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Anticancer potential of fused heterocycles: structural insights and mechanistic advances Cover

Anticancer potential of fused heterocycles: structural insights and mechanistic advances

Open Access
|Dec 2025

References

  1. Angre T, Kumar A, Singh AK, Thareja S, Kumar P. Role of collagen regulators in cancer treatment: a comprehensive review. Anticancer Agents Med Chem. 2022; 22:2956–84.
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394–424.
  3. Choi JS, Berdis AJ. Visualizing nucleic acid metabolism using non-natural nucleosides and nucleotide analogs. Biochim Biophys Acta. 2016; 1864:165–76.
  4. Rusu A, Moga IM, Uncu L, Hancu G. The role of five-membered heterocycles in the molecular structure of antibacterial drugs used in therapy. Pharmaceutics. 2023; 15:2554. doi: 10.3390/pharmaceutics15112554
  5. Pandey A, Sharma V, Kumar A. Role of extended conjugation on electronic, electrochemical, and antimicrobial properties of FeN4-Macrocyclic complexes. Results Chem. 2024; 11:101782. doi: 10.1016/j.rechem.2024.101782
  6. Pandey A, Sharma V. Electrochemical, antimicrobial, and theoretical investigations of synthetic tetra-aza/penta-aza-macrocyclic complexes. Nano Life. 2023; 13:2350002. doi: 10.1142/S1793984423500022
  7. Alvarez-Builla J. Modern Heterocyclic Chemistry; Vaquero JJ, Barluenga J, Eds.; Wiley-VCH: Weinheim, Germany, 2011; pp 1–9.
  8. Ferreira PM, Maia HL, Monteiro LS. Synthesis of 2, 3, 5-substituted pyrrole derivatives. Tetrahedron Lett. 2002; 43:4491–3.
  9. Kijewska M, Sharfalddin AA, Jaremko Ł, Cal M, Setner B, Siczek M, et al. Lossen rearrangement of p-toluenesulfonates of N-oxyimides in basic condition, theoretical study, and molecular docking. Front Chem. 2021; 9:662533. doi: 10.3389/fchem.2021.662533
  10. Kumar A, Singh AK, Singh H, Vijayan V, Kumar D, Naik J, et al. Nitrogen containing heterocycles as anticancer agents: a medicinal chemistry perspective. Pharmaceuticals (Basel). 2023; 16:299. doi: 10.3390/ph16020299
  11. Ebenezer O, Jordaan MA, Carena G, Bono T, Shapi M, Tuszynski JA. An overview of the biological evaluation of selected nitrogen-containing heterocycle medicinal chemistry compounds. Int J Mol Sci. 2022; 23:8117. doi: 10.3390/ijms23158117
  12. Akhtar MJ, Yar MS, Khan AA, Ali Z, Haider MR. Recent advances in the synthesis and anticancer activity of some molecules other than nitrogen containing heterocyclic moeities. Mini Rev Med Chem. 2017; 17:1602–32.
  13. Aatif M, Raza MA, Javed K, Nashre-Ul-Islam SM, Farhan M, Alam MW. Potential nitrogen-based heterocyclic compounds for treating infectious diseases: a literature review. Antibiotics (Basel). 2022; 11:1750. doi: 10.3390/antibiotics11121750
  14. Sperka T, Pitlik J, Bagossi P, Tözsér J. Beta-lactam compounds as apparently uncompetitive inhibitors of HIV-1 protease. Bioorg Med Chem Lett. 2005; 15:3086–90.
  15. O’Driscoll M, Greenhalgh K, Young A, Turos E, Dickey S, Lim DV. Studies on the antifungal properties of N-thiolated beta-lactams. Bioorg Med Chem. 2008; 16:7832–7.
  16. Srivastava SK, Srivastava SL, Srivastava SD. Synthesis of new 2-chloro-phenothiazinothiadiazol-2-oxoaze tidines: antimicrobial and antiinflammatory agents. Indian J Chem. 2000; 39:464–7.
  17. Clader JW, Burnett DA, Caplen MA, Domalski MS, Dugar S, Vaccaro W, et al. 2-Azetidinone cholesterol absorption inhibitors: structure activity relationships on the heterocyclic nucleus. J Med Chem. 1996; 39:3684–93.
  18. Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem. 2004; 47:1–9.
  19. Burnett DA, Caplen MA, Davis HR, Burrier RE, Clader JW. 2-Azetidinones as inhibitors of cholesterol absorption. J Med Chem. 1994; 37:1733–6.
  20. Burnett DA. Beta-lactam cholesterol absorption inhibitors. Curr Med Chem. 2004; 11:1873–87.
  21. Lall MS, Ramtohul YK, James MN, Vederas JC. Serine and threonine beta-lactones: a new class of hepatitis A virus 3C cysteine proteinase inhibitors. J Org Chem. 2002; 67:1536–47.
  22. Goel RK, Mahajan MP, Kulkarni SK. Evaluation of anti-hyperglycemic activity of some novel monocyclic beta lactams. J Pharm Pharm Sci. 2004; 7:80–3.
  23. Saturnino C, Fusco B, Saturnino P, De Martino G, Rocco F, Lancelot JC. Evaluation of analgesic and anti-inflammatory activity of novel beta-lactam monocyclic compounds. Biol Pharm Bull. 2000; 23:654–6.
  24. Banik BK, Becker FF, Banik I. Synthesis of anticancer beta-lactams: mechanism of action. Bioorg Med Chem. 2004; 12:2523–8.
  25. Banik BK, Banik I, Becker FF. Stereocontrolled synthesis of anticancer beta-lactams via the Staudinger reaction. Bioorg Med Chem. 2005; 13:3611–22.
  26. Bandyopadhyay D, Cruz J, Banik BK. Novel synthesis of 3-pyrrole substituted β-lactams via microwave-induced bismuth nitrate-catalyzed reaction. Tetrahedron. 2012; 68:10686–95.
  27. Banik I, Becker FF, Banik BK. Stereoselective synthesis of beta-lactams with polyaromatic imines: entry to new and novel anticancer agents. J Med Chem. 2003; 46:12–5.
  28. Zhang X, Jia Y. Recent Advances in β-lactam derivatives as potential anticancer agents. Curr Top Med Chem. 2020; 20:1468–80.
  29. Abraham EP. The beta-lactam antibiotics. Sci Am. 1981; 244:76–86.
  30. Smith DM, Kazi A, Smith L, Long TE, Heldreth B, Turos E, et al. A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage. Mol Pharmacol. 2002; 61:1348–58.
  31. Kazi A, Hill R, Long TE, Kuhn DJ, Turos E, Dou QP. Novel N-thiolated beta-lactam antibiotics selectively induce apoptosis in human tumor and transformed, but not normal or nontransformed, cells. Biochem Pharmacol. 2004; 67:365–74.
  32. Bagshawe KD. Antibody directed enzymes revive anti-cancer prodrugs concept. Br J Cancer. 1987; 56:531–2.
  33. Bagshawe KD, Springer CJ, Searle F, Antoniw P, Sharma SK, Melton RG, et al. A cytotoxic agent can be generated selectively at cancer sites. Br J Cancer. 1988; 58:700–3.
  34. Diaz P, Horne E, Xu C, Hamel E, Wagenbach M, Petrov RR, et al. Modified carbazole destabilize microtubules and kill glioblastoma multiform cells. Eur J Med Chem. 2018; 159:74–89.
  35. Chowdhary S, Shalini, Arora A, Kumar V. A mini review on isatin, an anticancer scaffold with potential activities against neglected tropical diseases (NTDs). Pharmaceuticals (Basel). 2022; 15:536. doi: 10.3390/ph15050536
  36. Justo LA, Durán R, Alfonso M, Fajardo D, Faro LRF. Effects and mechanism of action of isatin, a MAO inhibitor, on in vivo striatal dopamine release. Neurochem Int. 2016; 99:147–57.
  37. Silva BV. Isatin, a versatile molecule: studies in Brazil. J Braz Chem Soc. 2013; 24:707–20.
  38. Pandeya SN, Smitha S, Jyoti M, Sridhar SK. Biological activities of isatin and its derivatives. Acta Pharm. 2005; 55:27–46.
  39. Varun V, Sonam S, Kakkar R. Isatin and its derivatives: a survey of recent syntheses, reactions, and applications. Medchemcomm. 2019; 10:351–68.
  40. Cheke RS, Patil VM, Firke SD, Ambhore JP, Ansari IA, Patel HM, et al. Therapeutic outcomes of isatin and its derivatives against multiple diseases: recent developments in drug discovery. Pharmaceuticals (Basel). 2022; 15:272. doi: 10.3390/ph15030272
  41. Nath P, Mukherjee A, Mukherjee S, Banerjee S, Das S, Banerjee S. Isatin: a scaffold with immense biodiversity. Mini Rev Med Chem. 2021; 21:1096–112.
  42. Abdel-Aziz HA, Elsaman T, Al-Dhfyan A, Attia MI, Al-Rashood KA, Al-Obaid ARM. Synthesis and anti-cancer potential of certain novel 2-oxo-N′-(2-oxoindolin-3-ylidene)-2H-chromene-3-carbohydrazides. Eur J Med Chem. 2013; 70:358–63.
  43. Aboul-Fadl T, Abdel-Aziz HA, Abdel-Hamid MK, Elsaman T, Thanassi J, Pucci MJ. Schiff bases of indoline-2,3-dione: potential novel inhibitors of Mycobacterium tuberculosis (Mtb) DNA gyrase. Molecules. 2011; 16:7864–79.
  44. Xu Z, Zhang S, Gao C, Fan J, Zhao F, Lv Z. Isatin hybrids and their anti-tuberculosis activity. Chin Chem Lett. 2017; 28:159–67.
  45. Chiyanzu I, Clarkson C, Smith PJ, Lehman J, Gut J, Rosenthal PJ, et al. Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives. Bioorg Med Chem. 2005; 13:3249–61.
  46. Thakur RK, Joshi P, Baranwal P, Sharma G, Shukla SK, Tripathi R, et al. Synthesis and antiplasmodial activity of glycol-conjugate hybrids of phenylhydrazono-indolinones and glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones. Eur J Med Chem. 2018; 155:764–71.
  47. Guo H. Isatin derivatives and their anti–bacterial activities. Eur J Med Chem. 2019; 164:678–88.
  48. Osman HM, Elsaman T, Yousef BA, Elhadi E, Ahmed AAE, Eltayib EM, et al. Schiff bases of isatin and adamantine-1-carbohydrazide: synthesis, characterization and anticonvulsant activity. J Chem. 2021; 2021:6659156. doi: 10.1155/2021/6659156
  49. Li W, Zhao SJ, Gao F, Tu JY, Xu Z. Synthesis and in vitro anti-tumour, anti-mycobacterial and anti-HIV activities of diethylene glycol tethered bis-isatin derivatives. Chemistry Select. 2018; 3:10250–4.
  50. Devale TL, 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; 70:256–66.
  51. Da Silva JEM, Garden SJ, Pinto AC. The chemistry of isatin: a review from 1975 to 1999. J Braz Chem Soc. 2001; 12:273–324.
  52. Gao S, Zang J, Gao Q, Liang X, Ding Q, Li X, et al. 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; 25:2981–94.
  53. Eldehna WM, Nocentini A, Al-Rashood ST, Hassan GS, Alkahtani HM, Almehizia AA, et al. Tumor-associated carbonic anhydrase isoform IX and XII inhibitory properties of certain isatin-bearing sulfonamides endowed with in vitro antitumor activity towards colon cancer. Bioorg Chem. 2018; 81:425–32.
  54. Wang J, Yun D, Yao J, Fu W, Huang F, Chen L, et al. Design, synthesis and QSAR study of novel isatin analogues inspired Michael acceptor as potential anticancer compounds. Eur J Med Chem. 2018; 144:493–503.
  55. Rana S. Isatin derived spirocyclic analogues with α-methylene-γ-butyrolactone as anticancer agents: a structure-activity relationship study. J Med Chem. 2016; 59:5121–7.
  56. Senwar KR, Reddy TS, Thummuri D, Sharma P, Naidu VGM, Srinivasulu G, et al. Design, synthesis and apoptosis inducing effect of novel (Z)-3-(30-methoxy-40-(2-amino-2-oxoethoxy)-benzylidene) indolin-2-ones as potential antitumour agents. Eur J Med Chem. 2016; 118:34–46.
  57. Issa S, Prandina A, Bedel N, Rongved P, Yous S, Le Borgne M, et al. Carbazole scaffolds in cancer therapy: a review from 2012 to 2018. J Enzyme Inhib Med Chem. 2019; 34:1321–46.
  58. Wang G, Sun S, Guo H. Current status of carbazole hybrids as anticancer agents. Eur J Med Chem. 2022; 229:113999. doi: 10.1016/j. ejmech.2021.113999
  59. Ceramella J, Iacopetta D, Barbarossa A, Caruso A, Grande F, Bonomo MG, et al. Carbazole derivatives as kinase-targeting inhibitors for cancer treatment. Mini Rev Med Chem. 2020; 20:444–65.
  60. Caruso A, Iacopetta D, Puoci F, Cappello AR, Saturnino C, Sinicropi MS. Carbazole derivatives: a promising scenario for breast cancer treatment. Mini Rev Med Chem. 2016; 16:630–43.
  61. Li PH, Jiang H, Zhang WJ, Li YL, Zhao MC, Zhou W, et al. Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers. Eur J Med Chem. 2018; 145:498–510.
  62. Hermawan A, Putri H. Integrative bioinformatics analysis reveals possible target and mechanism of ellipticine against breast cancer stem cells. Indones J Pharm. 2021; 32:64–73.
  63. Sinicropi MS, Iacopetta D, Rosano C, Randino R, Caruso A, Saturnino C, et al. N-thioalkylcarbazoles derivatives as new anti-proliferative agents: synthesis, characterisation and molecular mechanism evaluation. J Enzyme Inhib Med Chem. 2018; 33:434–44.
  64. Wilson SC, Howard PW, Forrow SM, Hartley JA, Adams LJ, Jenkins TC, et al. Design, synthesis, and evaluation of a novel sequence-selective epoxide-containing DNA cross-linking agent based on the pyrrolo[2, 1-c][1,4]benzodiazepine system. J Med Chem. 1999; 42:4028–41.
  65. Kitamura T, Sato Y, Mori M. Synthetic study of (+)-anthramycin using ring-closing enyne metathesis and cross-metathesis. Tetrahedron. 2004; 60:9649–57.
  66. Kamal A, Shankaraiah N, Reddy KL, Devaiah V. Selective reduction of aromatic azides in solution/solid-phase and resin cleavage by employing BF3 OEt2/EtSH. Preparation of DC-81. Tetrahedron Lett. 2006; 47:4253–7.
  67. Kamal A, Khan MN, Srikanth YV, Reddy KS, Juvekar A, Sen S, et al. Synthesis, DNA-binding ability and evaluation of antitumour activity of triazolo[1,2,4]benzothiadiazine linked pyrrolo[2,1-c][1,4] benzodiazepine conjugates. Bioorg Med Chem. 2008; 16:7804–10.
  68. Kamal A, Kumar PP, Sreekanth K, Seshadri BN, Ramulu P. Synthesis of new benzimidazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates with efficient DNA-binding affinity and potent cytotoxicity. Bioorg Med Chem Lett. 2008; 18:2594–8.
  69. Kamal A, Khan MN, Reddy KS, Ahmed SK, Kumar MS, Juvekar A, et al. 1,2,4-benzothiadiazine linked pyrrolo[2,1-c][1,4] benzodiazepine conjugates: synthesis, DNA-binding affinity and cytotoxicity. Bioorg Med Chem Lett. 2007; 17:5345–8.
  70. Thurston DE, Bose DS. Synthesis of DNA-Interactive pyrrolo [2, 1-c][1, 4] benzodiazepines. Chem Rev. 1994; 94:433–65.
  71. Kamal A, Laxman N, Ramesh G, Srinivas O, Ramulu P. Synthesis of C-8 alkylamino substituted pyrrolo[2,1-c][1,4]benzodiazepines as potential anti-cancer agents. Bioorg Med Chem Lett. 2002; 12:1917–9.
  72. Thurston DE, Bose DS, Thompson AS, Howard PW, Leoni A, Croker SJ, et al. Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents. J Org Chem. 1996; 61:8141–7.
  73. O’Neil IA, Thompson S, Kalindjian SB, Jenkins TC. The synthesis and biological activity of C2-fluorinated pyrrolo [2, 1-c][1, 4] benzodiazepines. Tetrahedron Lett. 2003; 44:7809–12.
  74. Kamal A, Reddy DR, Reddy PMM. Synthesis and DNA-binding ability of pyrrolo [2, 1-c][1, 4] benzodiazepine-azepane conjugates. Bioorg Med Chem Lett. 2006; 16:1160–3.
  75. Kamal A, Reddy BS, Reddy GS, Ramesh G. Design and synthesis of C-8 linked pyrrolobenzodiazepine–naphthalimide hybrids as anti-tumour agents. Bioorg Med Chem Lett. 2002; 12:1933–5.
  76. Kamal A, Reddy GSK, Reddy KL, Raghavan S. Efficient solid–phase synthesis of DNA-interactive pyrrolo [2, 1-c][1, 4] benzodiazepine antitumour antibiotics. Tetrahedron Lett. 2002; 43:2103–6.
  77. Kamal A, Srinivas O, Ramulu P, Ramesh G, Kumar PP. Synthesis of novel C2 and C2–C8 linked pyrrolo [2, 1-c][1, 4] benzodiazepine-naphthalimide hybrids as DNA-binding agents. Bioorg Med Chem Lett. 2003; 13:3577–81.
  78. Kamal A, Shankaraiah N, Markandeya N, Reddy CS. An efficient selective reduction of aromatic azides to amines employing BF3·OEt2/NaI: synthesis of pyrrolobenzodiazepines. Synlett. 2008; 2008:1297–300.
  79. Kamal A, Maddamsetty VR, Reddy BS. The newer synthetic strategies for DNA binding pyrrolobenzodiazepine antibiotics. Chem Heterocycl Compd. 1998; 34:1342–58.
  80. Kamal A, Howard PW, Reddy BN, Reddy BP, Thurston DE. Synthesis of pyrrolo [2, 1-c][1, 4] benzodiazepine antibiotics: oxidation of cyclic secondary amine with TPAP. Tetrahedron. 1997; 53:3223–30.
  81. Berry JM, Howard PW, Thurston DE. Solid-phase synthesis of DNA-interactive pyrrolo [2, 1-c][1, 4] benzodiazepines. Tetrahedron Lett. 2000; 41:6171–4.
  82. Bose DS, Idrees M, Todewale IK, Jakka NM, Rao JV. Hybrids of privileged structures benzothiazoles and pyrrolo[2,1-c] [1,4] benzodiazepine-5-one, and diversity-oriented synthesis of benzothiazoles. Eur J Med Chem. 2012; 50:27–38.
  83. Kamal A, Ramakrishna G, Lakshma Nayak V, Raju P, Subba Rao AV, Viswanath A, et al. Design and synthesis of benzo[c,d] indolone-pyrrolobenzodiazepine conjugates as potential anticancer agents. Bioorg Med Chem. 2012; 20:789–800.
  84. Chen CY, Lee PH, Lin YY, Yu WT, Hu WP, Hsu CC, et al. Synthesis, DNA-binding abilities and anticancer activities of triazolepyrrolo[2,1-c][1,4]benzodiazepines hybrid scaffolds. Bioorg Med Chem Lett. 2013; 23:6854–9.
  85. Robins RK, Hitchings GH. Studies on condensed pyrimidine systems. XIX. A new synthesis of pyrido [2, 3–d] pyrimidines. The condensation of 1, 3–diketones and 3-ketoaldehydes with 4-aminopyrimidines. J Am Chem Soc. 1958; 80:3449–57.
  86. Gangjee A, Adair OO, Queener SF. Synthesis and biological evaluation of 2,4-diamino-6-(arylaminomethyl)pyrido[2,3-d] pyrimidines as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase and as antiopportunistic infection and antitumor agents. J Med Chem. 2003; 46:5074–82.
  87. Elzahabi HSA, Nossier ES, Khalifa NM, Alasfoury RA, El-Manawaty MA. Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold. J Enzyme Inhib Med Chem. 2018; 33:546–57.
  88. Ibrahim DA, Ismail NS. Design, synthesis and biological study of novel pyrido [2, 3-d] pyrimidine as anti-proliferative CDK2 inhibitors. Eur J Med Chem. 2011; 46:5825–32.
  89. Naresh Kumar R, Jitender Dev G, Ravikumar N, Krishna Swaroop D, Debanjan B, Bharath G, et al. Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d] pyrimidine derivatives as promising anticancer and antibacterial agents. Bioorg Med Chem Lett. 2016; 26:2927–30.
  90. Hou J, Wan S, Wang G, Zhang T, Li Z, Tian Y, et al. Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor. Eur J Med Chem. 2016; 118:276–89.
  91. Faidallah HM, Rostom SA, Khan KA. Synthesis of some polysubstituted nicotinonitriles and derived pyrido [2, 3-d] pyrimidines as in vitro cytotoxic and antimicrobial candidates. J Chem. 2016; 2016:2135893. doi: 10.1155/2016/2135893
  92. Behalo MS, Mele G. Synthesis and evaluation of pyrido [2, 3-d] pyrimidine and 1, 8-naphthyridine derivatives as potential antitumor agents. J Heterocycl Chem. 2017; 54:295–300.
  93. Banda V, Gaddameedi Jitender D, Gautham Santhosh K, Pillalamarri Sambasiva R, Chavva K, Rajesh P, et al. 2018. Studies on synthesis of novel pyrido [2, 3-d] pyrimidine derivatives and their anticancer activity. J Heterocycl Chem. 2018; 55:2538–44.
  94. Al-Warhi T, Sallam AM, Hemeda LR, El Hassab MA, Aljaeed N, Alotaibi OJ, et al. Identification of novel cyanopyridones and pyrido[2,3–D]pyrimidines as anticancer agents with dual VEGFR-2/HER–2 inhibitory action: synthesis, biological evaluation and molecular docking studies. Pharmaceuticals (Basel). 2022; 15:1262. doi: 10.3390/ph15101262
  95. Ding J, Liu T, Zeng C, Li B, Ai Y, Zhang X, et al. Design, synthesis, and anti-breast-cancer activity evaluation of pyrrolo (pyrido)[2, 3–d] pyrimidine derivatives. Chem Heterocycl Compd. 2022; 58:438–48.
DOI: https://doi.org/10.2478/abm-2025-0035 | Journal eISSN: 1875-855X | Journal ISSN: 1905-7415
Language: English
Page range: 358 - 374
Published on: Dec 31, 2025
In partnership with: Paradigm Publishing Services
Publication frequency: 6 issues per year

© 2025 Aaysha Pandey, Shubham Sharma, Kamal Kishore, Swati Rani, Man Vir Singh, Gangotri Pemawat, published by Chulalongkorn University
This work is licensed under the Creative Commons Attribution 4.0 License.