Design, Synthesis and Therapeutic Potential of Some 6, 6'-(1,4- phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine)analogues

Author(s): Sanjiv Kumar, Balasubramanian Narasimhan*, Siong Meng Lim, Kalavathy Ramasamy, Vasudevan Mani, Syed Adnan Ali Shah.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: A series of 6, 6'-(1,4-phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine) derivatives has been synthesized by Claisen-Schmidt condensation and its chemical structures was confirmed by FT-IR, 1H/13C-NMR spectral and elemental analyses. The molecular docking study was carried out to find the interaction between active bis-pyrimidine compounds with CDK-8 protein. The in vitro antimicrobial potential of the synthesized compounds was determined against Gram-positive and Gram-negative bacterial species as well fungal species by tube dilution technique. Antimicrobial results indicated that compound 11y was found to be most potent one against E. coli (MICec = 0.67 µmol/mL) and C. albicans (MICca = 0.17 µmol/mL) and its activity was comparable to norfloxacin (MIC = 0.47 µmol/mL) and fluconazole (MIC = 0.50 µmol/mL), respectively.

Conclusion: Anticancer screening of the synthesized compounds using Sulforhodamine B (SRB) assay demonstrated that compounds 2y (IC50 = 0.01 µmol/mL) and 4y (IC50= 0.02 µmol/mL) have high antiproliferative potential against human colorectal carcinoma cancer cell line than the reference drug (5- fluorouracil) and these compounds also showed best dock score with better potency within the ATP binding pocket and may also be used lead for rational drug designing.

Keywords: Antimicrobial, antiproliferative, bis-pyrimidines, molecular docking, synthesis, C. albicans.

Borodina, E.A.; Orlova, N.A.; Gatilov, Y.V.; Salnikova, O.I. Reaction of polyfluorinated chalcones with guanidine. Russ. J. Org. Chem., 2015, 51(12), 1745-1752.
Kumar, S.; Lim, S.M.; Ramasamy, K.; Vasudevan, M.; Shah, S.A.A.; Narasimhan, B. Bis-pyrimidine acetamides: design, synthesis and biological evaluation. Chem. Cent. J., 2017, 11(80), 1-14.
Cocco, M.T.; Congiu, C.; Onnis, V.; Piras, R. Synthesis and antitumor evaluation of 6-thioxo-, 6-oxo- and 2,4-dioxopyrimidine derivatives. Farmaco, 2001, 56, 741-748.
Meneghesso, S.; Vanderlinden, E.; Stevaert, A.; McGuigan, C.; Balzarini, J.; Naesens, L. Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus. Antiviral Res., 2012, 94, 35-43.
Anupama, B.; Dinda, S.C.; Prasad, Y.R.; Rao, A.V. Synthesis and antimicrobial activity of some new 2,4,6-trisubstituted pyrimidines. Int. J. Res. Pharm. Chem., 2012, 2(2), 231-236.
Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R. Synthesis and anti-inflammatory activities of some thiazolo[3,2-a]pyrimidine derivatives. Farmaco, 1999, 54, 588-593.
Ashour, H.M.; Shaaban, O.G.; Rizk, O.H.; El-Ashmawy, I.M. Synthesis and biological evaluation of thieno [2′,3′:4,5]pyrimido [1,2-b][1,2,4]triazines and thieno [2,3-d][1,2,4]triazolo[1,5-a] pyrimidines as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2013, 62, 341-351.
Chaudhary, A.; Sharma, P.K.; Verma, P.; Dudhe, R. Synthesis of novel pyrimidine derivative and its biological evaluation Analele UniversităŃii din Bucuresti - Chimie (serie nouă), 2011, 20(2), 123-140.
Bhalgat, C.M.; Ali, M.I.; Ramesh, B.; Ramu, G. Novel pyrimidine and its triazole fused derivatives: Synthesis and investigation of antioxidant and anti-inflammatory activity. Arab. J. Chem., 2014, 7, 986-993.
Kumar, D.; Khan, S.I.; Tekwani, B.L.; Diwan, P.P.; Rawat, S. 4-Aminoquinoline-pyrimidine hybrids: Synthesis, antimalarial activity, heme binding and docking studies. Eur. J. Med. Chem., 2015, 89, 490-502.
Kumar, S.; Lim, S.M.; Ramasamy, K.; Vasudevan, M.; Shah, S.A.A.; Selvaraj, M.; Narasimhan, B. Synthesis, molecular docking and biological evaluation of bis-pyrimidine Schiff base derivatives. Chem. Cent. J., 2017, 11(89), 1-16.
Chandrasekaran, S.; Nagarajan, S. Microwave-assisted synthesis and anti-bacterial activity of some 2-amino-6-aryl-4-(2-thienyl)pyrimidines. Farmaco, 2005, 60(4), 279-282.
Fathalla, O.A.; Zeid, I.F.; Haiba, M.E.; Soliman, A.M.; Abd-Elmoez, S.I.; El-Serwy, W.S. Synthesis, antibacterial and anticancer evaluation of some pyrimidine derivatives. World. J. Chem., 2009, 4(2), 127-132.
Nagaraj, A.; Reddy, C.S. Synthesis and biological study of novel bis-chalcones, bis-thiazines and bis-pyrimidines. J. Iran. Chem. Soc., 2008, 5(2), 262-267.
Kandeel, M.M.; Mounir, A.A.; Refaat, H.M.; Kassab, A.E. Synthesis of effective anticancer thieno[2,3-d]pyrimidine-4-ones and thieno[3,2-e]triazolo[4,3-c]pyrimidines. Int. J. Pharm. Pharm. Sci., 2012, 4(3), 438-448.
Abdellatif, K.R.A.; Abdelall, E.K.A.; Abdelgawad, M.A.; Ahmed, R.R.; Bakr, R.B. Synthesis and anticancer activity of some new pyrazolo[3,4-d] pyrimidin-4-one derivatives. Molecules, 2014, 19, 3297-3309.
Saini, M.; Kumar, P.; Kumar, M.; Kalavathy, R.; Mani, V.; Mishra, R.K.; Majeed, A.B.A.; Narasimhan, B. Synthesis, in vitro antimicrobial, anticancer evaluation and QSAR studies of N′-(substituted)-4-(butan-2-lideneamino)benzohydrazides. Arab. J. Chem., 2014, 7(4), 448-460.
Deep, A.; Kumar, P.; Narasimhan, B.; Mishra, R.K.; Mani, V.; Ramasamy, K.; Meng, L.S. 2-Azetidinone derivatives: synthesis, antimicrobial, anticancer evaluation and QSAR studies. Acta. Pol. Pharm. Drug Res., 2016, 73, 65-78.
Asiri, A.M.; Khan, S.A. Synthesis and anti-bacterial activities of a bis-chalcone, derived from thiophene and its bis-cyclized products. Molecules, 2011, 16, 523-531.
Cappuccino, J.C.; Sherman, N. Microbiology-a laboratory manual., Addison Wesley, California, pp 263. 1999.
Pharmacopoeia of India, vol. I. Controller of publication, ministry of health department; Govt. of India, New Delhi, p. 37,. , 2007.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112.
Kaur, R.; Kaur, P.; Sharma, S.; Singh, G.; Mehndiratta, S.; Bedi, P.M.S.; Nepali, K. Anti-cancer pyrimidines in diverse scaffolds: a review of patent literature. Recent Pat. Anti-Canc, 2015, 10(1), 23-71.
Singh, J.; Kumar, M.; Mansuri, R.; Sahoo, G.C.; Deep, A. Inhibitor designing, virtual screening and docking studies for methyltransferase: A potential target against dengue virus. J. Pharm. Bioallied Sci., 2016, 8(3), 188-194.
Peyressatre, M.; Prével, C.; Pellerano, M.; Morris, M.C. Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancer, 2015, 7, 179-237.
Kaur, M.; Velmurugan, B.; Tyagi, A.; Agarwal, C.; Singh, R.P.; Agarwal, R. Silibinin suppresses growth of human colorectal carcinoma SW480 Cells in culture and xenograft through downregulation of β-catenin-dependent signaling. Neoplasia, 2010, 12(5), 415-424.
Sharma, V.; Chitranshi, N.; Agarwal, A.K. Significance and biological importance of pyrimidine in the microbial world. Int. J. Med. Chem., 2014, 1-31.
Maddila, S.; Gorle, S.; Seshadri, N.; Lavanya, P.; Jonnalagadda, S.B. Synthesis, antibacterial and antifungal activity of novel benzothiazole pyrimidine derivatives. Arab. J. Chem., 2016, 9, 681-687.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [609 - 621]
Pages: 13
DOI: 10.2174/1389557519666181210162413
Price: $58

Article Metrics

PDF: 23
PRC: 1