Author(s):
Dipanjan Karati, Shankar Thapa, Mahalakshmi Suresha Biradar
Email(s):
karatibabai@gmail.com , tshankar551@gmail.com , mahalakshmisb12@gmail.com
DOI:
10.52711/0974-4150.2024.00048 
Address:
Dipanjan Karati1*, Shankar Thapa2, Mahalakshmi Suresha Biradar3
1Department of Pharmaceutical Technology, School of Pharmacy, Techno India University, Kolkata, West Bengal, 700091, India.
2Department of Pharmaceutical Technology, Department of Pharmaceutical Technology, Universal College of Medical Science, Siddharthnagar, 32900, Nepal.
3Department of Pharmaceutical Technology, Al-Ameen College of Pharmacy, Bengaluru, 560027, India.
*Corresponding Author
Published In:
Volume - 17,
Issue - 5,
Year - 2024
ABSTRACT:
This study demonstrates the scope for N-(5-cyano-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-yl)-2-(phenylamino)acetamide to develop as promising anticancer agents. Several N-(5-cyano-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-yl)-2-(phenylamino)acetamide derivatives were synthesized by reflux method and assessed their anticancer activity by in silico research. The yield of the compounds was moderate to high. The functional groups were measured by the IR ranges at 3300cm-1 (NH), 1656 cm-1 (CO) and 1180 (C=S) wavelength. The synthesized compounds have high binding energy against 7A2A protein as an EGFR inhibitor. Compound C2 and C4 showed best affinity of -7.7 and -7.2kcal/mol, correspondingly. The molecules have been tested for their toxicity. The result shows that all the compounds have affinity towards the EGFR protein. The toxicity prediction suggests that all the synthesized substances are relatively safe, having a low likelihood of causing harm at the given doses.
Cite this article:
Dipanjan Karati, Shankar Thapa, Mahalakshmi Suresha Biradar. Synthesis, and Evaluation of Novel N-(5-cyano-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-yl)-2-(phenylamino) acetamide derivatives by In silico investigations as an anticancer scaffold. Asian Journal of Research in Chemistry.2024; 17(5):278-4. doi: 10.52711/0974-4150.2024.00048
Cite(Electronic):
Dipanjan Karati, Shankar Thapa, Mahalakshmi Suresha Biradar. Synthesis, and Evaluation of Novel N-(5-cyano-6-phenyl-2-thioxo-2,3-dihydropyrimidin-4-yl)-2-(phenylamino) acetamide derivatives by In silico investigations as an anticancer scaffold. Asian Journal of Research in Chemistry.2024; 17(5):278-4. doi: 10.52711/0974-4150.2024.00048 Available on: https://ajrconline.org/AbstractView.aspx?PID=2024-17-5-4
6. REFERENCES:
1. WHO, “Cancer,” WHO, 2023. https://www.who.int/health-topics/cancer#tab=tab_1 (accessed Apr. 07, 2024).
2. Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Molecular Cancer. 2018; 17: 1-9. doi: 10.1186/s12943-018-0793-1.
3. Bou Antoun N, Chioni AM. Dysregulated signalling pathways driving anticancer drug resistance. International Journal of Molecular Sciences. 2023; 24(15): 12222. doi: 10.3390/ ijms241512222.
4. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers. 2017; 9(5): 52, doi: 10.3390/cancers9050052.
5. Zubair T, Bandyopadhyay D. Small molecule EGFR inhibitors as anti-cancer agents: discovery, mechanisms of action, and opportunities. International Journal of Molecular Sciences. 2023 Jan 31; 24(3): 2651, doi: 10.3390/ijms24032651.
6. Jain MS, Barhate SD, Shimpi RD. Mobocertinib is an Oral kinase inhibitor targeted against EGFR and used in the treatment of Non-small cell Lung cancer: A Review. Asian Journal of Pharmaceutical Research. 2022; 12(2): 179-82.
7. Dhivya S, Gangopadhyay S, Kumar SP, Sarkar G. Serum creatinine and eGFR are affected in female hypothyroid patients with poor Thyroid control. Asian Journal of Pharmacy and Technology. 2020; 10(4): 241-4.
8. Cascone T, Morelli MP, Ciardiello F. Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer. Annals of Oncology. 2006; 17: ii46-8, doi: 10.1093/annonc/mdj921.
9. Naishima NL, Faizan S, Raju RM, Sruthi AS, Veena NG, Sharma GK, Vasanth KS, Shivaraju VK, Ramu R, Kumar BP. Design, synthesis, analysis, evaluation of cytotoxicity against MCF-7 breast cancer cells, 3D QSAR studies and EGFR, HER2 inhibition studies on Novel Biginelli 1, 4-dihydropyrimidines. Journal of Molecular Structure. 2023; 1277: 134848, doi: 10.1016/ j.molstruc.2022.134848.
10. Elzahabi HS, Nossier ES, Alasfoury RA, El-Manawaty M, Sayed SM, Elkaeed EB, Metwaly AM, Hagras M, Eissa IH. Design, synthesis, and anti-cancer evaluation of new pyrido [2, 3-d] pyrimidin-4 (3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers. Journal of Enzyme Inhibition and Medicinal Chemistry. 2022; 37(1): 1053-76. doi: 10.1080/14756366.2022.2062752.
11. Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X. Discovery of 4, 6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC. European Journal of Medicinal Chemistry. 2020; 187: 111943, doi: 10.1016/ j.ejmech.2019.111943.
12. Yadav TT, Moin Shaikh G, Kumar MS, Chintamaneni M, Yc M. A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship. Frontiers in Chemistry. 2022; 10: 861288, doi: 10.3389/fchem.2022.861288.
13. Wang YT, Yang PC, Zhang JY, Sun JF. Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy. Molecules. 2024; 29(7): 1448. doi: 10.3390/molecules29071448.
14. M. K. Mahapatra MK. Karuppasamy M. Fundamental considerations in drug design, no. January. 2022.
15. Lin X, Li X, Lin X. A review on applications of computational methods in drug screening and design. Molecules. 2020 Mar 18; 25(6): 1375. doi: 10.3390/molecules25061375.
16. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017 Mar 3; 7(1): 42717, doi: 10.1038/srep42717.
17. Morak-Młodawska B, Jeleń M, Martula E, Korlacki R. Study of lipophilicity and ADME properties of 1, 9-diazaphenothiazines with anticancer action. International Journal of Molecular Sciences. 2023 Apr 9; 24(8): 6970, doi: 10.3390/ijms24086970.
18. Niggenaber J, Heyden L, Grabe T, Müller MP, Lategahn J, Rauh D. Complex crystal structures of EGFR with third-generation kinase inhibitors and simultaneously bound allosteric ligands. ACS Medicinal Chemistry Letters. 2020 Nov 5; 11(12): 2484-90, doi: 10.1021/acsmedchemlett.0c00472.
19. Mendelsohn LD. ChemDraw 8 ultra, windows and macintosh versions. Journal of chemical information and computer sciences. 2004 Nov 22; 44(6): 2225-6, doi: 10.1021/ci040123t.
20. O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. Journal of cheminformatics. 2011 Dec; 3: 1-4.
21. Madhavi Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. Journal of computer-aided molecular design. 2013 Mar; 27: 221-34, doi: 10.1007/s10822-013-9644-8.
22. Sriharsha SN, Jainab NH, Biradar MS, Thapa S, Venkatesh ES, Bidye DP, Pujar G, Dixit S. Novel β-L-1, 3-thiazolidine pyrimidine nucleoside analogues: Design, synthesis, molecular docking, and anti-HIV activity. Journal of Molecular Structure. 2023 Dec 15; 1294: 136304. doi: 10.1016/j.molstruc.2023.136304.
23. Gazgalis D, Zaka M, Abbasi BH, Logothetis DE, Mezei M, Cui M. Protein binding pocket optimization for virtual high-throughput screening (vHTS) drug discovery. ACS omega. 2020 Jun 10; 5(24): 14297-307, doi: 10.1021/acsomega.0c00522.
24. Gote S, Thapa S, Dubey S, Nargund SL, Biradar MS. Computational investigation of quinazoline derivatives as Keap1 inhibitors for Alzheimer's disease. Informatics in Medicine Unlocked. 2023 Jan 1; 41: 101334, doi: 10.1016/ j.imu.2023.101334.
25. Otuokere IE, Amaku FJ, Alisa CO. In silico geometry optimization, excited-state properties of (2E)-N-Hydroxy-3-[3-(Phenylsulfamoyl) Phenyl] prop-2-enamide (Belinostat) and its molecular docking studies with Ebola Virus glycoprotein. Asian Journal of Pharmaceutical Research. 2015; 5(3): 131-7.
26. Patadiya N, Vaghela V. Design, in-silico ADME Study and molecular docking study of novel quinoline-4-on derivatives as Factor Xa Inhibitor as Potential anti-coagulating agents. Asian Journal of Pharmaceutical Research. 2022; 12(3): 207-11.
27. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry. 2010 Jan 30; 31(2): 455-61, doi: 10.1002/jcc.21334.
28. Pawar S, Kulkarni C, Gadade P, Pujari S, Kakade S, Rohane SH, Redasani VK. Molecular Docking using different Tools. Asian Journal of Pharmaceutical Research. 2023 Dec 1; 13(4).
29. Shinde SA, Mhetar MJ, Parit AG, Thombre AR. In-silico investigation and ADMET prediction of potential antifungal phytochemicals against lanosterol 14-alpha demethylase inhibitors. Asian Journal of Pharmaceutical Research. 2024; 14(1): 33-8.
30. Thapa S, Nargund SL, Biradar MS. Molecular design and in-silico analysis of trisubstituted benzimidazole derivatives as ftsz inhibitor. Journal of Chemistry. 2023 Mar 1; 2023: 1-9, doi: 10.1155/2023/9307613.
31. Seeliger D, de Groot BL. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. Journal of computer-aided molecular design. 2010 May; 24(5): 417-22 doi: 10.1007/s10822-010-9352-6.
32. Pant L, Thapa S, Dahal B, Khadka R, Biradar MS. In Silico and In Vitro Studies of Antibacterial Activity of Cow Urine Distillate (CUD). Evidence-Based Complementary and Alternative Medicine. 2024 Jan 8;2024, doi: https://doi.org/10.1155/2024/ 1904763.
33. Lagunin A, Stepanchikova A, Filimonov D, Poroikov V. PASS: prediction of activity spectra for biologically active substances. Bioinformatics. 2000 Aug; 16(8): 747-8, doi: 10.1093/ bioinformatics/16.8.747.
34. Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV, Poroikov VV. Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chemistry of Heterocyclic Compounds. 2014 Jun; 50: 444-57, doi: 10.1007/s10593-014-1496-1.
35. Drwal MN, Banerjee P, Dunkel M, Wettig MR, Preissner R. ProTox: a web server for the in silico prediction of rodent oral toxicity. Nucleic acids research. 2014 Jul 1; 42(W1): W53-8, doi: 10.1093/nar/gku401.
36. Thapa S, Biradar MS, Nargund SL, Ahmad I, Patel H, Lamsal A. Synthesis, molecular docking, molecular dynamic simulation studies, and anti-tubercular activity evaluation of substituted benzimidazole derivatives, doi: 10.1155/2024/9986613.
37. Waters LJ, Quah XL. Predicting skin permeability using HuskinDB. Scientific data. 2022 Sep 23; 9(1): 584, doi: 10.1038/s41597-022-01698-4.
38. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews. 1997 Jan 15;23(1-3):3-25, doi: 10.1016/j.addr.2012.09.019.
39. Morris-Schaffer K, McCoy MJ. A review of the LD50 and its current role in hazard communication. ACS Chemical Health & Safety. 2020 Dec 21; 28(1): 25-33, doi: 10.1021/acs.chas.0c00096.
40. Tripathi J, Mahto MK, Bhaskar M, Shahbazi S. Molecular docking and toxicity analysis of novel atorvastatin structural analogues with HMG-CoA reductase. Asian Journal of Research In Chemistry. 2012; 5(3): 386-9.
41. Sravani M, Duganath N, Gade DR, Reddy CH. Insilico analysis and docking of imatinib derivatives targeting BCR-ABL oncoprotein for chronic myeloid leukemia. Asian Journal of Research in Chemistry. 2012; 5(1): 153-8.
42. Govindammal M, Prasath M, Sathya B, Selvapandiyan M. Investigation on the Binding Interaction Between Clomipramine and Doxepin with LeuT by Molecular Docking Analysis. Asian Journal of Research in Chemistry. 2017; 10(4): 486-90.
43. Chauhan R, D'Souza HL, Shabnam RS, Abraham J. Phytochemical and cytotoxicity analysis of seeds and leaves of Adenanthera pavonina. Research Journal of Pharmacy and Technology. 2015; 8(2): 198-203.