Synthesis, anti-tubercular evaluation and molecular docking studies of Nitrogen-rich piperazine-pyrimidine-pyrazole Hybrid Motifs

Vavaiya, B.; Patel, S.; Pansuriya, V.; Marvaniya, V.; Patel, P.

Growing Science » Current Chemistry Letters » Synthesis, anti-tubercular evaluation and molecular docking studies of Nitrogen-rich piperazine-pyrimidine-pyrazole Hybrid Motifs

Journals

CCL Volumes

Volume 1 (23)
- Issue 1 (7)
- Issue 2 (5)
- Issue 3 (6)
- Issue 4 (5)

Volume 2 (26)
- Issue 1 (7)
- Issue 2 (6)
- Issue 3 (6)
- Issue 4 (7)

Volume 3 (30)
- Issue 1 (7)
- Issue 2 (10)
- Issue 3 (8)
- Issue 4 (5)

Volume 4 (21)
- Issue 1 (5)
- Issue 2 (5)
- Issue 3 (6)
- Issue 4 (5)

Volume 5 (20)
- Issue 1 (5)
- Issue 2 (5)
- Issue 3 (5)
- Issue 4 (5)

Volume 6 (20)
- Issue 1 (5)
- Issue 2 (5)
- Issue 3 (5)
- Issue 4 (5)

Volume 7 (15)
- Issue 1 (4)
- Issue 2 (4)
- Issue 3 (4)
- Issue 4 (3)

Volume 8 (20)
- Issue 1 (5)
- Issue 2 (5)
- Issue 3 (5)
- Issue 4 (5)

Volume 9 (20)
- Issue 1 (5)
- Issue 2 (5)
- Issue 3 (5)
- Issue 4 (5)

Volume 10 (43)
- Issue 1 (5)
- Issue 2 (7)
- Issue 3 (17)
- Issue 4 (14)

Volume 11 (43)
- Issue 1 (14)
- Issue 2 (11)
- Issue 3 (10)
- Issue 4 (8)

Volume 12 (78)
- Issue 1 (21)
- Issue 2 (22)
- Issue 3 (20)
- Issue 4 (15)

Volume 13 (68)
- Issue 1 (23)
- Issue 2 (17)
- Issue 3 (16)
- Issue 4 (12)

Volume 14 (20)
- Issue 1 (20)

Countries

Current Chemistry Letters

ISSN 1927-730x (Online) - ISSN 1927-7296 (Print) Quarterly Publication Volume 11 Issue 1 pp. 95-104 , 2022

Synthesis, anti-tubercular evaluation and molecular docking studies of Nitrogen-rich piperazine-pyrimidine-pyrazole Hybrid Motifs Pages 95-104 Download PDF

Authors: Bhavinkumar Vavaiya, Shivani Patel, Vrajlal Pansuriya, Vanita Marvaniya, Popatbhai Patel

DOI: 10.5267/j.ccl.2021.9.001

Keywords: Pyrimidine, Pyrazole, Piperazine, Molecular Docking, Antitubercular Activity

Abstract: A convenient and efficient synthesis of a series of ethyl-1-(6-(4-substitutedacetylatedpiperazin-1-yl)pyrimidin-4-yl)-5-amino-1H-pyrazole-4-carboxylate (8a-8j) has been developed by five steps which include activation of a methylene group, hydrazinolysis, cyclisation and chloro-amine coupling reactions. Moreover, our proposed mechanism was confirmed in this study demonstrating that ethyl 5-amino-1-(6-chloropyrimidin-4-yl)-1H-pyrazole-4-carboxylate is the key intermediate to fulfill the desired outcomes. In silico and in vitro studies were carried out to identify the active agents among the developed adducts against mycobacterium tuberculosis (PDB ID:4TRO). Compound 8a (Docking Score: -26.81 and MIC: 1.6 ug/mL) was found to be the most potent among the synthesized molecules. All the synthesized compounds showed acceptable drug-like properties which make them suitable for further lead modification using in silico design approaches.

How to cite this paper

 Vavaiya, B., Patel, S., Pansuriya, V., Marvaniya, V & Patel, P. (2022). Synthesis, anti-tubercular evaluation and molecular docking studies of Nitrogen-rich piperazine-pyrimidine-pyrazole Hybrid Motifs.Current Chemistry Letters, 11(1), 95-104.

Refrences

1. Singh, R., Dwivedi, S., Gaharwar, U., Meena, R., Rajamani, P., Prasad, T. (2020) Recent updates on drug resistance in Mycobacterium tuberculosis. J ApplMicrobiol, 128 (6) 1547-1567.
2. Grzelak, E.M., Choules, M.P., Gao, W. (2019) Strategies in anti-Mycobacterium tuberculosis drug discovery based on phenotypic screening. J Antibiot, 72 (1) 719-728.
3. Petersen, E., Maeurer, M., Marais, B., Migliori, G., Mwaba, P., Ntoumi, F., Vilaplana, C., Kim, K., Schito, M., Zumla, A. (2017) World TB day 2017: advances, challenges and opportunities in the “End-TB” era. Int J Infect Dis., 56 (1) 1-5.
4. Matteelli, A., Rendon, A., Tiberi, S., Abri, S.-A., Voniatis, C., Cristina, A., Carvalho, C., Centis, R. (2018) Tuberculosis elimination: where are we now? EurRespir Rev., 27 (148) 180035.
5. Kapadiya, K.,Kavadia, K.,Manvar, P.,Khunt, R.(2015) Synthesis of Nitrogen and Oxygen based Pyrazole Derivatives and Its Antitubercular and Antimicrobial Activity. Anti-Infect. Agents, 13 (2) 129-138.
6. Kerru, N.; Gummidi, L.; Maddila, S.; Gangu, K.K.; Jonnalagadda, S.B. (2020) A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications. Molecules, 25 (8) 1909.
7. Kalaria, P.N.,Karad, S.C.,Raval, D.K. (2018) A review on diverse heterocyclic compounds as the privileged scaffolds in antimalarial drug discovery. Eur. J. Med. Chem., 158 (1) 917-936.
8. Kerru, N., Maddila, S., Jonnalagadda, S.B. (2019) Design of carbon–carbon and carbon–heteroatom bond formation reactions under green conditions. Curr. Org. Chem., 23 (28) 3156-3192.
9. Tomar, A., Mall, A.,Verma, M. (2011) Piperazine: the molecule of diverse pharmacological importance. Int. J. Res. Ayurveda Pharm.. 2 (5) 1547-1548.
10. Kumar, H., Saini, D., Jain, S., Jain, N. (2013) Pyrazole scaffold: a remarkable tool in the development of anticancer agents. Eur. J. Med. Chem., 70, 248-258.
11. Gomha, S.,Edrees, M.,Faty, R., Muhammad, Z.,Mabkhot, Y. (2017) Chem. Cent. J., 11 (37) 1-12.
12. Aggarwal, R., Bansal, A.,Rozas, I., Kelly, B.,Kaushik, P.,Kaushik, D. (2013) Synthesis, biological evaluation and molecular modeling study of 5-trifluoromethyl-Δ²-pyrazoline and isomeric 5/3-trifluoromethylpyrazole derivatives as anti-inflammatory agents. Eur. J. Med. Chem., 70, 350-357.
13. Mukarram, S.,Bandgar, B. P., Shaikh, R. U.,Ganapure, S. D., Chavan, H. V. (2017) Synthesis of novel α,α-diﬂuoro-β-hydroxycarbonylpyrazolederivatives as antioxidant, anti-inﬂammatory and anticanceragents. Med. Chem. Res., 26 (1) 262-273.
14. Aggarwal, R., Bansal, A.,Rozas, I.,Diez-Cecilia, E., Kaur, A., Mahajan, R., Sharma, J. (2014) p-Toluenesulfonic acid-catalyzed solvent-free synthesis and biological evaluation of new 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazole derivatives. Med. Chem. Res., 23 (3) 1454–1464.
15. Aggarwal, R., Kumar, R., Kumar, S.,Garg, G., Mahajan, R., Sharma, J. (2011) Synthesis and antibacterial activity of some 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides, 3-trifluoromethylpyrazol-1-thiocarboxamides and 4-aryl-2-(5(3)-trifluoromethyl-1-pyrazolyl)thiazoles. J. Fluorine Chem., 132 (11) 965-972.
16. Aggarwal, R., Kumar, V., Gupta, G. K., Kumar, V. (2013) Synthesis of some new 3,5-diamino-4-(4'-fluorophenylazo)-1-aryl/heteroarylpyrazoles as antimicrobial agents. Med. Chem. Res., 22 (8) 3566-3573.
17. Yadava, U., Shukla, B. K.,Roychoudhury, M., Kumar, D. (2015) Pyrazolo[3,4-d]pyrimidines as novel inhibitors of O-acetyl-L-serine sulfhydrylase of Entamoebahistolytica: an in silico study. J. Mol. Model., 21 (4) 96-108.
18. Manikannan, R.,Venkatesan, R.,Muthusubramanian, S.,Yogeeswari, P.,Sriram, D. (2010) Pyrazole derivatives from azines of substituted phenacyl aryl/cyclohexyl sulfides and their antimycobacterial activity. Bioorg. Med. Chem. Lett., 20 (23) 6920-6924.
19. Özdemir, A.,Altıntop, M. D.,Kaplancıklı, Z. A., Can, Ö. D.,Özkay, Ü. D.,Turan-Zitouni, G. (2015) Synthesis and Evaluation of New 1,5-Diaryl-3-[4-(methyl-sulfonyl)phenyl]-4,5-dihydro-1H-pyrazole Derivatives as Potential Antidepressant Agents. Molecules, 20 (2) 2668–2684.
20. Cieplik, J., Stolarczyk, M., Pluta, J., Gubrynowicz, O., Bryndal, I., Lis, T., Mikulewicz, M. (2015) Synthesis and antibacterial properties of pyrimidine derivatives. Acta Pol Pharm., 72 (1) 53-64.
21. Alptuzun, V., Cakiroglu, G., Limoncu, M.E., Erac, B., Hosgor-Limoncu, M., Erciyas, E. (2013) Synthesis and antileishmanial activity of novel pyridinium-hydrazone derivatives. J Enzyme Inhib Med Chem., 28 (5) 960-967.
22. Reddy, B. N., Ruddarraju, R. R., Kiran, G., Pathak, M., Reddy, A. R. (2019) NovelPyrazolo[3,4‐d]pyrimidine‐Containing Amide Derivatives: Synthesis, Molecular Docking, In Vitro and In Vivo Antidiabetic Activity. ChemistrySelect, 4 (34) 10072–10078
23. Abu-Hashem, A. A., Youssef, M. M., Hussein, H. A. R. (2011) Synthesis, Antioxidant, Antituomer Activities of Some New Thiazolopyrimidines, Pyrrolothiazolopyrimidines and Triazolopyrrolothiazolopyrimidines Derivatives. Jnl Chin. Chem. Soc.,58 (1) 41–48.
24. Mohamed, A.M., El-Sayed, W.A., Alsharari, M.A., Al-Qalawi, H.R., Germoush, M.O. (2013) Anticancer activities of some newly synthesized pyrazole and pyrimidine derivatives. Arch Pharm Res., 36 (9) 1055-1065.
25. Ortner, N.J., Striessnig, J. (2016) L-type calcium channels as drug targets in CNS disorders. Channels (Austin)10(1)7-13.
26. Alam, O., Khan, S.A., Siddiqui, N., Ahsan, W., Verma, S.P., Gilani, S.J. (2010) Antihypertensive activity of newer 1,4-dihydro-5-pyrimidine carboxamides: synthesis and pharmacological evaluation. Eur J Med Chem., 45 (11) 5113-5119.
27. Kapadiya, K., Khunt R. (2019) Discovery of hybrid purine-quinoline molecules and their cytotoxic evaluation. Lett Drug Des Discov.,16 (1) 21-28.
28. Ismail, N., Ali, G., Ibrahim, D., Elmetwali, A. (2016) Medicinal attributes of pyrazolo[1,5-a]pyrimidine based scaffold derivatives targeting kinases as anticancer agents. Future J. Pharm. Sci., 2 (2) 60-70.
29. Thriveni, K., Padmashali, B., Siddesh, M., Sandeep, C. (2014) Synthesis of Pyrimidine Incorporated Piperazine Derivatives and their Antimicrobial Activity. Indian J. Pharm. Sci., 76 (4) 267-378.
30. Claudio, V., Amanda, D.,Vanderlan, B., Eliezer, B., Carlos, F. (2007). Molecular Hybridization: A Useful Tool in the Design of New Drug Prototypes. Curr. Med. Chem.,14 (17) 1829-1852.