized by condensation of imesatin with different aromatic aldehydes. These compounds were screened for the in-vivo analgesic activity by the tail-immersion method at a dose of 200 mg/kg body weight. Among the tested compounds, 30i exhibited better analgesic activity with a percentage analgesic activity of 62.62% at 180 minutes when compared to standard Pentazocine (66.11%). The analgesic activity results showed that Schiff bases bearing electron-donating substituents produced significant activity ²⁸.

8. Anticonvulsant Activity: A new 1-(amino-N-arylmethanethio)- 3- (1- substituted benzyl-2, 3-dioxoindolin-5-yl)urea (31) were designed and synthesized from 5-Nitroindoline-2, 3-dione. Their in vivo anticonvulsant screenings were performed by two most adopted seizure models: maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ).

The results revealed that compound 31f was found active in MES screening while compounds 31h, 351, 31k and 31l showed significant anticonvulsant activity in both the screenings and were devoid of any neurotoxicity. Compound 31h and 31i showed marked protection at 300 mg/kg against MES and scPTZ screening ²⁹.

In another study, design and synthesis of novel 1-(substituted benzylidene)- 3- (1 (morpholino / piperidino methyl)-2, 3-dioxoindolin- 5- yl) urea derivatives  (32) were reported. All the compounds were screened for anticonvulsant activity using Maximal Electroshock Seizure (MES) test and Subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 32c, 32g, 32j, and 32n were found active in MES model, while 32o showed significant anticonvulsant activity in scPTZ model. Among these compounds, 32c revealed protection in MES at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration, respectively ³⁰.

Synthesis of some new isatin-3-[N2-(2-benzal-aminothiazol-4-yl)] hydrazones (33) and their anticonvulsant activity were reported. Anti-convulsant effect was performed by MES and PTZ models.

It is evident that 33b, 33e, 33h, 33i, and 33j showed anticonvulsant effect at the dose levels of 10 and 100mg/kg in the MES test and except 33j, all other derivatives exhibited anticonvulsant effect at 10 and 100mg/kg in PTZ induced convulsions test. They significantly possess anti-convulsant activity by restoring the GABA levels in mice brain was studied ³¹.

In another work, a series of novel isatin-1-N-phenylacetamide derivatives (34) were synthesized and screened for their in-vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. The results showed that 34b was found to be the most potent compound of the series with an ED₅₀ of 91.3 mg/kg and TD₅₀ of >1,000 mg/kg than the reference drug phenobarbital (ED₅₀ = 21.8 mg/kg and TD₅₀ = 69 mg/kg) ³².

9. Anti-Diabetic Activity: A novel series of chromone-isatin derivatives (35) were synthesized and their in-vitro α-glucosidase inhibitory activity was evaluated.

All the synthesized compounds shown excellent to potent inhibitory activity in the range of IC₅₀ = 3.18 ± 0.12–16.59 ± 0.17 µM as compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 µM).

In particular, compound 35j (IC₅₀ = 3.18 ± 0.12 µM) with a hydroxyl group at the 7-position of chromone and a 4-bromobenzyl group at the N1-positions of isatin, was found to be the most active compound.

A molecular docking study was also investigated to define the possible binding mode of compounds with the active site of Saccharomyces cerevisiae α-glucosidase ³³.

In another study, Synthesis of isatin based Schiff bases (36) in three steps, via an esterification by reacting different carboxylic acid with methanol were reported ³⁴. The synthesized compounds were evaluated for α-glucosidase inhibition. Among the series, compound 36d having IC₅₀ value of 2.2 ± 0.25 μM) showed excellent inhibitory potential many fold better than the standard acarbose (IC₅₀ = 840 ± 1.73 μM). The binding interaction of these active compounds was confirmed through molecular docking study (PDB Code: 3AJ7).

Antioxidant Activity: A series of new 1, 3‑dihydro‑3‑(2‑phenyl‑2‑oxoethylidene)‑2H‑indol‑2‑ones (37) were synthesized and their in-vitro antioxidant activity was determined by 2, 2‑diphenyl‑1‑picrylhydrazyl (DPPH) free radical scavenging assay. The results showed that the majority of compounds with halogen substitution at position 5 of isatin ring exhibited good antioxidant activity within a concentration range of 5‑100 μg/ml ³⁵.

CONCLUSION: The basic core of the isatin molecule is prone to several structural modifications and thus intensified its chemical and biological significance towards drug design. Isatin derivative is an excellent candidate having a broad spectrum of activities against various emerging diseases. Hence isatin, a prominent nucleus, should be used as a promising precursor for novel drug development strategies.

ACKNOWLEDGEMENT: We express our sincere thanks to our Dean, Dr. S. Jayanthi, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Govt. of Puducherry Institution), Puducherry, for her kind support.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

REFERENCES:

1. Gonzalez A, Quirante J and Nieto J: Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters. 2009; 19(17): 5270-73.
2. Azizian J, Mohammadi MK, Firuzi O, Razzaghi-asl N and Miri R: Synthesis, biological activity and docking study of some new isatin Schiff base derivatives. Medicinal Chemistry Research. 2011; 55: 48-55.
3. Karthikeyana C, Solomon VR, Leeb H and Trivedia P: Design, synthesis and biological evaluation of some isatin-linked chalcones as novel anti-breast cancer agents: A molecular hybridization approach. Biomedicine and Preventive Nutrition 2013; 3 (4): 325-30.
4. Ke S, Shi L and Yang Z: Discovery of novel isatin-dehydroepiandrosterone conjugates as potential anticancer agents. Bioorganic and Medicinal Chemistry Letters 2015; 25(20): 4628-31.
5. Abo-Ashour MF: Novel hydrazido benzene sulfonamides-isatin conjugates: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies. European Journal of Medicinal Chemistry 2018; 157: 28-36.
6. Matesic L: N-Phenethyl and N-naphthylmethyl isatins and analogues as in-vitro cytotoxic agents. Bioorganic and Medicinal Chemistry Letters, 2008; 16: 3118-24.
7. Liang C: Synthesis, in-vitro and in-vivo antitumor activity of symmetrical bis-Schiff base derivatives of isatin. European Journal of Medicinal Chemistry 2014; 74: 742-50.
8. Gao S: Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups. Bioorganic and Medicinal Chemistry Letters 2017; 25(12): 2981-94.
9. Feng LS: Synthesis and in-vitro antimycobacterial activity of balofloxacin ethylene isatin derivatives. European Journal of Medicinal Chemistry 2010; 45(8): 3407-12.
10. Sriram D, Yogeeswari P and Gopal G: Synthesis, anti-HIV and antitubercular activities of lamivudine prodrugs. European Journal of Medicinal Chemistry 2005; 40(12): 1373-76.
11. Chen R: Ciprofloxacin-1,2,3-triazole-isatin hybrids tethered via amide: Design, synthesis, and in-vitro anti-mycobacterial activity evaluation. Bioorganic & Medicinal Chemistry Letters 2019; 29: 2635-37.
12. Kumar SB: Synthesis, antitubercular and anticancer activity of new Baylis–Hillman adduct-derived N-cinnamyl-substituted isatin derivatives. Medicinal Chemistry Research 2014; 1934-40.
13. Maddela S and Makula A: Design, synthesis and docking study of some novel isatin- quinoline hybrids as potential antitubercular agents. Anti-Infective Agents 2016; 14: 53-62.
14. Singh G and Luntha P: Synthesis and antimicrobial activity of new 1alkyl/ cyclohexyl-3,3-diaryl-10-methylspiro[azetidine-2,30-indoline]-20,4-diones. European Journal of Medicinal Chemistry 2009; 44: 2265-69.
15. Pandeya, Sriram D, Nath G and Clercq ED: Synthesis, antibacterial, antifungal and anti-HIV activities of norfloxacin Mannich bases. European Journal of Medicinal Chemistry 2000; 35: 249-55.
16. Venkateshan, Rajapandi and Kaniga: Synthesis, antibacterial evaluation and docking studies of some novel isatin derivatives. Indian Drugs 2018; 55(3): 7-12.
17. Meenakshi, Gopal and Sarangapani: Synthesis, characterization and antimicrobial activity of some novel schiff and mannich bases of isatin. International Journal of Pharmacy and Pharmaceutical Sciences 2014; 6(6): 318-22.
18. Liu W: Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors. Bioorganic & Medicinal Chemistry Letters 2014; 22(1): 292-302.
19. Zhou L: Isatin Compounds as Noncovalent SARS Coronavirus 3C-like Protease Inhibitors. Journal of Medicinal Chemistry 2006; 49: 3440-43.
20. Chen LR: Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors. Bioorganic & Medicinal Chemistry Letters 2005; 15: 3058-62.
21. Shibinskaya MO: Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines. European Journal of Medicinal Chemistry 2010; 45(3): 1237-43.
22. Thanh ND: Synthesis and evaluation of in-vivo antioxidant, in-vitro antibacterial, MRSA and antifungal activity of novel substituted isatin N-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)thiosemicarbazones. European Journal of Medicinal Chemistry 2016; 123: 532-43.
23. Tiwari S, Pathak P and Sagar R: Efficient synthesis of new 2,3-dihydrooxazole-spirooxindoles hybrids as antimicrobial agents. Bioorganic & Medicinal Chemistry Letters 2016; 26(10): 2513-16.
24. Raj R: Azide-alkyne cycloaddition en route to 1H-1,2,3-triazole-tethered 7-chloroquinoline-isatin chimeras: Synthesis and antimalarial evaluation. European Journal of Medicinal Chemistry 2013; 62: 590-96.
25. Kumar K: 1H-1, 2, 3-triazole tethered isatin-ferrocene conjugates: Synthesis and in-vitro antimalarial evaluation. European Journal of Medicinal Chemistry 2014; 87: 801-04.
26. Prasad BD: Synthesis, characterization and anti-inflammatory activity of isatin derivatives. International Journal of Biological & Pharmaceutical Research 2012; 3(1): 182-87.
27. Naglah AM: New inducible nitric oxide synthase and cyclooxygenase-2 inhibitors, nalidixic acid linked to isatin schiff bases via certain L-amino acid bridges. Molecules 2016; 21: 498-510.
28. Chinnasamy RP, Sundararajan R and Govindaraj S: Synthesis, characterization and analgesic activity of novel Schiff base of isatin derivatives. J of Adv Pharmaceutical Technology & Research 2010; 1(3): 342-47.
29. Siddiqui N, Alam MS and Stables JP: Synthesis and anticonvulsant properties of 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea derivatives. European Journal of Medicinal Chemistry. 2011; 46(6): 2236-42.
30. Prakash CR and Raja S: Design, synthesis and antiepileptic properties of novel 1-(substituted benzy-lidene)- 3- (1(morpholino / piperidino methyl)-2,3-dioxoindolin-5-yl)urea derivatives. European Journal of Medicinal Chemistry 2011; 46(12): 6057-65.
31. Eggadi V, Kulandaivelu U, Sharvanabhava and Jupall VR: Screening of the anticonvulsant activity of some isatin derivatives in experimental seizure models and its effect on brain GABA levels in mice. American Journal of Pharmacological Sciences 2013; 1(3): 42-46.
32. Xie C: Structure-based design, synthesis and anticon-vulsant activity of isatin-1-N-phenylacetamide derivatives. Medicinal Chemistry Research 2014; 23: 2161-68.
33. Wang G: Synthesis, in-vitro α-glucosidase inhibitory activity and docking studies of novel chromone-isatin derivatives. Bioorganic & Medicinal Chemistry Letters 2018; 28(2): 113-16.
34. Rahim F: Isatin based Schiff bases as inhibitors of α-glucosidase: synthesis, characterization, in-vitro evaluation and molecular docking studies. Bioorganic Chemistry 2015; 60: 42-48.
35. Gupta AK, Kalpana S and Malik JK: Synthesis and in-vitro antioxidant activity of new 3‑substituted‑2‑oxindole derivatives. Indian Journal of Pharmaceutical Sciences 2012; 74(5): 481-86.
    

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    How to cite this article:

    Sowmiya P and Girija K: A recent survey on chemical and biological significance of isatin derivatives. Int J Pharm Sci & Res 2021; 12(10): 5161-73. doi: 10.13040/IJPSR.0975-8232.12(10).5161-73.

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