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Review
. 2025 Sep 8;15(39):32188-32231.
doi: 10.1039/d5ra05002b. eCollection 2025 Sep 5.

A comprehensive review and recent advances on isatin-based compounds as a versatile framework for anticancer therapeutics (2020-2025)

Muna A Alshams  1 , Mohamed S Nafie  1   2   3 , Heba F Ashour  4 , Asmaa S A Yassen  4   5
Affiliations
Review

A comprehensive review and recent advances on isatin-based compounds as a versatile framework for anticancer therapeutics (2020-2025)

Muna A Alshams et al. RSC Adv. .

Abstract

Isatin (1H-indole-2,3-dione) is a privileged nitrogen-containing heterocyclic framework that has received considerable attention in anticancer drug discovery owing to its general biological behavior and structural diversity. This review focuses on isatin-heterocyclic hybrids as a valuable model in the development of new anti-cancer drugs that may reduce side effects and help overcome drug resistance, discussing their synthetic approaches and mechanism of action as apoptosis induction through kinase inhibition. With various chemical modifications, isatin had an excellent ability to build powerful isatin hybrids and conjugates targeting multiple oncogenic pathways. It is worth mentioning that isatin-hybrids exhibited anticancer activity against various cancer cell lines, such as breast, liver, colon, lung, and multidrug-resistant carcinomas. Their mechanisms include mitochondrial-mediated apoptosis, caspase activation, tubulin polymerization inhibition, and kinase modulation, particularly VEGFR-2, EGFR, CDK2, and STAT-3. Numerous synthesized isatin-based compounds have shown superior cytotoxicity compared to established chemotherapeutics, with favorable IC50 values and minimal toxicity toward normal cells. In addition, this review summarizes more recent synthetic innovations, e.g., microwave-assisted and multi-component techniques, which offer improved pharmacological profiles of these isatin-heterocyclic hybrids with improved cytotoxicity and target signaling pathways. Overall, these results underscore the value of isatin as a flexible scaffold for the rational design of new anticancer agents. To increase bioavailability and targeted delivery, especially in solid tumors, and to lead to the creation of novel, potent anticancer therapies, nano-formulation drug delivery systems with revolutionary drug signaling pathways will be further advocated in the future.

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Conflict of interest statement

The authors declare that they have no financial or personal interests.

Figures

Fig. 1
Fig. 1. Bioactive natural products containing isatin.
Fig. 2
Fig. 2. Isatin-based marketed anti-cancer drugs.
Fig. 3
Fig. 3. Structure of isatin.
Fig. 4
Fig. 4. Possible substitution on the isatin scaffold.
Fig. 5
Fig. 5. Tautomerism in isatin. (A) Lactam form, (B) lactim form and (C) imide form.
Fig. 6
Fig. 6. The signaling therapeutic pathways of isatin-based derivatives as anti-cancer agents. This figure is partially generated by Biorender and reproduced from our previously published work.
Fig. 7
Fig. 7. Hybridization of isatin core with other anti-cancer pharmacophores.
Scheme 1
Scheme 1. Synthesis of isatin–quinazoline 7. Reagents and conditions: (i) HCONH2, reflux, 6 h; (ii) HNO3, H2SO4, 90 °C, 30 min; (iii) HCOOH, H2SO4, reflux, 1 h; (iv) Fe, NH4C1, iPrOH, reflux, 1.5 h; (v) EtOH, gl. AcOH (cat.), reflux, 4–6 h.
Scheme 2
Scheme 2. Synthesis of isatin–quinazoline hybrid 12. Reagents and conditions: (i) CuC12·2H2O, EtOH, reflux, 16 h; (ii) Fe, HC1; (iii) EtOH, gl. AcOH (cat.) reflux, 6 h.
Scheme 3
Scheme 3. Synthesis of isatin–indole hybrid 17. Reagents and conditions: (i) MeOH, H2SO4 (cat.), reflux, 4 h; (ii) N2H4·H2O, MeOH, reflux, 2 h; (iii) EtOH, gl. AcOH (cat.), reflux, 4 h.
Scheme 4
Scheme 4. Synthesis of isatin–indole hybrid 23. Reagents and conditions: (i) DMF, POC13, reflux 8 h, (ii) KMnO4, acetone, stirring, r.t., 12 h, (iii) MeOH, H2SO4 (cat.), reflux, 7 h, (iv) N2H4·H2O, MeOH, reflux, 4 h, (v) gl. AcOH, reflux, 5–7 h.
Scheme 5
Scheme 5. Synthesis of isatin–indole hybrid 29. Reagents and conditions: (i) KOH, HC1, H2O; (ii) EtOH, H+, reflux, 10 h; (iii) N2H4·H2O, EtOH, reflux, 2 h; (iv) EtOH, gl. AcOH (cat.), reflux, 4 h.
Scheme 6
Scheme 6. Synthesis of isatin–indole hybrid 32. Reagents and conditions: (i) EtOH, SOC12, reflux, 6 h; (ii) N2H4·H2O, EtOH, reflux, 2 h; (iii) gl. AcOH, reflux, 4 h.
Scheme 7
Scheme 7. Synthesis of isatin–indole hybrid 36. Reagents and conditions: (i) DMF, POC13, reflux, 8 h; (ii) DMF, NaH, stirring, r.t., 24 h; (iii) N2H4·H2O, EtOH, reflux, 2 h; (iv) EtOH, gl. AcOH (cat.), reflux, 3 h.
Scheme 8
Scheme 8. Synthesis of isatin-1,2,3-triazole hybrid 44. Reagents and conditions: (i) acetone, r.t., 2–3 h; (ii) NaN3, DMF, r.t., 24 h; (iii) K2CO3, DMF, r.t., 24 h; (iv) CuSO4·5H2O, sodium ascorbate, n-BuOH/H2O (1 : 1 v/v), DMF, 24 h.
Scheme 9
Scheme 9. Synthesis of isatin-1,2,3-triazole hybrid 51. Reagents and conditions: (i) K2CO3, DMF, 100 °C, 10 min, MW; (ii) NaN3, DMF, 120 °C, 20 min, MW; (iii) TMSI, NaH, DMSO, r.t.; (iv) K2CO3, DMF, 60 °C, 2 h; (v) DMSO, CuI, DIPEA, 80 °C, 10 min, MW.
Scheme 10
Scheme 10. Synthesis of isatin-1,2,3-triazole hybrid 56. Reagents and conditions: (i) K2CO3, DMF, r.t., 4 h; (ii) sodium d-isoascorbate, CuSO4·5H2O, t-butanol/H2O, MW, 100 °C, 2 h; (iii) EtOH, r.t., 2 h.
Scheme 11
Scheme 11. Synthesis of isatin-1,2,3-triazole hybrid 63. Reagents and conditions: (i) Et2NH, DMSO, reflux, 6 h; (ii) N2H4·H2O, EtOH, reflux, 4 h; (iii) K2CO3, KI, MeCN, reflux, 6 h; (iv) EtOH, gl. AcOH (cat.), reflux, 12 h.
Scheme 12
Scheme 12. Synthesis of isatin-1,2,3-triazole hybrid 70. Reagents and conditions: (i) chloral hydrate, Na2SO4, NH2OH·HCL, HC1, H2O, 85 °C, 3 h; (ii) conc. H2SO4, 60 °C, 0.5 h, 90 °C, 1.5 h; (iii) N2H4·H2O, EtOH, H2O, 100 °C, 10 h; (iv) NaNO2, HC1, NaN3, DCM, H2O, 0–5 °C, 3–5 h; (v) CuSO4·5H2O, ascorbic acid, KI, DMF, H2O, 50 °C, 6–10 h; (vi) EtOH, piperidine, 80 °C, 4–8 h.
Scheme 13
Scheme 13. Synthesis of isatin-1,2,3-triazole hybrid 74. Reagents and conditions: (i) K2CO3, DMF, r.t., 3 h; (ii) CuSO4·5H2O, sodium ascorbate, t-BuOH, H2O, r.t., sonication, 1 h; (iii) iPrOH, 65 °C, sonication, 1 h.
Scheme 14
Scheme 14. Synthesis of isatin-1,2,4-triazole hybrid 86. Reagents and conditions: (i) NaOH (aq.), r.t., 1 h; (ii) MeOH, Pd/C, r.t., 3 h; (iii) heating, 75 °C, 40 min; (iv) HC1, NaNO2, 0–5 °C, 20 min; (v) AcONa, 0–10 °C, 3 h; (vi) EtOH, N2H4·H2O, reflux, 1 h; (vii) EtOH, AcOH, reflux, 2 h.
Scheme 15
Scheme 15. Synthesis of isatin-1,2,4-triazole hybrid 94. Reagents and conditions: (i) MeOH, H2SO4, reflux, 8 h; (ii) N2H4·H2O, MeOH, r.t., 4 h; (iii) EtOH, conc. HC1, reflux, 6 h; (iv) NaOH, H2O, reflux, 4 h; (v) reflux, 140 °C, 5 h, r.t., overnight; (vi) EtOH, K2CO3, reflux, 4 h.
Scheme 16
Scheme 16. Synthesis of isatin–pyrazole hybrid 99. Reagents and conditions: (i) MeOH, 60 °C, 9 h; (ii) PdC12(PPh3)2, CuI, sodium laurylsulfate, K2CO3, water, 65 °C, 7 h; (iii) N2H4·H2O, 65 °C, 12 h.
Scheme 17
Scheme 17. Synthesis of isatin–pyrazole hybrid 102. Reagents and conditions: (i) K2CO3, TBAB, MeCN, reflux, 24 h; (ii) EtOH, AcOH (cat.), 50–60 °C, 24 h.
Scheme 18
Scheme 18. Synthesis of isatin–sulphonamide hybrid 111. Reagents and conditions: (i) PTSA, cyclohexane, reflux, 24 h; (ii) Pd/C, H2, MeOH, r.t., 24 h; (iii) pyridine, DCM, r.t., 24 h; (iv) gl. AcOH, HC1, 30 °C, overnight; (v) PTSA, MeOH, 80 °C, 8 h.
Scheme 19
Scheme 19. Synthesis of isatin–sulphonamide hybrid 118. Reagents and conditions: (i) dioxane, Et3N, stirring, r.t., 20 h; (ii) acetone, K2CO3, KI, stirring, r.t., 2 h; (iii) N2H4·H2O, EtOH, reflux, 4 h; (iv) EtOH, gl. AcOH (cat.), reflux, 6 h.
Scheme 20
Scheme 20. Synthesis of isatin–sulphonamide hybrid 123. Reagents and conditions: (i) HOSO2C1, SOC12, 0 °C, 30 min, r.t., 26 h; (ii) EtOH, ammonia, r.t.; (iii) N2H4·H2O, EtOH, gl. AcOH (cat.) reflux, 4 h; (iv) K2CO3, MeCN, reflux, 5 h; (v) EtOH, gl. AcOH (cat.), reflux, 4 h.
Scheme 21
Scheme 21. Synthesis of isatin–sulphonamide hybrid 126. Reagents and conditions: (i) EtNH2, MeOH.
Scheme 22
Scheme 22. Synthesis of isatin–hydrazone hybrid 133. Reagents and conditions: (i) N2H4·H2O, EtOH, reflux, 6 h; (ii) K2CO3, DMF, 100 °C, 9 h; (iii) EtOH, gl. AcOH (cat.), reflux, 7 h; (iv) gl. AcOH, AcONa, reflux, 6 h.
Scheme 23
Scheme 23. Synthesis of isatin–hydrazone hybrid 140. Reagents and conditions: (i) NaHCO3, 0 °C, 1–2 h; (ii) acetone, H2O, NaHCO3, 0 °C to r.t., overnight; (iii) N2H4·H2O, EtOH, reflux, 6–12 h; (iv) EtOH, AcOH (cat.), reflux, 6–8 h.
Scheme 24
Scheme 24. Synthesis of isatin–hydrazone hybrid 144. Reagents and conditions: (i) EtOH, reflux, 7 h; (ii) N2H4·H2O, EtOH, reflux, 5 h; (iii) EtOH, AcOH, reflux, 6–9 h.
Scheme 25
Scheme 25. Synthesis of isatin–hydrazone hybrid 147. Reagents and conditions: (i) N2H4·H2O, reflux, 1 h; (ii) EtOH, gl. AcOH (cat.), reflux, 3–7 h.
Scheme 26
Scheme 26. Synthesis of isatin–hydrazone hybrid 153. Reagents and conditions: (i) EtOH, TEA, reflux, 6 h; (ii) reflux, 5 h; (iii) N2H4·H2O, iPrOH, reflux, 6 h; (iv) gl. AcOH, reflux, 3–5 h.
Scheme 27
Scheme 27. Synthesis of isatin–hydrazone hybrid 156. Reagents and conditions: (i) N2H4·H2O, MeOH, reflux, 1 h; (ii) EtOH, gl. AcOH, reflux, 4 h.
Scheme 28
Scheme 28. Synthesis of isatin–hydrazone hybrid 161. Reagents and conditions: (i) toluene, stirring, 90 °C, 2 h; (ii) N2H4·H2O, EtOH, reflux, 4 h; (iii) gl. AcOH, reflux, 4 h.
Scheme 29
Scheme 29. Synthesis of isatin–hydrazone hybrid 162. Reagents and conditions: (i) N2H4·H2O, EtOH, reflux, 1 h; (ii) EtOH, gl. AcOH (cat.), reflux, 3 h.
Scheme 30
Scheme 30. Synthesis of isatin–hydrazone hybrid 164. Reagents and conditions: (i) N2H4·H2O, EtOH, reflux, 1 h; (ii) EtOH, gl. AcOH (cat.), reflux, 3 h.
Scheme 31
Scheme 31. Synthesis of isatin–hydrazone hybrid 166. Reagents and conditions: (i) KI, K2CO3, MeCN, reflux, 4 h; (ii) EtOH, AcOH (cat.), reflux, 4–6 h.
Scheme 32
Scheme 32. Synthesis of isatin–hydrazone hybrid 172. Reagents and conditions: (i) EtONa, stirring, r.t., 8–10 h; (ii) gl. AcOH, reflux, 5–7 h; (iii) EtOH, TEA, reflux, 22–25 h.
Scheme 33
Scheme 33. Synthesis of isatin–benzofuran hybrid 177. Reagents and conditions: (i) MeCN, K2CO3, reflux, 4 h; (ii) N2H4·H2O, MeOH, reflux, 3 h; (iii) EtOH, gl. AcOH (cat.), reflux, 4–7 h.
Scheme 34
Scheme 34. Synthesis of isatin–thiazolidine hybrid 181. Reagents and conditions: (i) gl. AcOH, AcONa, reflux, 5 h; (ii) DMF, K2CO3, KI, reflux, 6 h.
Scheme 35
Scheme 35. Synthesis of isatin–thiazolidine hybrid 187. Reagents and conditions: (i) K2CO3, DMF, 80 °C, 45 min; (ii) EtOH, gl. AcOH (cat.), reflux, 2 h; (iii) EtOH, AcONa (cat.), reflux, 24 h.
Scheme 36
Scheme 36. Synthesis of isatin–thiazolidine hybrid 189. Reagents and conditions: (i) K2CO3, DMF, KI, 80 °C, 45 min; (ii) EtOH, gl. AcOH (cat.), reflux, 3 h; (iii) EtOH, AcONa (cat.), reflux, 24 h.
Scheme 37
Scheme 37. Synthesis of isatin–thiazolidine hybrid 194. Reagents and conditions: (i) EtOH, piperidine, reflux, 24 h; (ii) Cs2CO3, MeCN, 80 °C, 10 h; (iii) PdC12(PPh3)2, Cul, K2CO3, sodium lauryl sulfate, H2O, 65 °C, 8 h; (iv) N2H4·H2O, 65 °C, 12 h.
Scheme 38
Scheme 38. Synthesis of isatin–thiazolidine hybrids 197 and 199. Reagents and conditions: (i) (a) H2O, 0–5 °C, stirring, 15 min; (b) conc. HC1, reflux, 10 h; (ii) AcOH, AcONa, reflux, 6 h; (iii) KOH, EtOH, reflux; (iv) DMF, K2CO3, KI, reflux, 6 h.
Scheme 39
Scheme 39. Synthesis of isatin–thiazole hybrid 206. Reagents and conditions: (i) DCM, −25 °C to r.t.; (ii) TFA, DCM, 0 °C; (iii) toluene, reflux, 2 h; (iv) AcOH, reflux, 4 h.
Scheme 40
Scheme 40. Synthesis of isatin–thiadiazole hybrid 208. Reagents and conditions: (i) H2SO4, MeOH, reflux, 16 h; (ii) N2H4·H2O, reflux, 4 h; (iii) KSCN, HC1, H2O, reflux, 5 h; (iv) H2SO4, stirring, r.t., 6 h; (v) (a) reflux, 5 h; (b) stirring, r.t., 24 h; (vi) EtOH, K2CO3, reflux, 4 h.
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