Generic placeholder image

Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Isatin: A Scaffold with Immense Biodiversity

Author(s): Priyobrata Nath, Agnish Mukherjee, Sougata Mukherjee, Sabyasachi Banerjee, Samarpita Das and Subhasis Banerjee*

Volume 21, Issue 9, 2021

Published on: 25 November, 2020

Page: [1096 - 1112] Pages: 17

DOI: 10.2174/2211536609666201125115559

Price: $65


Isatin is an endogenous and a significant category of fused heterocyclic components and has widely been a part of several potential biologically useful synthetics. Since its discovery, tons of research work has been conducted with respect to the synthesis, chemical properties, and biological and industrial applications. It contains an indole nucleus having both lactam and keto moiety, which, while being a part of a molecular framework, exerted several biological effects, viz.; anti-microbial, anti-tubercular, anticonvulsant, anti-cancer, etc. Isatin derivatives are synthetically significant substrates, which can be utilized for the synthesis of huge diversified chemical entities of which few members emerged as drugs. The reason for this review is to provide extensive information pertaining to the chemistry and its significance in altering several pathological states of isatin and its derivatives. A Structure-Activity Relationship study thus developed through a gamut of scientific information indicates the importance of mostly electron-withdrawing groups, halogens, nitro, alkoxy, and, to a minor extent, groups with positive inductive effects, such as methyl at position 1, 5, 6 and 7 of isatin in alleviating several clinical conditions. It is also observed from the survey that the presence of two oxo groups at positions 2 and 3 sometimes becomes insignificant as a fusion with a heterocycle at these positions resulted in a biologically relevant compound.

Keywords: Isatin, anti-microbial, anticonvulsant, anti-cancer, anti-tubercular, anti-inflammatory.

Graphical Abstract
Bhrigu, B.; Pathak, D.; Siddiqui, N.; Alam, M.S.; Ahsan, W. Search for biological active isatins: A short review. Int. J. Pharm. Sci. Drug Res., 2010, 2(4), 229-235.
Pal, M.; Sharma, K.N.; Priyanka Jha, K.K. Synthetic and biological multiplicity of isatin: A review. J. Adv. Sci. Res., 2011, 2(2), 35-44.
Aggarwal, O.P. Organic chemistry reactions and reagents. Krishna Prakashan Media (P). Ltd., 2009, 46, 658-660.
Pharswan, R.; Chaudhary, M. A review on isatin and its pharmacological profile. Am. J. Pharmtech. Res., 2016, 6(5), 735-752.
Moradi, R.; Ziarani, G.M.; Lashgari, N. Recent applications of isatin in the synthesis of organic compounds. ARKIVOC, 2017, 2017(1), 148-201.
Khan, F.A.; Maalik, A. Advances in pharmacology of isatin and its derivatives: A review. Trop. J. Pharm. Res., 2015, 14(10), 1937-1942.
Chaudhary, D.K.; Ahmad, S.; Maity, S.; Alam, M.S. Isatin: Diverse biological profile. Scholars Res. Libr. Der Pharmacia Lett., 2013, 5(1), 285-295.
Hans, R.H.; Wiid, I.J.; van Helden, P.D.; Wan, B.; Franzblau, S.G.; Gut, J.; Rosenthal, P.J.; Chibale, K. Novel thiolactone-isatin hybrids as potential antimalarial and antitubercular agents. Bioorg. Med. Chem. Lett., 2011, 21(7), 2055-2058.
[] [PMID: 21376591]
Akhaja, T.N.; Raval, J.P. Design, synthesis and in vitro evaluation of tetrahydropyrimidine–isatin hybrids as potential antitubercular and antimalarial agents. Chin. Chem. Lett., 2012, 23(7), 785-788.
Kumar, K.; Pradines, B.; Madamet, M.; Amalvict, R.; Benoit, N.; Kumar, V. 1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation. Eur. J. Med. Chem., 2014, 87, 801-804.
[] [PMID: 25440881]
Nisha; Gut, J.; Rosenthal, P.J.; Kumar, V. β-amino-alcohol tethered 4-aminoquinoline-isatin conjugates: Synthesis and antimalarial evaluation. Eur. J. Med. Chem., 2014, 84, 566-573.
[] [PMID: 25062007]
Raj, R.; Gut, J.; Rosenthal, P.J.; Kumar, V. 1H-1,2,3-Triazole-tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates: Synthesis and antimalarial evaluation. Bioorg. Med. Chem. Lett., 2014, 24(3), 756-759.
[] [PMID: 24424135]
Hans, R.H.; Gut, J.; Rosenthal, P.J.; Chibale, K. Comparison of the antiplasmodial and falcipain-2 inhibitory activity of β-amino alcohol thiolactone-chalcone and isatin-chalcone hybrids. Bioorg. Med. Chem. Lett., 2010, 20(7), 2234-2237.
[] [PMID: 20206517]
Raj, R.; Singh, P.; Haberkern, N.T.; Faucher, R.M.; Patel, N.; Land, K.M.; Kumar, V. Synthesis of 1H-1,2,3-triazole linked β-lactam-isatin bi-functional hybrids and preliminary analysis of in vitro activity against the protozoal parasite Trichomonas vaginalis. Eur. J. Med. Chem., 2013, 63, 897-906.
[] [PMID: 23631874]
Kumar, K.; Liu, N.; Yang, D.; Na, D.; Thompson, J.; Wrischnik, L.A.; Land, K.M.; Kumar, V. Synthesis and antiprotozoal activity of mono- and bis-uracil isatin conjugates against the human pathogen Trichomonas vaginalis. Bioorg. Med. Chem., 2015, 23(16), 5190-5197.
[] [PMID: 25999204]
Prakash, C.R.; Raja, S. Synthesis, characterization and in vitro antimicrobial activity of some novel 5-substituted Schiff and Mannich base of isatin derivatives. J. Saudi Chem. Soc., 2013, 17(3), 337-344.
Zhang, X.M.; Guo, H.; Li, Z.S.; Song, F.H.; Wang, W.M.; Dai, H.Q.; Zhang, L.X.; Wang, J.G. Synthesis and evaluation of isatin-β-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species. Eur. J. Med. Chem., 2015, 101, 419-430.
[] [PMID: 26185006]
Tehrani, K.H.M.E.; Hashemi, M.; Hassan, M.; Kobarfard, F.; Mohebbi, S. Synthesis and antibacterial activity of Schiff bases of 5-substituted isatins. Chin. Chem. Lett., 2016, 27(2), 221-225.
Lian, Z.M.; Sun, J.; Zhu, H.L. Design, synthesis and antibacterial activity of isatin derivatives as FtsZ inhibitors. J. Mol. Struct., 2016, 1117, 8-16.
Ugale, V.; Patel, H.; Patel, B.; Bari, S. Benzofurano-isatins: Search for antimicrobial agents. Arab. J. Chem., 2017, 10(1), S389-S396.
Aboul-Fadl, T.; Bin-Jubair, F.A.; Aboul-Wafa, O. Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building. Eur. J. Med. Chem., 2010, 45(10), 4578-4586.
[] [PMID: 20696500]
Feng, L.S.; Liu, M.L.; Zhang, S.; Chai, Y.; Wang, B.; Zhang, Y.B.; Lv, K.; Guan, Y.; Guo, H.Y.; Xiao, C.L. Synthesis and in vitro antimycobacterial activity of 8-OCH(3) ciprofloxacin methylene and ethylene isatin derivatives. Eur. J. Med. Chem., 2011, 46(1), 341-348.
[] [PMID: 21146257]
Xu, Z.; Zhang, S.; Song, X.; Qiang, M.; Lv, Z. Design, synthesis and in vitro anti-mycobacterial evaluation of gatifloxacin-1H-1,2,3-triazole-isatin hybrids. Bioorg. Med. Chem. Lett., 2017, 27(16), 3643-3646.
[] [PMID: 28720502]
Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Varoli, L.; Cremonini, M.A.; Placucci, G.; Cervellati, R.; Greco, E. New isatin derivatives with antioxidant activity. Eur. J. Med. Chem., 2010, 45(4), 1374-1378.
[] [PMID: 20060202]
Song, J.; Hou, L.; Ju, C.; Zhang, J.; Ge, Y.; Yue, W. Isatin inhibits proliferation and induces apoptosis of SH-SY5Y neuroblastoma cells in vitro and in vivo. Eur. J. Pharmacol., 2013, 702(1-3), 235-241.
[] [PMID: 23376416]
Eldehna, W.M.; Altoukhy, A.; Mahrous, H. Abdel-Aziz, H.A. Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. Eur. J. Med. Chem., 2015, 90, 684-694.
[] [PMID: 25499988]
Van der Walt, E.M.; Milczek, E.M.; Malan, S.F.; Edmondson, D.E.; Castagnoli, N., Jr; Bergh, J.J.; Petzer, J.P. Inhibition of monoamine oxidase by (E)-styrylisatin analogues. Bioorg. Med. Chem. Lett., 2009, 19(9), 2509-2513.
[] [PMID: 19342233]
Manley-King, C.I.; Bergh, J.J.; Petzer, J.P. Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues. Bioorg. Med. Chem., 2011, 19(1), 261-274.
[] [PMID: 21134756]
Justo, L.A.; Durán, R.; Alfonso, M.; Fajardo, D.; Faro, L.R.F. Effects and mechanism of action of isatin, a MAO inhibitor, on in vivo striatal dopamine release. Neurochem. Int., 2016, 99, 147-157.
[] [PMID: 27374845]
Sin, N.; Venables, B.L.; Combrink, K.D.; Gulgeze, H.B.; Yu, K.L.; Civiello, R.L.; Thuring, J.; Wang, X.A.; Yang, Z.; Zadjura, L.; Marino, A.; Kadow, K.F.; Cianci, C.W.; Clarke, J.; Genovesi, E.V.; Medina, I.; Lamb, L.; Krystal, M.; Meanwell, N.A. Respiratory syncytial virus fusion inhibitors. Part 7: Structure-activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo. Bioorg. Med. Chem. Lett., 2009, 19(16), 4857-4862.
[] [PMID: 19596574]
Pawar, V.; Lokwani, D.; Bhandari, S.; Mitra, D.; Sabde, S.; Bothara, K.; Madgulkar, A. Design of potential reverse transcriptase inhibitor containing isatin nucleus using molecular modeling studies. Bioorg. Med. Chem., 2010, 18(9), 3198-3211.
[] [PMID: 20381364]
Kang, I.J.; Wang, L.W.; Hsu, T.A.; Yueh, A.; Lee, C.C.; Lee, Y.C.; Lee, C.Y.; Chao, Y.S.; Shih, S.R.; Chern, J.H. Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(7), 1948-1952.
[] [PMID: 21356589]
Devale, T.L.; Parikh, J.; Miniyar, P.; Sharma, P.; Shrivastava, B.; Murumkar, P. Dihydropyrimidinone-isatin hybrids as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Chem., 2017, 70, 256-266.
[] [PMID: 28160944]
Solomon, V.R.; Hu, C.; Lee, H. Hybrid pharmacophore design and synthesis of isatin-benzothiazole analogs for their anti-breast cancer activity. Bioorg. Med. Chem., 2009, 17(21), 7585-7592.
[] [PMID: 19804979]
González, A.; Quirante, J.; Nieto, J.; Almeida, M.R.; Saraiva, M.J.; Planas, A.; Arsequell, G.; Valencia, G. Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(17), 5270-5273.
[] [PMID: 19651509]
Khan, K.M.; Khan, M.; Ali, M.; Taha, M.; Rasheed, S.; Perveen, S.; Choudhary, M.I. Synthesis of bis-Schiff bases of isatins and their antiglycation activity. Bioorg. Med. Chem., 2009, 17(22), 7795-7801.
[] [PMID: 19837595]
Matesic, L.; Locke, J.M.; Vine, K.L.; Ranson, M.; Bremner, J.B.; Skropeta, D. Synthesis and anti-leukaemic activity of pyrrolo [3, 2, 1-hi] indole-1, 2-diones, pyrrolo [3, 2, 1-ij] quinoline-1, 2-diones and other polycyclic isatin derivatives. Tetrahedron, 2012, 68(34), 6810-6819.
Teoh, S.G.; Ali, A.Q.; Salhin, A.; Eltayeb, N.E.; Ahamed, M.B.K.; Majid, A.A. Synthesis of isatin thiosemicarbazones derivatives: In vitro anti-cancer, DNA binding and cleavage activities. Spectrochim. Acta A, 2014, 125, 476-448.
Teoh, S.G.; Ali, A.Q.; Eltayeb, N.E.; Ahamed, M.B.K.; Majid, A.A. Synthesis of copper (II) complexes of isatin thiosemicarbazone derivatives: In vitro anti-cancer, DNA binding, and cleavage activities. Polyhedron, 2014, 74, 6-15.
Han, K.; Zhou, Y.; Liu, F.; Guo, Q.; Wang, P.; Yang, Y.; Song, B.; Liu, W.; Yao, Q.; Teng, Y.; Yu, P. Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl) isatin derivatives as anticancer agents. Bioorg. Med. Chem. Lett., 2014, 24(2), 591-594.
[] [PMID: 24360564]
Ke, S.; Shi, L.; Yang, Z. Discovery of novel isatin-dehydroepiandrosterone conjugates as potential anticancer agents. Bioorg. Med. Chem. Lett., 2015, 25(20), 4628-4631.
[] [PMID: 26320625]
Teng, Y.O.; Zhao, H.Y.; Wang, J.; Liu, H.; Gao, M.L.; Zhou, Y.; Han, K.L.; Fan, Z.C.; Zhang, Y.M.; Sun, H.; Yu, P. Synthesis and anti-cancer activity evaluation of 5-(2-carboxyethenyl)-isatin derivatives. Eur. J. Med. Chem., 2016, 112, 145-156.
[] [PMID: 26890120]
Nam, N.H.; Huong, T.L.; Dung, T.M.; Dung, P.T.; Oanh, D.T.; Quyen, D.; Thao, T.; Park, S.H.; Kim, K.R.; Han, B.W.; Yun, J.; Kang, J.S.; Kim, Y.; Han, S.B. Novel isatin-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. Eur. J. Med. Chem., 2013, 70, 477-486.
[] [PMID: 24185378]
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. Eur. J. Med. Chem., 2014, 74, 742-750.
[] [PMID: 24176732]
Gao, S.; Zang, J.; Gao, Q.; Liang, X.; Ding, Q.; Li, X.; Xu, W.; Chou, C.J.; Zhang, Y. Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups. Bioorg. Med. Chem., 2017, 25(12), 2981-2994.
[] [PMID: 28511906]
Singh, P.; Kaur, S.; Kumar, V.; Bedi, P.M.; Mahajan, M.P.; Sehar, I.; Pal, H.C.; Saxena, A.K. Synthesis and in vitro cytotoxic evaluation of N-alkylbromo and N-alkylphthalimido-isatins. Bioorg. Med. Chem. Lett., 2011, 21(10), 3017-3020.
[] [PMID: 21482109]
Kumar, K.; Sagar, S.; Esau, L.; Kaur, M.; Kumar, V. Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation. Eur. J. Med. Chem., 2012, 58, 153-159.
[] [PMID: 23124212]
Singh, P.; Sharma, P.; Anand, A.; Bedi, P.M.; Kaur, T.; Saxena, A.K.; Kumar, V. Azide-alkyne cycloaddition en route to novel 1H-1,2,3-triazole tethered isatin conjugates with in vitro cytotoxic evaluation. Eur. J. Med. Chem., 2012, 55, 455-461.
[] [PMID: 22818042]
Nagarsenkar, A.; Guntuku, L.; Guggilapu, S.D. K, D.B.; Gannoju, S.; Naidu, V.G.M.; Bathini, N.B. Synthesis and apoptosis inducing studies of triazole linked 3-benzylidene isatin derivatives. Eur. J. Med. Chem., 2016, 124, 782-793.
[] [PMID: 27639369]
Ibrahim, H.S.; Abou-Seri, S.M.; Ismail, N.S.M.; Elaasser, M.M.; Aly, M.H.; Abdel-Aziz, H.A. Bis-isatin hydrazones with novel linkers: Synthesis and biological evaluation as cytotoxic agents. Eur. J. Med. Chem., 2016, 108, 415-422.
[] [PMID: 26706352]
Jiang, Y.; Hansen, T.V. Isatin 1,2,3-triazoles as potent inhibitors against caspase-3. Bioorg. Med. Chem. Lett., 2011, 21(6), 1626-1629.
[] [PMID: 21324681]
Indira Chandran, V.; Matesic, L.; Locke, J.M.; Skropeta, D.; Ranson, M.; Vine, K.L. Anti-cancer activity of an acid-labile N-alkylisatin conjugate targeting the transferrin receptor. Cancer Lett., 2012, 316(2), 151-156.
[] [PMID: 22115965]
Zhou, Y.; Zhao, H.Y.; Han, K.L.; Yang, Y.; Song, B.B.; Guo, Q.N.; Fan, Z.C.; Zhang, Y.M.; Teng, Y.O.; Yu, P. 5-(2-carboxyethenyl) isatin derivative induces G2/M cell cycle arrest and apoptosis in human leukemia K562 cells. Biochem. Biophys. Res. Commun., 2014, 450(4), 1650-1655.
[] [PMID: 25044115]
Sharma, P.; Senwar, K.R.; Jeengar, M.K.; Reddy, T.S.; Naidu, V.G.; Kamal, A.; Shankaraiah, N. H2O-mediated isatin spiro-epoxide ring opening with NaCN: Synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation. Eur. J. Med. Chem., 2015, 104, 11-24.
[] [PMID: 26413726]
Sreekanth, A.; Muralisankar, M.; Basheer, S.M.; Haribabu, J.; Bhuvanesh, N.S.; Karvembu, R. An investigation on the DNA/protein binding, DNA cleavage and in vitro anticancer properties of SNO pincer type palladium (II) complexes with N-substituted isatin thiosemicarbazone ligands. Inorg. Chim. Acta, 2017, 466, 61-70.
Evdokimov, N.M.; Magedov, I.V.; McBrayer, D.; Kornienko, A. Isatin derivatives with activity against apoptosis-resistant cancer cells. Bioorg. Med. Chem. Lett., 2016, 26(6), 1558-1560.
[] [PMID: 26883150]
Liu, W.; Zhu, H.M.; Niu, G.J.; Shi, E.Z.; Chen, J.; Sun, B.; Chen, W.Q.; Zhou, H.G.; Yang, C. Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors. Bioorg. Med. Chem., 2014, 22(1), 292-302.
[] [PMID: 24316352]
Gabr, M.T.; El-Gohary, N.S.; El-Bendary, E.R.; El-Kerdawy, M.M.; Ni, N. Isatin-β-thiocarbohydrazones: Microwave-assisted synthesis, antitumor activity and structure-activity relationship. Eur. J. Med. Chem., 2017, 128, 36-44.
[] [PMID: 28147307]
Ibrahim, H.S.; Abou-Seri, S.M.; Tanc, M.; Elaasser, M.M.; Abdel-Aziz, H.A.; Supuran, C.T. Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII. Eur. J. Med. Chem., 2015, 103, 583-593.
[] [PMID: 26408817]
Subba Reddy, B.V.; Rajeswari, N.; Sarangapani, M.; Prashanthi, Y.; Ganji, R.J.; Addlagatta, A. Iodine-catalyzed condensation of isatin with indoles: A facile synthesis of di(indolyl)indolin-2-ones and evaluation of their cytotoxicity. Bioorg. Med. Chem. Lett., 2012, 22(7), 2460-2463.
[] [PMID: 22386528]
Akdemir, A.; Güzel-Akdemir, Ö.; Karalı, N.; Supuran, C.T. Isatin analogs as novel inhibitors of Candida spp. β-carbonic anhydrase enzymes. Bioorg. Med. Chem., 2016, 24(8), 1648-1652.
[] [PMID: 26951893]
Raval, J.P.; Akhaja, T.N. Design, synthesis, in vitro evaluation of tetrahydropyrimidine–isatin hybrids as potential antibacterial, antifungal and anti-tubercular agents. Chin. Chem. Lett., 2012, 23(4), 446-449.
Saravanan, G.; Alagarsamy, V.; Dineshkumar, P. Anticonvulsant activity of novel 1-(morpholinomethyl)-3-substituted isatin derivatives. Bull. Fac. Pharm. Cairo Univ., 2014, 52(1), 115-124.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy