Exploring The Overview on Investigation of Isatin Hybrids as Potential Cancer Cell Degrader

Abstract

Isatin (1H indole 2,3-dione), one of the heterocyclic scaffold, identified in humans and various plant species. Isatin and its derivatives are synthesized synthetically by many researchers due to its diverse pharmacological actions like anticancer, anti-TB, antimicrobial, antifungal, antioxidant, anti-inflammatory, anti-HIV etc. Based on the literature surveys, confirms the profile of isatin derivatives and their pharmacological importance. This review represents the development of novel isatin analogues as a potent chemotherapeutic agent. Structural modification of isatin by substitution at position N, carbonyl groups at position 2 and 3 leads to the development of biologically potential analogues. It also include the evidence of various literature surveys. Discovery of new isatin hybrid molecule via hybridization is one of the approach to overcome drug resistance, improve efficiency, reduce toxicity and enhance specificity. Structural activity relationship also represents provide the development of novel isatin analogues having potent activity and less toxicity. This can be utilised for future development of novel derivatives.

Keywords

Introduction

Isatin is one of the important heterocyclic compound utilized in organic synthesis and biological application. Isatin is having molecular formula C6H5NO2 and chemically 1H indole 2,3-dione / indole quinone used to synthesize wide range of heterocyclic scaffold for various drug synthesis[1]. More advances during last 25 years based on the use of isatins on organic synthesis and various biological applications.in 1841, Erdmann and Laurent synthesized isatin by oxidation reaction of indigo in presence of nitric acid and chromic acid[2].

Isatin, also found from several plants, animals and fungai. It is an important component of coal tar. It can be synthesized by Sand Meyer reaction i.e., cyclization of the product obtained by the condensation of chloral hydrate, aniline and hydroxylamine in sulfuric acid[3].

It exists in two forms, lactum and lactim form[4].

Furthermore, substituted isatin compounds are also naturally exists. Eg, methoxy phenyl pentyl isatin, extracted from tumerigenic plant Melochia tomentosa in the carribbean. Isatins are also discovered in fungai, Streptomyces albus and Chaetomium globosum[5].

Isatin scaffold possess various pharmacological properties including analgesic[6], anti-cancer[7], anti- inflammatory[8], anti-tubercular[9], anti-microbial[10], anti-fungal[11] and anti-viral[12].

Structure of isatin based drugs [13-15]:

Sunitinib

Semaxinib

Toceranib

Nintedanib

Oranitinib

Biologically active analogues are prepared by incorporating pharmacophore into the heterocycles.

Discovery of various biologically active agents by substitution of isatins at N or Phenyl ring replacing C2 and C3 Oxygen, especially for anti-tumor agents[16]. Isatin is formed as Tryptophan or Epinephrine (Adrenaline) metabolites in humans. Endogenous isatin block Monoamine oxidase (MAO) by binding to MAO-B isoform. Isatin can be directly synthesized chemically, so medicinal chemists are more encouraged to synthesize various isatin derivatives in search for various pharmacological actions. Various isatin hybrids also acts as Tyrosine kinase receptor inhibitors (iRTK). These inhibitory effect produced is due to its indolic behaviour which is similar to natural substrate of kinases i.e., ATP. Various studies shows the evidence of anti-cancerous activity of isatin derivatives by interact with other kinases.

Thus isatin derivatives displays anti-cancer, anti-tubercular, anti-malarial, anti-fungal, antibacterial, anticonvulsant, anti-leishmanial and anti-viral activities. For the discovery of drugs in cancer therapy, researchers conducted more studies on isatin derivatives. Sunitinib and Toceranib are approved medications for various cancer types. Semaxanib, Orantinib and Nintedanib are the pursuing clinical trial medications [17].

Cancer is becoming a serious threat across the world. According to WHO Global Health Observatory Report from 2018, 9.6 million people died due to cancer. Although the recent advancement in cancer therapy continues, novel drugs with higher potency, selectivity and decreased toxicity are still needed. Indeed, the successful cancer treatment will arise from understanding the basics of cell cycle [18].

Eukaryotic cell growth and division are occurred at three phases: late G1, G2/M and Metaphase to Anaphase transition. These are the ‘checkpoints’ that ensures the order, integrity and fidelity of the key cell cycle events.

Development of novel synthetic compounds with more therapeutic benefit is the major challenges for the researchers. For the treatment of complex disease like cancer, Molecular design based on the multitarget ligand paradigm, combines active heterocyclic pharmacophores into single molecule. The resulting hybrids shows variety of mechanisms and acts as promising lead for therapies [19]. 

CHEMISTRY

Isatin, a heterocyclic scaffold, also known as 1H-indole-2,3-dione and indole quinone having Nitrogen atom at position 1 and two Carbonyl group at position 2 and 3. It comprise of six and five membered ring as cyclic planars [20].

Possible isatin hybrids substitutions

VARIOUS SUBSTITUTED ISATIN HYBRIDS [21-22]

Isatin-1,2,3-Triazole Hybrids

Isatin-Thiazole Hybrids

Isatin Thiazolidinedione Hybrids

Isatin Benzimidazole Hybrids

Isatin-Imidazole  Hybrids

Isatin-Benzofuran Hybrids

Isatin-Coumarin Hybrids

Isatin-Imine Hybrids

Isatin-Quinoline Hybrids

Isatin-Chalcone Hybrids

Isatin Sulfonamide Hybrids

Isatin-Quinazoline Hybrids

Isatin-Pyridine Hybrids

Isatin possess many pharmacological properties like anti-cancer, anti-fungal, anti-viral, anti-malarial, anti-TB etc. Among these actions its cytotoxic potential and its potentiality on different cancer cells are previously studied by many researchers shown in figure 1[23]. Isatin produces tumor inhibitory action via different mechanisms consist of apoptosis induction, cell cycle arrest, anti-angiogenesis, topoisomerases inhibition, epigenetic regulation, inhibition of P13K/AKT/mTOR pathway. Isatin derivatives also acts as histone deacetylases (HDAC) inhibitor, carbonic anhydrase inhibitor, epidermal growth factor receptor-tyrosin kinase(EGFR-TK) inhibitor, tubulin inhibitor and thereby inhibit further proliferation of tumor cells shown in figure[24].

Figure 1- Cytotoxic potentiality of Isatin

Figure 2 – Mechanism of inhibition of isatin.

 

C2-Substituted isatin Derivatives

C3-Substituted Isatin Derivatives

C5-Substituted isatin Derivatives

Spiro Derivatives

REVIEW OF LITERATURE

1. Yani Hou etal, reviewed that Derivatives a and b showed potent anti-tumor activity and active against multi-drug resistant cancer cells. Derivative c showed broad spectrum anti-cancer activity and Derivative d having IC50 value at Nano molar level was highly active against different cancer cells [31-33].

2. K. L. Vineet etal, reviewed on synthesis of isatin derivatives as cytotoxic and anti- proliferative agents and these derivatives were synthesized using substitution at position N, C2 and C3. Also reviewed on synthesizing derivatives using mono, di or tri substitution of the aryl ring [34].

3. Nikolai M. Evdokimov etal. Reviewed on evaluation of indirubin derivatives and related isatin heterocycles against cancer cells with apoptosis sensitive as well as apoptosis resistant cells. Most of the compounds shows similar activity against apoptosis sensitive and resistant cells [35-36].

4. Sulayman A. Ibrahim etal, synthesize various isatin derivatives and those compounds were tested against K562, HepG2 and HT-29 cell lines. All the synthesized compounds showed anticancer action, where compound 4e was found most powerful with IC50 value 24.9µM, 20.27µM and 6.10µM respectively [37].

5. Ibrahim etal in 2016 developed a series of bis isatin-hydrazide derivatives and evaluate their anti-cancer potential against HepG2 (liver), MCF-7 (breast) and HCT-116 (colon) cell lines. Most of the compounds showed moderate action, while compound 5a exhibit potent cytotoxicity against MCF-7 and HCT-16 with IC50 value 1.8µM and 3.31µM with respect to standard doxorubicin. Compound 5a also found active against HepG2 with IC50 6.99µM [38].
6. Yu-Ou Teng etal synthesized 43 novel di/tri substituted isatin derivatives against     human T lymphocyte cells Jurkat using MTT assay via camptothecin as positive control. Compound 6d showed potent anti-proliferative action with IC50 0.O3µM than  other derivatives. Further studies proved that it exhibit action through mitochondrial apoptotic pathway by apoptosis induction [39-41].

7. Abdel-Aziz etal synthesized isatin-benzoazine scaffolds and are screened for anti-cancer action towards HT-29(colon), ZR-75(breast) and A-549(lung) cancer cell lines. Compounds 7b-d, isatin-phthalazine derivatives exhibit potent anti-cancer action, compound 7c with IC50 value 9.5µM showed more potent action against NCI-H6AR cancer cell lines [42].

8. In 2020, Al-Wabli et al, evaluated the antiproliferative activity of novel isatin-based conjugates on HT-29, ZR-75, and A-549 cell lines. Compound 8m had strong antiproliferative properties in vitro compared to other conjugates. All evaluated human cancer cell lines had an average IC50 value of 1.17 M, nearly seven times higher than the standard sunitinib (IC50 8.11 M) [43].

9. In 2020, Nazari et al. synthesized triazol/spiroindolinequinazoline dione, triazol/indolin-3-thiosemicarbazone, and triazol/thiazolindolin-2-one conjugates for anticancer properties. The provided compounds were tested for their cytotoxic ability against various cancer lines, including A375, PC3, LNCaP, MDA, MB231, and normal cell HDF. The majority of chemicals were discovered to be more potent than the positive control. The triazol-linked oxindol-thiosemicarbazone analogue 9b demonstrated remarkable potency against all investigated cancer cell lines, with IC50 values ranging from 15.32 to 29.23 M compared to the reference etoposide [44-45].

10. Kumar et al in 2020 demonstrated a one-pot multicomponent synthesis of isatin-derived imidazole hybrids with dual-purpose anti-inflammatory and cancer properties. Anticancer activity was tested on MCF-7 (breast cancer cell line) and MCF-10A (normal breast epithelial cells) using MTT assay. Compared to the manufactured hybrids, compound 10m resulted in 40% cell death in MCF-7 cells at 0.75 M and 70% survival in MCF 10A cells at 8.0M. Compound 10m demonstrated a 10-fold increase in cytotoxicity against the breast cancer cell line [46].

SAR of isatin as anti-cancer agent

Structure activity relationship, relates isatin scaffold with its pharmacological action, which is important for designing novel isatin derivatives with improved potency, reduced toxicity and better bioavailability [47]. From the literature surveys, reported that various substitution possess diverse pharmacological actions. Carbonyl group in isatin linked with hydrazine, imines or hydrazides possess potent inhibition of CDK and kinase [48].

Imidazole and pyrrole linked derivatives acts as potent receptor tyrosine kinase (RTK) inhibition. Substitution at aromatic or aliphatic moiety leads to destabilization of microtubules [49]. Para or Meta substitution produce potent anti-cancer action as compared to Ortho substituted derivatives. Halogenated derivatives acts as potent antitumor agent [50-51].

CONCLUSION

Isatin is used extensively for synthesizing diverse molecules. Isatin molecules can be exists naturally as well as synthetically. It can be synthesized by various methods by condensation of aromatic/aliphatic substituted amines. Various isatin analogues possess diverse pharmacological actions like anticancer, antimicrobial, antiviral, anti TB, antimalarial etc.

This review aims to reveal the rationalized information regarding isatin analogues on their anti-cancer efficiency. Based on the information from previously cited literatures, anti-proliferative action of isatin was evaluated for renal, breast, lings, leukaemia, colon, liver, melanoma, kidney, sarcoma and pancreatic cancer. Isatin analogues exerts their anti- proliferative action by binding on targets CDK2, EGFR, VEGFR-2, Bax, Bcl2 etc. Various structural derivatization like halogenation on aromatic ring, substitution at carbonyl group at C3 position, substitution at C2 and N- substitution will improve anticancer potential.

By designing and developing isatin hybrids with various heterocycles to develop novel therapeutic approach with more economic, safer and efficient derivatives. Isatin, one of the versatile heterocycle acts as promising lead for future to develop potential anticancer agents.

REFERENCES

1. Vishnu J Ram, Ramendra Pratap, Five-membered heterocycles, the chemistry of heterocycles, 2019.
2. J Braz, The chemistry of isatins : a review from 1975-1999, chem. soc. 12(B) june 2001.
3. Y.Guo and F. Chen, Zhongcaoyao. Synthesis of novel isatin-type 5’-(4-alkyl/aryl-1H-1,2,3-triazoles) via 1, 3-dipolar cycloaddition reaction. 1986, 17,8(CA 104 : 213068f).
4. Jr. Streitwieser, Andrew, Healthcock and H. Clayton. Introduction to Organic Chemistry (3rd edition). pp 1038-1040. ISBN : 0-02-418140-4.
5. Mohammad Altamimi, Saeed Ali Syed, Burak Tuzun, Mohammed Rashid Alhazani, Synthesis, biological evaluation and molecular d0cking of isatin hybrids as anti-cancer and anti-microbial agents, Journal of Enzyme inhibition and Medicinal chemistry. Volume 39, 2024.
6.  Ke,S.; Shi, L.; Yang, Z. Discovery of novel isatin–dehydroepiandrosterone conjugates as potential anticancer agents. Bioorg. Med. Chem. Lett. 2015, 25, 4628–4631.
7.  Pawar, V.S.; Lokwani, D.K.; Bhandari, S.V.; Bothara, K.G.; Chitre, T.S.; Devale, T.L.; Modhave, N.S.; Parikh, J.K. Design, docking study and ADMEprediction of Isatin derivatives as anti-HIV agents. Med. Chem. Res. 2011, 20, 370–380. 
8.  Abbas, S.Y.; Farag, A.A.; Ammar, Y.A.; Atrees, A.A.; Mohamed, A.F.; El-Henawy, A.A. Synthesis, characterization, and antiviral activity of novel fluorinated isatin derivatives. Mon. Fur Chem. 2013, 144, 1725–1733. [PubMed]
9.  Liang, C.; Xia, J.; Lei, D.; Li, X.; Yao, Q.; Gao, J. Synthesis, in vitro and in vivo antitumor Eur. J. Med. Chem. 2014, 74, 742–750.
10.  Jarrahpour,A.; Sheikh, activity of symmetrical bis-Schiff base derivatives of isatin.
11. J.; ElMounsi, I.; Juneja, H.; Hadda, T.BenComputationalevaluationandexperimentalin vitroantibacterial, antifungal and antiviral activity of bis-Schiff bases of isatin and its derivatives. Med. Chem. Res. 2013, 22, 1203–1211.
12. Raj, R.; Biot, C.; Carrère-Kremer, S.; Kremer, L.; Guérardel, Y.; Gut, J.; Rosenthal, P.J.; Forge, D.; Kumar, V. 7-Chloroquinoline–isatin Conjugates: Antimalarial, Antitubercular, and Cytotoxic Evaluation. Chem. Biol. Drug Des. 2014, 83, 622–629.
13.  Venkateshwarlu, D.; Kulandaivelu, U.; Sheshagiri, S.; Jupalli, V. Evaluation of Antioxidant, Antimicrobial and Anticancer activity of Thiazole Tagged Isatin Hydrazones. J. Pharm. Chem. 2016, 3, 4. 
14.  Rajanarendar, E.; Ramakrishna, S.; Govardhan Reddy, K.; Nagaraju, D.; Reddy, Y.N. A facile synthesis, anti-inflammatory and analgesic activity of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,3-indoline]-2,4,9-triones. Bioorg. Med. Chem. Lett. 2013, 23, 3954–3958.
15.  El-Faham, A.; Hozzein, W.N.; Wadaan, M.A.M.; Khattab, S.N.; Ghabbour, H.A.; Fun, H.-K.; Siddiqui, M.R. Microwave Synthesis, Characterization, and Antimicrobial Activity of Some Novel Isatin Derivatives. J. Chem. 2015, 2015, 716987. 
16.  Mondal, P.; Jana, S.; Balaji, A.; Ramakrishna, R.; Kanthal, L.K. Synthesis of Some New Isoxazoline Derivatives of Chalconised Indoline 2-one as a Potential Analgesic, Antibacterial and Anthelmimtic Agents. J. Young Pharm. 2012, 4, 38–41.
17.  Firke, S.; Cheke, R.; Ugale, V.; Khadse, S.; Gagarani, M.; Surana, S.B. Rationale design, synthesis, and pharmacological evaluation of isatin analogues as antiseizure agents. Lett. Drug Des. Discov. 2021, 18, 1. [CrossRef]
18. Hany S Ibrahim, Hatem A Abdel Aziz. 3-Hydrazino indoline-2-one derivatives: chemical investigation of their target as anticancer agents 2016, European Journal of Medicinal Chemistry.
19. Adrián Puerta 1, Aday González-Bakker 1, Pedro Brandão 2, Marta Pineiro 3, Anthony J Burke 4, Elisa Giovannetti  etal, Early pharmacological profiling of isatin derivatives as potent and selective cytotoxic agents, Biochemical pharmacology, Volume 222, 2024.
20.  Mohamed A. Yousef a, Ahmed M. Ali a, Wael M. El-Sayed b, Wesam S. Qayed etal, Design and synthesis of novel isatin-based derivatives targeting cell cycle checkpoint pathways as potential anticancer agents, bioorganic chemistry, volume 105, 2020
21.  A.Q. Ali et al.Synthesis of isatin thiosemicarbazones derivatives: In vitro anti-cancer, DNA binding and cleavage activities Spectrochimica Acta Part A: Mol. Biomol. Spectrosc.(2014)
22. Rameshwar S Cheke 1,*, Vaishali M Patil 2, Sandip D Firke etal, Therapeutic Outcomes of Isatin and Its Derivatives against Multiple Diseases: Recent Developments in Drug Discovery , Pharmaceuticals (Basel),2022
23.  Hou Y, Shang C, Wang H, Yun J. Isatin–azole hybrids and their anticancer activities. Arch Pharm. 2020;353(1):1900272.
24. Maddela S, Mathew GE, Parambi DG, Aljoufi F, Mathew B. Dual acting isatin-heterocyclic hybrids: recent highlights as promising pharmacological agents. Lett Drug Des Discovery. 2019;16(2):220–36.
25. Zebbiche Z, Tekin S, Küçükbay H, Yüksel F, Boumoud B. Synthesis and anticancer properties of novel hydrazone derivatives incorporating pyridine and isatin moieties. Arch Pharm. 2021;354(5):2000377.
26. Ferraz de Paiva RE, Vieira EG, Rodrigues da Silva D, Wegermann CA, Costa Ferreira AM. Anticancer compounds based on isatin-derivatives: strategies to ameliorate selectivity and efficiency. Front Mol Biosci. 2021;7:627272.
27. Zebbiche Z, Tekin S, Küçükbay H, Yüksel F, Boumoud B. Synthesis and anticancer properties of novel hydrazone derivatives incorporating pyridine and isatin moieties. Arch Pharm. 2021;354(5):2000377.
28. Sandmeyer T. Über isonitrosoacetanilide und derenKondensationzuIsatinen. Helvetica ChimicaActa. 1919;2(1):234–42.
29. Kakkar R. Isatin and its derivatives: a survey of recent syntheses, reactions, and applications. MedChemComm. 2019;10(3):351–68.
30. AA Sabah, MS Al-Rawi, JH Tomma, Study the toxicity and anticancer activity of some new amic acid and their derivatives of mefenemic acid. Indian Journal of Forensic Medicine and Toxicology. https://doi.org/10.37506/ijfmt.(2020) 14(1): 642-648.
31. Liang C, Xia J, Lei D, Li X, Yao Q, Gao J. Synthesis, in vitro and in vivo antitumor activity of symmetrical bis-Schiff base derivatives of isatin. European journal of medicinal chemistry. 2014 Mar 3;74:742-50.
32.  Vine KL, Matesic L, Locke JM, Skropeta D. Recent highlights in the development of isatin-based anticancer agents. Adv. Anticancer Agents Med. Chem. 2013 Jun 14;2:254-312.
33. Joaquim FM, Simon JG, Angelo CP. The Chemistry of Isatins: a Review from 1975 to 1999. J. Braz. Chem. Soc. 2001;12(3):273-324. 1856 International Journal of Research Publication and Reviews Vol (2) Issue (7) (2021) Page 1852-1857 1857.
34.  Hou Y, Shang C, Wang H, Yun J. Isatin–azole hybrids and their anticancer activities. Archiv der Pharmazie. 2020 Jan;353(1):1900272.
35. Ranson M, Skropeta D, Locke J, Matesic L, Perrow KL. Cytotoxic and anticancer activities of Isatin and its derivatives: a comprehensive review from 2000-2008.
36. Evdokimov NM, Magedov IV, McBrayer D, Kornienko A. Isatin derivatives with activity against apoptosis-resistant cancer cells. Bioorganic & medicinal chemistry letters. 2016 Mar 15;26(6):1558-60.
37.  Ali AQ, Teoh SG, Eltayeb NE, Ahamed MB, Majid AA. Synthesis of copper (II) complexes of isatinthiosemicarbazone derivatives: In vitro anti-cancer, DNA binding, and cleavage activities. Polyhedron. 2014 May 28;74:6-15.
38.  Taher AT, Khalil NA, Ahmed EM. Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents. Archives of pharmacal research. 2011 Oct;34(10):1615-21.
39.  Grewal AS. Isatin derivatives with several biological activities. Int. J. Pharm. Res. 2014 Jan;6(17):4.
40.  Kakkar R. Isatin and its derivatives: a survey of recent syntheses, reactions, and applications. MedChemComm. 2019;10(3):351-68.
41. Karthikeyan C, Solomon VR, Lee H, Trivedi P. Design, synthesis and biological evaluation of some isatin-linked chalcones as novel anti-breast cancer agents: a molecular hybridization approach. Biomedicine & Preventive Nutrition. 2013 Oct 1;3(4):325-30.
42.  Ibrahim SA, Elsaman T. Cytotoxic and anticancer activities of indoline-2,3-dione (Isatin) and its derivatives. Journal of Pharmaceutical Research International.2018 Feb 27:1-9.
43.  Gudipati R, Anreddy RN, Manda S. Synthesis, characterization and anticancer activity of certain 3-{4-(5-mercapto-1, 3, 4-oxadiazole 2-yl) phenylimino} indolin-2-one derivatives. Saudi Pharmaceutical Journal. 2011 Jul 1;19(3):153-8.
44. Gabr, M.T.; El-Gohary, N.S.; El-Bendary, E.R.; El-Kerdawy, M.M.; Ni, N. Isatin--thiocarbohydrazones: Microwave-assisted synthesis, antitumor activity and structure-activity relationship. Eur. J. Med. Chem. 2017, 128, 36–44.  [PubMed]
45.  Gangarapu, K.; Thumma, G.; Manda, S.; Jallapally, A.; Jarapula, R.; Rekulapally, S. Design, synthesis and molecular docking of novel structural hybrids of substituted isatin based pyrazoline and thiadiazoline as antitumor agents. Med. Chem. Res. 2017, 26, 819–829.
46. Zou,Y. Benzofuran-isatin conjugates as potent VEGFR-2 and cancer cell growth inhibitors. J. Heterocycl. Chem. 2020, 57, 510–516.
47. Alkahtani, H.M.; Alanazi, M.M.; Aleanizy, F.S.; Alqahtani, F.Y.; Alhoshani, A.; Alanazi, F.E.; Almehizia, A.A.; Abdalla, A.N.; Alanazi, M.G.; El-Azab, A.S.; et al. Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies. Saudi Pharm. J. 2019, 27, 682–693.
48. Xu,K.; Liu, Y.; Wang, R.; Cai, P.; Fang, Y. Design, Synthesis, and Anticancer Activities of Benzofuran–Isatin Hybrids Tethered by Pentylene and Hexylene. J. Heterocycl. Chem. 2019, 56, 2052–2055.
49. Jiang, D.; Zhang, G. Ciprofloxacin/Gatifloxacin-1,2,3-triazole-isatin Hybrids and Their in Vitro Anticancer Activity. J. Heterocycl. Chem. 2019, 56, 2966–2969. 
50. Al-Wabli, R.I.; Almomen, A.A.; Almutairi, M.S.; Keeton, A.B.; Piazza, G.A.; Attia, M.I. New Isatin-Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity. Drug Des. Devel. Ther. 2020, 14, 483–495.
51. Rajesh Kumar, M.; Violet Dhayabaran, V.; Sudhapriya, N.; Manikandan, A.; Gideon, D.A.; Annapoorani, S. p-TSA.H2O mediated one-pot, multi-component synthesis of isatin derived imidazoles as dual-purpose drugs against inflammation and cancer. Bioorg. Chem. 2020, 102, 104046.