Synthesis And Pharmacological Evaluation of Some Novel Benzhydryl Piperazine Derivatives for Anti-Cancer Activity
Keywords:
Cancer, Piperazine, Cell line, characterizationAbstract
The creation of novel anticancer drugs is required to address the issues of toxicity and adverse effects. Derivatives of benzohydryl piperazine have recently been discovered to have cytotoxic and nanomolar epidermal growth factor receptor (EGFR) inhibitory action. The impact of benzhydryl piperazine derivatives on anticancer activity has been investigated in this work. Using gefitinib as the reference, a panel of three cancer cell lines—human pancreatic carcinoma (MIAPaCa-2), human colon carcinoma (HCT-116), and adenocarcinomic human alveolar basal epithelial cells (A-549)—were used to assess a series of six benzhydryl piperazine derivatives. According to the data, the majority of the compounds had encouraging efficacy; however, compound 3c was the most active, exhibiting cytotoxicity significantly superior to that of gefitinib. 4.63 µM against the HCT-116 colon cancer line, 30.11 µM against the MIAPaCa-2 cell line, and 5.71 µM against the A-549 cell line were its IC50 values. These substances will be discovered to be well suited to the active site and might be demonstrating anticancer potential through EGFR inhibition
Downloads
Metrics
References
Piton J.; Vocat A.; Lupien A.; Foo C. S.; Riabova O.; Makarov V.; Cole S. T. Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2018, 62, e00681 10.1128/aac.00681-18.
Yempalla K. R.; Munagala G.; Singh S.; Magotra A.; Kumar S.; Rajput V. S.; Bharate S. S.; Tikoo M.; Singh G. D.; Khan I. A.; Vishwakarma R. A.; Singh P. P. Nitrofuranyl methyl piperazines as new anti-TB agents: identification, validation, medicinal chemistry, and PK studies. ACS Med. Chem. Lett. 2015, 6, 1041–1046. 10.1021/acsmedchemlett.5b00141.
Naidu K. M.; Nagesh H. N.; Singh M.; Sriram D.; Yogeeswari P.; Sekhar K. V. G. C. Novel amide and sulphonamide derivatives of 6-(piperazin-1-yl) phenanthridine as potent Mycobacterium tuberculosis H37Rv inhibitors. Eur. J. Med. Chem. 2015, 92, 415–426. 10.1016/j.ejmech.2015.01.013.
Ghorab M. M.; El-Gaby M. S.; Soliman A. M.; Alsaid M. S.; Abdel-Aziz M. M.; Elaasser M. M. Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety. Chem. Cent. J. 2017, 11, 42–54. 10.1186/s13065-017-0271-7.
Tiwari R.; Möllmann U.; Cho S.; Franzblau S. G.; Miller P. A.; Miller M. J. Design and syntheses of anti-tuberculosis agents inspired by BTZ043 using a scaffold simplification strategy. ACS Med. Chem. Lett. 2014, 5, 587–591. 10.1021/ml500039g.
Chung M.; Malatesta P.; Bosquesi P.; Yamasaki P.; Santos J. L. D.; Vizioli E. Advances in drug design based on the amino acid approach: Taurine analogues for the treatment of CNS diseases. Pharmaceuticals 2012, 5, 1128–1146. 10.3390/ph5101128.
Wang M.; Rakesh K. P.; Leng J.; Fang W.-Y.; Ravindar L.; Channe Gowda D.; Qin H.-L. Amino acids/peptides conjugated heterocycles: A tool for the recent development of novel therapeutic agents. Bioorg. Chem. 2018, 76, 113–129. 10.1016/j.bioorg.2017.11.007.
Kotha S. The building block approach to unusual α-amino acid derivatives and peptides. Acc. Chem. Res. 2003, 36, 342–351. 10.1021/ar020147q.
Berrino E.; Bua S.; Mori M.; Botta M.; Murthy V. S.; Vijayakumar V.; Tamboli Y.; Bartolucci G.; Mugelli A.; Cerbai E.; Supuran C. T.; Carta F. Novel sulfamide-containing compounds as selective carbonic anhydrase I inhibitors. Molecules 2017, 22, 1049. 10.3390/molecules22071049.
Vishvakrama P, Sharma S. Liposomes: an overview. Journal of Drug Delivery and Therapeutics. 2014 Jun 24:47-55.
Vishvakarma P. Design and development of montelukast sodium fast dissolving films for better therapeutic efficacy. Journal of the Chilean Chemical Society. 2018 Jun;63(2):3988-93.
Vishvakarma P, Mandal S, Verma A. A review on current aspects of nutraceuticals and dietary supplements. International Journal of Pharma Professional’s Research (IJPPR). 2023;14(1):78-91.
Prabhakar Vishvakarma, Jaspreet Kaur, Gunosindhu Chakraborthy, Dhruv Kishor Vishwakarma, Boi Basanta Kumar Reddy, Pampayya Thanthati, Shaik Aleesha, Yasmin Khatoon. Nephroprotective Potential of Terminalia Arjuna Against Cadmium-Induced Renal Toxicity by In-Vitro Study. J. Exp. Zool. India Vol. 28, No. 1, pp. 939-944, 2025
Novack GD, Stark LG and Peterson SL: Anti-convulsant effects of benzhydryl piperazines on Pentylenetetrazol-induced seizures in mice. Neuropharmacology 1978; 17: 659-633.
Choi D, Stables JP and Kohn H: Synthesis and anti-convulsant activities of N-Benzyl-2-acetamido-propionamide derivatives. Journal of Medicinal Chemistry 1996; 39: 1907–1916.
Maria Laura B, Andrea C, Vincenza A, Manuela B and Rita B: Design, synthesis and biological evaluation of ambenonium derivatives as Ach Einhibitors. ILFARMACO 2003; 58(9): 917-928.
Iriepa I, Madrid AI, Galvez E and Bellanato J: Synthesis, structural and conformational study of some amides derived from N-methylpiperazine. Journal of Molecular Structure 2006; 787: 8-13.
Ling Gan L, Fang B & Zhou CH: Synthesis of Azole-containing Piperazine Derivatives and Evaluation of their Antibacterial, Antifungal and Cytotoxic Activities Bulletin of Korean Chemical Society 2010; 31: 12 Cheung HS, Cushman DW (1973) Inhibition of homogeneous angiotensin-converting enzyme of rabbit lung by synthetic venom peptides of Bothrops jararaca. Biochim Biophys Acta 293:451–463
Farzaliev VM, Abbasova MT, Ashurova AA, Babaeva GB, Ladokhina NP, Kerimova YM (2009) Synthesis of N, N0-bis(alkyloxymethyl)piperazines and examination of their antimicrobial properties. Russ J Appl Chem 82:928–930
GGillard M, Perren CVD, Moguilevsky N, Massingham R, Chatelain P (2002) Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: contribution of Lys191 and Thr194. Mol Pharmacol 61:391–399
Guo CC, Tong RB, Li KL (2004) Chloroalkyl piperazine and nitrogen mustard porphyrins: synthesis and anticancer activity. Bioorg Med Chem 12:2469–2475
Jain KS, Bariwal JB, Kathiravan MK, Phoujdar MS, Sahne RS, Chauhan BS, Shahb AK, Yadav MR (2008) Recent advances in selective a1-adrenoreceptor antagonists as antihypertensive agents. Bioorg Med Chem 16:4759–4800
Cushman DW, Cheung HS, Sabo EF, Ondetti MA (1977) Design of potent competitive inhibitors of angiotensin-converting enzyme, carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry 16:5484–5491
Dorsey JM, Miranda MG, Cozzib NV, Pinneya KG (2004) Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile. Bioorg Med Chem 12:1483–1491
Ehlers MR, Fox EA, Strydom DJ, Riordan JF (1989) Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc Natl Acad Sci USA 86:7741–7745
Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11(3):217–227.
Kamal A, Tamboli JR, Vishnuvardhan MVPS, Adil SF, Nayak VL, Ramakrishna S (2013) Synthesis and anticancer activity of heteroaromatic linked 4β-amido podophyllotoxins as apoptotic inducing agents. Bioorganic Med Chem Lett 23(1):273–280
Sussman JL, Lin D, Jiang J, Manning NO, Prilusky J, Ritter O, Abola EE (1998) Protein Data Bank (PDB): database of three-dimensional structural information of biological macromolecules. Acta Crystallogr Sect D Biol Crystallogr 54:1078–1084 Kimura M, Masuda T, Yamada K, Kubota N, Kawakatsu N, Mitani M, Kishii K, Inazuy M, Namiki T (2002) Novel diphenylalkyl piperazine derivatives with dual calcium antagonistic and antioxidative activities. Bioorg Med Chem Lett 12:1947–1950
Kumar CSA, Prasad SBB, Vinaya K, Chandrappa S, Thimmegowda NR, Kumar YCS, Swarup S, Rangappa KS (2009) Synthesis and in vitro anti-proliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines. Eur J Med Chem 44:1223–1229
Mayence A, Eynde JJV, LeCour L Jr, Walker LA, Tekwani BL, Huang TL (2004) Piperazine-linked bisbenzamidines: a novel class of anti-leishmanial agents. Eur J Med Chem 39:547–553
McCombie SW, Tagat JR, Vice SF, Lin SL, Steensma R, Palani A, Neustadt BR, Baroudy BM, Strizki JM, Endres M, Cox K, Dan
N, Chou CC (2003) Piperazine-based CCR5 antagonists as HIV1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides. Bioorg Med Chem Lett 13:567–571
Kawasaki N, Miyataka H, Nishiki M, Matsumoto H, Inagaki N, Nagai H, Satoh T (1999) Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions. Chem Pharma Bull 47:181–185
Vishvakarma P, Mandal S, Pandey J, Bhatt AK, Banerjee VB, Gupta JK. An Analysis Of The Most Recent Trends In Flavoring Herbal Medicines In Today's Market. Journal of Pharmaceutical Negative Results. 2022 Dec 31:9189-98.
C¸ oban AY, Bayram Z, Sezgin FM, Durupinar B (2009) Effect of efflux pump inhibitor 1-(1-napthylmethyl)-piperazine to MIC values of ciprofloxacin in ciprofloxacin resistant Gram-negative bacteria. Mikrobiyol Bul 43:457–461
Prabhakar V, Agarwal S, Chauhan R, Sharma S. Fast dissolving tablets: an overview. International Journal of Pharmaceutical Sciences: Review and Research. 2012;16(1):17..
.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
