Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Mixed Ligand-metal Complexes of 2-(butan-2-ylidene) Hydrazinecarbothioamide- Synthesis, Characterization, Computer-Aided Drug Character Evaluation and in vitro Biological Activity Assessment

Author(s): Tahmeena Khan*, Rumana Ahmad, Iqbal Azad*, Saman Raza, Seema Joshi and Abdul R. Khan

Volume 17, Issue 1, 2021

Published on: 26 September, 2019

Page: [107 - 122] Pages: 16

DOI: 10.2174/1573409915666190926122103

Price: $65

Abstract

Background: Mixed ligand-metal complexes are efficient chelating agents because of their flexible donor ability. Mixed ligand complexes containing hetero atoms sulphur, nitrogen and oxygen have been probed for their biological significance.

Methods: Nine mixed ligand-metal complexes of 2-(butan-2-ylidene) hydrazinecarbothioamide (2- butanone thiosemicarbazone) with pyridine, bipyridine and 2-picoline as co-ligands were synthesized with Cu, Co and Zn salts. The complexes were tested against MDA-MB231 (MDA) and A549 cell lines. Antibacterial activity was tested against Staphylococcus aureus and Escherichia coli. The drug character of the complexes was evaluated on parameters viz. physicochemical properties, bioactivity scores, toxicity assessment and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile using various automated softwares. Molecular docking was performed against Ribonucleotide Reductase (RR) and topoisomerase II (topo II).

Results: The mixed ligand-metal complexes were synthesized by condensation reaction for 4-5 h. The characterization was done by elemental analysis, 1H-NMR, FT-IR, molar conductance and UV spectroscopic techniques. Molecular docking results showed that [Cu(C5H11N3S)(py)2(CH3COO)2], [Zn(C5H11N3S)(bpy)(SO4)] and [Zn(C5H11N3S)(2-pic)2(SO4)] displayed the lowest binding energies with respect to RR. Against topo II [Cu(C5H11N3S)(py)2(CH3COO)2], [Cu(C5H11N3S)(bpy)(CH3COO)2] and [Zn(C5H11N3S)(2-pic)2(SO4)] had the lowest energies. The druglikness assessment was done using Leadlikeness and Lipinski’s rules. Not more than two violations were obtained in case of each filtering rule showing drug-like character of the mixed ligand complexes. Some of the complexes exhibited positive bioactivity scores and almost all the complexes were predicted to be safe with no hazardous effects as predicted by the toxicity assessment. Ames test predicted the non-mutagenic nature of the complexes.

Conclusion: In vitro activity evaluation showed that [Zn(C5H11N3S)(py)2(SO4)], [Co(C5H11N3S(bpy) (Cl)2] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against MDA. Against A549 [Co(C5H11N3S)(py)2(Cl)2], [Cu(C5H11N3S)(py)2(CH3COO)2] and [Co(C5H11N3S(bpy)(Cl)2] were active. Antibacterial evaluation showed that [Co(C5H11N3S)(bpy)(Cl)2], [Zn(C5H11N3S)(2-pic)2(SO4)] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against S. aureus. Against E. coli, [Zn(C5H11N3S)(2- pic)2(SO4)] showed activity at 18-20 mg dose range.

Keywords: Computational, cancer, druglikeness, docking, mixed, thiosemicarbazone.

« Previous Next »
Graphical Abstract

[1]
Rafique, S.; Idrees, M.; Nasim, A.; Akbar, H.; Athar, A. Transition metal complexes as potential therapeutic agents. Biotechnol. Mol. Biol. Rev., 2010, 5(2), 38-45.
[2]
Hussain, R.K. Coordination compounds in biology the chemistry of vitamin B12 and model compounds., 1999 4(6), 67-77.
[3]
McCleverty, J.A.; Meyer, T.J. Comprehensive coordination chemistry II : from biology to nanotechnology., 2004.https://www.sciencedirect.com/referencework/9780080437484/comprehensive-coordination-chemistry-ii#book-info
[4]
Gupta, R.P.; Narayana, N.L. Synthesis of some mannich bases of 1-cyclohexylidene-N(1,2-dihydro-2-oxo-3H-indol-3-ylidene) thiosemicarbazones and their antibacterial activity. Pharm. Acta Helv., 1997, 72(1), 43-45.
[http://dx.doi.org/10.1016/S0031-6865(96)00027-1] [PMID: 9063087]
[5]
Yao, Y.; Cai, Q.; Kou, H.; Li, H.; Wang, D.; Yu, R.; Chen, Y.; Xing, X. Self-assembly of a novel manganiferrous coordination polymer with mixed ligand. Chem. Lett., 2004, 33(4), 1270-1272.
[http://dx.doi.org/10.1246/cl.2004.1270]
[6]
Felder, D.; Nierengarten, J.F.; Barigelletti, F.; Ventura, B.; Armaroli, N. Highly luminescent Cu(I)-phenanthroline complexes in rigid matrix and temperature dependence of the photophysical properties. J. Am. Chem. Soc., 2001, 123(26), 6291-6299.
[http://dx.doi.org/10.1021/ja0043439] [PMID: 11427053]
[7]
Sproules, S.; Wieghardt, K. Dithiolene radicals: Sulfur K-edge X-ray absorption spectroscopy and Harry’s intuition. Coord. Chem. Rev., 2011, 255(7-8), 837-860.
[http://dx.doi.org/10.1016/j.ccr.2010.12.006]
[8]
Coxall, R.A.; Harris, S.G.; Henderson, D.K.; Parsons, S.; Tasker, P.A.; Winpenny, R.E.P. Inter-ligand reactions: in situ formation of new polydentate ligands. J. Chem. Soc., Dalton Trans., 2000, 14, 2349-2356.
[http://dx.doi.org/10.1039/b001404o]
[9]
Chakraborty, S.; Munshi, P.; Lahiri, G.K. Dinuclear ruthenium(II) bipyridine complexes having non-symmetric α,α′-diimine based neutral bridging ligands: synthesis, spectroscopic and electrochemical properties. Polyhedron, 1999, 18(10), 1437-1444.
[http://dx.doi.org/10.1016/S0277-5387(99)00003-0]
[10]
Khan, T.; Azad, I.; Ahmad, R.; Raza, S.; Dixit, S.; Joshi, S.; Khan, A.R. Synthesis, characterization, computational studies and biological activity evaluation of Cu, Fe, Co and Zn complexes with 2-butanone thiosemicarbazone and 1,10-phenanthroline ligands as anticancer and antibacterial agents. EXCLI J., 2018, 17, 331-348.
[http://dx.doi.org/10.17179/excli2017-984] [PMID: 29743867]
[11]
Erkkila, K.E.; Odom, D.T.; Barton, J.K. Recognition and reaction of metallointercalators with DNA. Chem. Rev., 1999, 99(9), 2777-2796.
[http://dx.doi.org/10.1021/cr9804341] [PMID: 11749500]
[12]
Khan, T.; Dixit, S.; Ahmad, R.; Raza, S.; Azad, I.; Joshi, S.; Khan, A.R. Molecular docking, PASS analysis, bioactivity score prediction, synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes. J. Chem. Biol., 2017, 10(3), 91-104.
[http://dx.doi.org/10.1007/s12154-017-0167-y] [PMID: 28684996]
[13]
Khajah, M.A.; Almohri, I.; Mathew, P.M.; Luqmani, Y.A. Extracellular alkaline pH leads to increased metastatic potential of estrogen receptor silenced endocrine resistant breast cancer cells. PLoS One, 2013, 8(10)e76327
[http://dx.doi.org/10.1371/journal.pone.0076327] [PMID: 24098477]
[14]
Azad, I.; Nasibullah, M.; Khan, T.; Hassan, F.; Akhter, Y. Exploring the novel heterocyclic derivatives as lead molecules for design and development of potent anticancer agents. J. Mol. Graph. Model., 2018, 81, 211-228.
[http://dx.doi.org/10.1016/j.jmgm.2018.02.013] [PMID: 29609141]
[15]
Khan, T.; Lawrence, A.J.; Azad, I.; Raza, S.; Joshi, S.; Khan, A.R. Computational drug designing and prediction of important parameters using in silico methods-a review. Curr. Comput. Aided Drug Des., 2019, 15(5), 384-397.
[http://dx.doi.org/10.2174/1573399815666190326120006] [PMID: 30914032]
[16]
Mohan, C.G.; Gandhi, T.; Garg, D.; Shinde, R. Computer-assisted methods in chemical toxicity prediction. Mini Rev. Med. Chem., 2007, 7(5), 499-507.
[http://dx.doi.org/10.2174/138955707780619554] [PMID: 17504185]
[17]
El-Sherif, A.A.; Shoukry, M.M.; Abd-Elgawad, M.M.A. Synthesis, characterization, biological activity and equilibrium studies of metal(II) ion complexes with tridentate hydrazone ligand derived from hydralazine. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2012, 98, 307-321.
[http://dx.doi.org/10.1016/j.saa.2012.08.034] [PMID: 23021889]
[18]
Kramer, J.A.; Sagartz, J.E.; Morris, D.L. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat. Rev. Drug Discov., 2007, 6(8), 636-649.
[http://dx.doi.org/10.1038/nrd2378] [PMID: 17643090]
[19]
Ames, B.N.; Mccann, J.; Yamasaki, E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat. Res., 1975, 31(6), 347-364.
[http://dx.doi.org/10.1016/0165-1161(75)90046-1] [PMID: 768755]
[20]
West, D.X.; Billeh, I.S.; Bain, G.A.; Valdés-Martínez, J.; Ebert, K.H.; Hernández-Ortega, S. Metal complexes of 2-acetylpyridine N(4)-dihexyl- and N(4)-dicyclohexylthiosemicarbazones. Trans. Met. Chem., 1996, 21(6), 573-582.
[http://dx.doi.org/10.1007/BF00229716]
[21]
Youssef, N.S.; Hegab, K.H. Synthesis and characterization of some transition metal complexes of thiosemicarbazones derived from 2‐acetylpyrrole and 2‐acetylfuran. Synth. React. Inorg. Met.-Org. Nano-Met. Chem., 2005, 35(5), 391-399.
[http://dx.doi.org/10.1081/SIM-200059215]
[22]
El-Sherif, A.A. Synthesis and characterization of some potential antitumor palladium(II) complexes of 2-aminomethylbenzimidazole and amino acids. J. Coord. Chem., 2011, 64(12), 2035-2055.
[http://dx.doi.org/10.1080/00958972.2011.587004]
[23]
Joseph, M.; Sreekanth, A.; Suni, V.; Kurup, M.R.P. Spectral characterization of iron(III) complexes of 2-benzoylpyridine N(4)-substituted thiosemicarbazones. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2006, 64(3), 637-641.
[http://dx.doi.org/10.1016/j.saa.2005.07.067] [PMID: 16386946]
[24]
Chandra, S.; Raizada, S.; Tyagi, M.; Sharma, P.K. Spectroscopic and biological approach of Ni(II) and Cu(II) complexes of 2-pyridinecarboxaldehyde thiosemicarbazone. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2008, 69(3), 816-821.
[http://dx.doi.org/10.1016/j.saa.2007.05.033] [PMID: 17627876]
[25]
Tada, R.; Chavda, N.; Shah, M.K. Synthesis and characterization of some new thiosemicarbazide derivatives and their transition metal complexes. J. Chem. Pharm. Res., 2011, 3(2), 290-297.
[26]
Bindu, P. Kurup M.R.P. E.S.R. and electrochemical studies of four- and five-coordinate copper(II) complexes containing mixed ligands. Trans. Met. Chem., 1997, 22(6), 578-582.
[http://dx.doi.org/10.1023/A:1018512708055]
[27]
Saswati.; Dinda, R.; Schmiesing, C.; Sinn, E.; Patil, Y.; Nethaji, M.; Evans, H.; Acharya, R. Mixed-ligand nickel(II) thiosemicarbazone complexes: synthesis, characterization and biological evaluation. Polyhedron, 2013, 50(1), 354-363.
[http://dx.doi.org/10.1016/j.poly.2012.11.031]
[28]
Ahuja, I.S.; Singh, R. 2-, 3- and 4-cyanopyridine complexes with some zinc(II), cadmium(II) and mercury(II) salts. J. Inorg. Nucl. Chem., 1974, 36(7), 1505-1513.
[http://dx.doi.org/10.1016/0022-1902(74)80614-7]
[29]
Agarwal, R.K.; Tyagi, B.S.; Srivastava, M.; Srivastava, A.K. Infrared and thermal investigations of oxozirconium(IV) halide complexes with some heterocyclic bases. Thermochim. Acta, 1983, 61(1–2), 241-245.
[http://dx.doi.org/10.1016/0040-6031(83)80320-7]
[30]
Mohamed, G.G.; Ibrahim, N.A.; Attia, H.A.E. Synthesis and anti-fungicidal activity of some transition metal complexes with benzimidazole dithiocarbamate ligand. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2009, 72(3), 610-615.
[http://dx.doi.org/10.1016/j.saa.2008.10.051] [PMID: 19119060]
[31]
Leovac. Synthesis and characterization of salicaldehyde Girad-T hydrazine complexes. Struct. Chem., 2007, 18, 113-119.
[http://dx.doi.org/10.1007/s11224-006-9136-8]
[32]
Azad, I.; Jafri, A.; Khan, T.; Akhter, Y.; Arshad, M.; Hassan, F.; Nasibullah, M. Evaluation of pyrrole-2,3-dicarboxylate derivatives: Synthesis, DFT analysis, molecular docking, virtual screening and in vitro anti-hepatic cancer study. J. Mol. Struct., 2019, 1176, 314-334.
[http://dx.doi.org/10.1016/j.molstruc.2018.08.049]
[33]
Singh, P.; Mishra, M.; Agarwal, S.; Sau, S.; Iyer, A.K.; Kashaw, S.K. Exploring the role of water molecules in the ligand binding domain of PDE4B and PDE4D: virtual screening based molecular docking of some active scaffolds. Curr. Comput. Aided Drug Des., 2019, 15(4), 334-366.
[http://dx.doi.org/10.2174/1573409914666181105153543] [PMID: 30394213]
[34]
Mali, D.P.; Bhatia, N.M. Hetero-Tricyclic lead scaffold as novel pde5a inhibitor for antihypertensive activity: in silico docking studies. Curr. Comput. Aided Drug Des., 2019, 15(4), 318-333.
[http://dx.doi.org/10.2174/1573409915666190214161221] [PMID: 30767749]
[35]
Jayabalakrishnan, C.; Natarajan, K. Ruthenium(II) carbonyl complexes with tridentate Schiff bases and their antibacterial activity. Trans. Met. Chem., 2002, 27(1), 75-79.
[http://dx.doi.org/10.1023/A:1013437203247]
[36]
Mapari, A.K.; Hate, M.S.; Mangaonkar, K.V. Synthesis, characterization and antimicrobial activity of mixed schiff base ligand complexes of Co(II), Ni(II), Cu(II) and Zn(II). E-J. Chem., 2011, 8(3), 1258-1263.
[http://dx.doi.org/10.1155/2011/598171]

Rights & Permissions Print Cite
Article Metrics
18
1
© 2024 Bentham Science Publishers | Privacy Policy