M. Sathish Kumar, M. Vijey Aanandhi
M. Sathish Kumar1, M. Vijey Aanandhi2*
1Research Scholar, Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, VISTAS, Pallavaram, Chennai - 600117 Tamilnadu, India.
2Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, VISTAS, Pallavaram, Chennai - 600117 Tamilnadu, India.
Volume - 14,
Issue - 6,
Year - 2021
The fused pyrimidine derivatives are potent tyrosine kinase and thymidylate synthase inhibitors. The compound 3-(4-sulphonyl amino)-2-methyl thio-6-phenyl azo-5, 7-dimethyl pyrido(2,3-d)pyrimidin-4-one was synthesized from Ethyl 2-amino-4,6-dimethylpyridine-3-carboxylate, benzene diazonium chloride, benzene sulphonyl amino isothiocyanate in subsequent reactions. 1-(1, 3-benzothiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidines were synthesized from 1, 3-benzothiazole, 2-thiol, Hydrazine Hydrate, 2-hydrazinyl-1, 3-benzothiazole and aldehydes in subsequent reactions. Twenty-five derivatives pyrimidine scaffolds were designed and performed molecular docking studies for the ability to inhibit the target protein using molecular docking simulation, selective compounds were synthesized and characterized by spectral methods. All the synthesized compounds evaluated for their antioxidant activity and MTT assay exhibited compounds 13c, 13e and 14d can be potential anticancer candidates against MCF-7, Hep G2 and Hela cell lines respectively. Based on all the studies conclude that good agreement was observed between the top-ranked docking scores and top experimental inhibitors when compared with standards ascorbic acid and imatinib. Hence, the compounds could be considered as new anticancer hits for further lead optimization.
Cite this article:
M. Sathish Kumar, M. Vijey Aanandhi. Design, Molecular docking, Synthesis and Biological evaluation of 5, 7 dimethyl pyrido(2, 3-d)pyrimidin-4-one and 4,5 dihydro pyrazolo (3, 4-d) pyrimidines for cytotoxic activity. Research Journal of Pharmacy and Technology. 2021; 14(6):3029-8. doi: 10.52711/0974-360X.2021.00530
M. Sathish Kumar, M. Vijey Aanandhi. Design, Molecular docking, Synthesis and Biological evaluation of 5, 7 dimethyl pyrido(2, 3-d)pyrimidin-4-one and 4,5 dihydro pyrazolo (3, 4-d) pyrimidines for cytotoxic activity. Research Journal of Pharmacy and Technology. 2021; 14(6):3029-8. doi: 10.52711/0974-360X.2021.00530 Available on: https://rjptonline.org/AbstractView.aspx?PID=2021-14-6-20
1. Tageldin GN, Fahmy SM, Ashour HM, Khalil MA, Nassra RA, Labouta IM. Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidines as anti-inflammatory agents. Bioorg Chem 2018; 78: 358-71.
2. Shah SS, Rivera G, Ashfaq M. Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoral, anti-bacterial and anti-inflammatory agents. Mini Rev Med Chem 2013; 13: 70-86.
3. Keche AP, Hatnapure GD, Tale RH, Rodge AH, Birajdar SS, Kamble VM. Novel pyramidine derivatives with aryl urea, thiourea and sulfonamide moieties: Synthesis, anti- inflammatory and antimicrobial evaluation. Bioorg Med Chem Lett 2012; 22: 3445-8.
4. Rostom SA, Ashour HM, Abd El Razik HA. Synthesis and biological evaluation of some novel polysubstituted pyrimidine derivatives as potential antimicrobial and anticancer agents. Arch Pharm (Weinheim) 2009; 342: 299-310.
5. Nassar E, El-Badry YA, Eltoukhy AM, Ayyad RR. Synthesis, in vitro antitumor and antimicrobial activity of some pyrazoline, pyridine and pyrimidine derivatives linked to indole moiety. J Am Sci 2010; 6: 463-71.
6. Hajimahdi Z, Zabihollahi R, Aghasadeghi MR, Zarghi A. Design, Synthesis, Docking Studies and Biological Activities Novel 2, 3-Diaryl-4-Quinazolinone Derivatives as Anti-HIV-1 Agents. Current HIV research. 2019 May 1; 17(3): 214-22.
7. Gadhachanda VR, Wu B, Wang Z, Kuhen KL, Caldwell J, Zondler H, et al. 4-Amino-pyrimidines as novel HIV-1 inhibitors. Bioorg Med Chem Lett 2007; 17: 260-5.
8. Pretorius SI, Breytenbach WJ, de Kock C, Smith PJ, N’Da DD. Synthesis, characterization and antimalarial activity of quinoline–pyrimidine hybrids. Bioorg Med Chem 2013; 21: 269-77.
9. Oliveira R, Guedes RC, Meireles P, Albuquerque IS, Gonçalves LM, Pires E, Bronze MR, Gut J, Rosenthal PJ, Prudêncio M, Moreira R. Tetraoxane–pyrimidine nitrile hybrids as dual stage antimalarials. Journal of Medicinal Chemistry. 2014 Jun 12; 57(11) :4916-23.
10. Mishra S, Singh P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. European Journal of Medicinal Chemistry. 2016 Nov 29; 124: 500-36.
11. Rashad AE, Mahmoud AE, Ali MM. Synthesis and anticancer effects of some novel pyrazolo [3, 4-d] pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells. European Journal of Medicinal Chemistry. 2011 Apr 1; 46(4): 1019-26.
12. Akhtar J, Khan AA, Ali Z, Haider R, Yar MS. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. European journal of medicinal chemistry. 2017 Jan 5; 125: 143-89.
13. Kamal A, Reddy JS, Ramaiah MJ, Dastagiri D, Bharti EV, Sagar MV, et al. Design, synthesis and biological evaluation of imidazopyridine/ pyrimidinechalcone derivatives as potential anticancer agents. Med Chem Commun 2010; 1: 355-60.
14. Shi JB, Tang WJ, Li R, Liu XH. Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: Synthesis and anticancer activity. Eur J Med Chem 2015; 90: 889-96.
15. Wang S, Meades C, Wood G, Osnowski A, Anderson S, Yuill R, Thomas M, Mezna M, Jackson W, Midgley C, Griffiths G. 2-Anilino-4-(thiazol-5-yl) pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity. Journal of Medicinal Chemistry. 2004 Mar 25; 47(7): 1662-75.
16. Joshi T, Pierroz V, Mari C, Gemperle L, Ferrari S, Gasser G. A Bis (dipyridophenazine)(2‐(2‐pyridyl) pyrimidine‐4‐carboxylic acid) ruthenium (II) Complex with Anticancer Action upon Photodeprotection. Angewandte Chemie International Edition. 2014 Mar 10; 53(11): 2960-3.
17. Kamal A, Tamboli JR, Nayak VL, Adil SF, Vishnuvardhan MV, Ramakrishna S. Synthesis of pyrazolo [1, 5-a] pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents. Bioorganic and Medicinal Chemistry Letters. 2013 Jun 1; 23(11): 3208-15.
18. Secrieru A, O’Neill PM, Cristiano ML. Revisiting the Structure and Chemistry of 3 (5)-Substituted Pyrazoles. Molecules. 2020 Jan; 25(1):42.
19. Kumar S, Narasimhan B. Therapeutic potential of heterocyclic pyrimidine scaffolds. Chemistry Central Journal. 2018 Dec 1;12(1): 38.
20. Deadman BJ, Hopkin MD, Baxendale IR, Ley SV. The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib. Organic and Biomolecular Chemistry. 2013; 11(11): 1766-800.
21. Zhao LM, Guo Z, Xue YJ, Min JZ, Zhu WJ, Li XY, Piao HR, Jin CH. Synthesis and evaluation of 3-substituted-4-(quinoxalin-6-yl) pyrazoles as TGF-β type I receptor kinase inhibitors. Molecules. 2018 Dec; 23(12): 3369.
22. Bacelar AH, Carvalho MA, Proença MF. Synthesis and in vitro evaluation of substituted pyrimido [5, 4-d] pyrimidines as a novel class of Antimycobacterium tuberculosis agents. European Journal of Medicinal Chemistry. 2010 Jul 1; 45(7): 3234-9.
23. Schenone S, Bruno O, Ranise A, Bondavalli F, Brullo C, Fossa P, Mosti L, Menozzi G, Carraro F, Naldini A, Bernini C. New pyrazolo [3, 4-d] pyrimidines endowed with A431 antiproliferative activity and inhibitory properties of Src phosphorylation. Bioorganic and Medicinal Chemistry Letters. 2004 May 17; 14(10): 2511-7.
24. Matyugina E, Khandazhinskaya A, Chernousova L, Andreevskaya S, Smirnova T, Chizhov A, Karpenko I, Kochetkov S, Alexandrova L. The synthesis and antituberculosis activity of 5′-nor carbocyclic uracil derivatives. Bioorganic and Medicinal Chemistry. 2012 Nov 15; 20(22): 6680-6.
25. Siddiqui AB, Trivedi AR, Kataria VB, Shah VH. 4, 5-Dihydro-1H-pyrazolo [3, 4-d] pyrimidine containing phenothiazines as antitubercular agents. Bioorganic and Medicinal Chemistry Letters. 2014 Mar 15; 24(6): 1493-5.
26. Gangjee A, Zaware N, Raghavan S, Yang J, Thorpe JE, Ihnat MA. N4-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo [2, 3-d] pyrimidines as potent multiple receptor tyrosine kinase inhibitors: Design, synthesis, and in vivo evaluation. Bioorganic and Medicinal Chemistry. 2012 Apr 1; 20(7): 2444-54.
27. Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL. Novel tricyclic indeno [2, 1-d] pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorganic and Medicinal Chemistry. 2012 Jul 15; 20(14): 4217-25.
28. Fares M, Abou-Seri SM, Abdel-Aziz HA, Abbas SE, Youssef MM, Eladwy RA. Synthesis and antitumor activity of pyrido [2, 3-d] pyrimidine and pyrido [2, 3-d][1, 2, 4] triazolo [4, 3-a] pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest. European Journal of Medicinal Chemistry. 2014 Aug 18; 83: 155-66.
29. Kalyukina M, Yosaatmadja Y, Middleditch MJ, Patterson AV, Smaill JB, Squire CJ. TAS‐120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. Chem Med Chem. 2019 Feb 19; 14(4): 494-500.
30. Loidreau Y, Marchand P, Dubouilh-Benard C, Nourrisson MR, Duflos M, Lozach O, Loaec N, Meijer L, Besson T. Synthesis and biological evaluation of N-arylbenzo [b] thieno [3, 2-d] pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors. European Journal of Medicinal Chemistry. 2012 Dec 1; 58: 171-83.
31. Said SA, Amr AE, Sabry NM, Abdalla MM. Analgesic, anticonvulsant and anti-inflammatory activities of some synthesized benzodiazipine, triazolopyrimidine and bis-imide derivatives. European Journal of Medicinal Chemistry. 2009 Dec 1;44(12): 4787-92.
32. El Azab IH, Khaled KM. Synthesis and reactivity of enaminone of naphtho [b] 1, 4-oxazine: One pot synthesis of novel isolated and heterocycle-fused derivatives with antimicrobial and antifungal activities. Russian Journal of Bioorganic Chemistry. 2015 Jul 1; 41(4): 421-36.
33. Roopan SM, Sompalle R. Synthetic chemistry of pyrimidines and fused pyrimidines: A review. Synth Commun 2016; 46: 645-72.
34. Raghunath SA, Manjunatha Y, Rayappa K. Synthesis, antimicrobial, and antioxidant activities of some new indole analogues containing pyrimidine and fused pyrimidine systems. Med Chem Res 2012; 21: 3809-17.
35. Aly AA, Ramadan M, Mohamed AM, Ishak EA. Thieno[2, 3-d]pyrimidines in the synthesis of new fused heterocyclic compounds of prospective antitumor and antioxidant agents. J Heterocyclic Chem 2012; 49: 1009-18.
36. Abunada NM, Hassaneen HM, Kandile NG, Miqdad OA. Synthesis and biological activity of some new pyrazoline and pyrrolo [3, 4-c] pyrazole-4, 6-dione derivatives: reaction of nitrilimines with some dipolarophiles. Molecules 2008; 13: 1011-24.
37. Ismail NS, Ibrahim DA, Serya RA. Pyrazolo [3, 4-d] pyrimidine based scaffold derivatives targeting kinases as anticancer agents. Future J Pharm Sci 2016; 2: 20-30.
38. Shanmugasundaram P, Aanandini MV, M Satish. Synthesis and biological evaluation of pyrido(2, 3-d)pyrimidine- carboxylate derivatives. Ind J Chem 2011; 50B: 284-9.
39. Kumar D, Khan SI, Tekwani BL, Diwan PP, Rawat S. 4-Aminoquinoline-pyrimidine hybrids: Synthesis, antimalarial activity, heme binding and docking studies. Eur J Med Chem 2015; 89: 490-502.
40. B.C. Revanasiddappa, M. Vijay Kumar, Hemanth Kumar, Synthesis and antioxidant activity of novel pyrazoline derivatives, Hygeia.J.D.Med.10 (1) August 2018; 43-49
41. Rahul. R, Rakesh Kumar Jat, J. Saravanan, Synthesis, and invitro antioxidant activity of novel 1, 3, 4-oxadiazole-2-thione, JIPBS, Vol 3(3), 114-122, 2016
42. Venkanna, B. Siva, B. Poornima, P.R. Rao Vadaparthi, K. Rajendra Prasad, K. Ashok Reddy, G. Bhanu Prakash Reddy, K. Suresh Babu, Phytochemical investigation of sesquiterpenes from the fruits of Schisandrachinensis and their cytotoxic activity, Fitoterapia 95 (2014) 102–108.