Synthesis of Novel Hydrazones of Levofloxacin Related Molecule and
their In Vitro Evaluation as Antioxidant, and Molecular Docking Studies

Bharat   B.   Kashid; Jaydeo    T.    Kilbile; Kishor    D.    Wani; Suhas.    M.    Pawar; Vijay    M.    Khedkar; Anil    A.    Ghanwat

doi:10.2174/1386207323666201229150734

Abstract

Objective: The research work aims to synthesize novel series of hydrazones and antioxidant screening. It also aims to evaluate the binding affinities and in silico methods for identifying possible drug targets of synthesized compounds.

Methods: This report briefly explains the synthesis of a novel series of hydrazones. It was synthesized via. hydrazinolysis of esters to obtain hydrazide, treated with aldehyde and acetophenone to get hydrazones. The spectral confirmed hydrazones exhibited excellent to comparable anti-oxidant as compared to the standard drugs Butylated hydroxytoluene (BHT) and Ascorbic acid. Molecular docking on myeloperoxidase (MPO) demonstrated the ability of this scaffold to correctly recognize the target and engage in significant bonded and non-bonded interactions with key residues therein.

Results and Discussion: In this study, we report effectively synthesized compounds BK-35, BK- 41, BK-26, BK-28, and BK-39 that showed the best DPPH radical scavenging activity. The docking results clearly showed the binding mode of hydrazones into the active site of Myeloperoxidase (MPO). In in-silico results, none of the synthesized compounds, BK-24 to BK- 41, violated Lipinski’s rule of five (miLog P ≤ 5).

Conclusions: In vitro preliminary anti-oxidant screening results in support by in Silico binding affinity data of novel hydrazones of levofloxacin related molecules BK-24 to BK-41 reported here have emerged as excellent anti-oxidant agents. The inference derived from the in vitro anti-oxidant screening data and the quantitative insights derived from the per-residue interaction analysis with MPO enzyme are now being fruitfully utilized for site-specific mutation around the nucleus to identify selective and potent anti-oxidants.

Keywords: Carbohydrazide, anti-oxidant, bio-activity, computational study, organic chemistry, mutation.

« Previous Next »

Graphical Abstract

[1] 
Schofer, K.; Schwan, S. Synthesis of N-acylhydrazines. J. Prakt. Chem.,  1850, 51, 185.
[2] 
Brehme, R.; Enders, D.; Fernandez, R.; Lassaletta, J.M.; Aldehyde, N. N‐dialkylhydrazones as neutral acyl anion equivalents: umpolung of the imine reactivity. Eur. J. Org. Chem.,  2007, 5629.
[http://dx.doi.org/10.1002/ejoc.200700746] 
[3] 
Corey, E.J.; Enders, D. Synthetic routes to polyfunctional molecules via metallated N, N-dimethylhydrazones. Tetrahedron Lett.,  1976, 17, 11.
[http://dx.doi.org/10.1016/S0040-4039(00)71309-8] 
[4] 
Belskaya, N.P.; Dehaen, W.; Bakulev, V.A. Synthesis and properties of hydrazones bearing amide, thioamide and amidine functions. Arch Org Chem.,  2010, 1, 275.
[5] 
(a) Xavier, A.J.; Thakur, M.; Marie, J.M. Synthesis and spectral characterisation of hydrazone based 14-membered octaazamacrocyclic Ni (II) complexes. J. Chem. Pharm. Res.,  2012, 4, 986.
(b) Kashid, B.B.; Salunkhe, P.H.; Dongare, B.B.; More, K.R.; Khedkar, V.M.; Ghanwat, A.A. Synthesis of novel of 2, 5-disubstituted 1, 3, 4- oxadiazole derivatives and their in vitro anti-inflammatory, anti-oxidant evaluation, and molecular docking study. Bioorg. Med. Chem. Lett.,  2020, 30(12)
[http://dx.doi.org/10.1016/j.bmcl.2020.127136] [PMID:  32280025] 
[6] 
Lesher, G.Y.; Froelich, E.J.; Gruett, M.D.; Bailey, J.H.; Brundage, R.P. 1,8-naphthyridine derivatives: A new class of chemotherapeutic agents. J. Med. Pharm. Chem.,  1962, 91, 1063-1065.
[http://dx.doi.org/10.1021/jm01240a021] [PMID:  14056431] 
[7] 
Ahmed, A.; Daneshtalab, M. Nonclassical biological activities of quinolone derivatives. J. Pharm. Pharm. Sci.,  2012, 15(1), 52-72.
[PMID:  22365088] 
[8] 
Hu, B.S.; Fung, C.P.; Liu, P.Y.; Lau, Y.J.; Shi, Z.Y.; Lin, Y.H. In vitro antimicrobial activity of levofloxacin against Streptococcus pneumoniae. Zhonghua Yi Xue Za Zhi (Taipei),  1997, 60(4), 191-194.
[PMID:  9439047] 
[9] 
Guo-qiang, Hu.; Guo-qiang, W.; Nan-nan, D.; Xiao-yi, W.; Tie-yao, C.; Song-qiang, X.; Huang, W-L. Design, synthesis and antitumor activity of fluoroquinolone C3 heterocyclic bis-oxadiazole methylsulfide derivatives derived from levofloxacin. Chem. Res. Chin. Univ.,  2012, 28(6), 980.
[10] 
Fu, J-M.; Wang, D-H.; Sun, J-P.; Kang, Y-H. p-Methoxycinnamaldehyde levofloxacin-3-ylhydrazone induces apoptosis of human hepatocarcinoma SMMC-7721 cells. Zhongguo Yaolixue Tongbao,  2011, 27(6), 801.
[11] 
Sun, J.P.; Shi, Z.Y.; Liu, S.M.; Kang, Y.H.; Hu, G.Q.; Huangfu, C.S.; Deng, J.B.; Liu, B. Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells. Cancer Cell Int.,  2013, 13, 67.
[http://dx.doi.org/10.1186/1475-2867-13-67] 
[12] 
Liang, H.X.; Fan, Y.Y.; Zhang, Y.; Huangfu, C.S.; Hu, G.Q.; Liu, B. Benzaldehyde levofloxacin schiff base induced apoptosis of human hepatocarcinoma cells. Int. J. Clin. Exp. Med.,  2016, 9(2), 1314.
[13] 
Sultana, N.; Arayne, M.S.; Rizvi, S.B.S.; Mesaik, M.A. Synthesis, characterization and biological evaluation of a series of levofloxacin carboxamide analogues. Bull. Korean Chem. Soc.,  2009, 30(10), 2294.
[http://dx.doi.org/10.5012/bkcs.2009.30.10.2294] 
[14] 
Sultana, N.; Arayne, M.S.; Naz, A.; Mesaik, M.A.; Mesaik, M.A. Identification of anti-inflammatory and other biological activities of 3-carboxamide, 3-carbohydrazide and ester derivatives of gatifloxacin. Chem. Cent. J.,  2013, 7(1), 6.
[http://dx.doi.org/10.1186/1752-153X-7-6] [PMID:  23316796] 
[15] 
Abdel-Aal, M.T.; El-Sayed, W.A.; El-Ashry, S.H. Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives. Arch. Pharm. (Weinheim),  2006, 339(12), 656-663.
[http://dx.doi.org/10.1002/ardp.200600100] [PMID:  17149795] 
[16] 
Lima, P.C.; Lima, L.M.; da Silva, K.C.M.; Léda, P.H.O.; de Miranda, A.L.P.; Fraga, C.A.; Barreiro, E.J. Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole. Eur. J. Med. Chem.,  2000, 35(2), 187-203.
[http://dx.doi.org/10.1016/S0223-5234(00)00120-3] [PMID:  10758281] 
[17] 
(a) Bukowski, L.; Janowiec, M. Methyl-1H-2-imidazo[4,5- b]pyridinecarboxylic acid and some of its derivatives with suspected antituberculotic activity. Pharmazie,  1996, 51(1), 27-30.
[http://dx.doi.org/10.1002/chin.199630179] [PMID:  8999430] 
(b) Cocco, M.T.; Congiu, C.; Onnis, V.; Pusceddo, M.C.; Schivo, M.L. Logu. A., De Synthesis and antimycobacterial activity of some isonicotinoylhydrazones. Eur. J. Med. Chem.,  1999, 34(12), 1071.
[http://dx.doi.org/10.1016/S0223-5234(99)00124-5] 
[18] 
Walcourt, A.; Loyevsky, M.; Lovejoy, D.B.; Gordeuk, V.R.; Richardson, D.R. Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites. Int. J. Biochem. Cell Biol.,  2004, 36(3), 401-407.
[http://dx.doi.org/10.1016/S1357-2725(03)00248-6] [PMID:  14687919] 
[19] 
Ergenç, N.; Günay, N.S.; Demirdamar, R. Synthesis and antidepressant evaluation of new 3-phenyl-5-sulfonamidoindole derivatives. Eur. J. Med. Chem.,  1998, 33(2), 143.
[http://dx.doi.org/10.1016/S0223-5234(98)80039-1] 
[20] 
(a) Küçükgüzel, Ş.G.; Rollas, S.; Erdeniz, H.; Kiraz, M. Synthesis, characterization and antimicrobial evaluation of ethyl 2- arylhydrazono-3-oxobutyrates. Eur. J. Med. Chem.,  1999, 34(2), 153.
[http://dx.doi.org/10.1016/S0223-5234(99)80048-8] 
(b) Hussain, I.; Ali, A. Exploring the Pharmacological Activities of Hydrazone Derivatives: A Review. J. Phytochemistry Biochem.,  2017, 1, 104.
(c) Popiołek, Ł. Hydrazide-hydrazones as potential antimicrobial agents: overview of the literature since 2010. Med. Chem. Res.,  2017, 26(2), 287-301.
[http://dx.doi.org/10.1007/s00044-016-1756-y] [PMID: 28163562] 
(d) Kashid, B.B.; Ghanwat, A.A.; Khedkar, V.M.; Dongare, B.B.; Shaikh, S.H.; Deshpande, P.P.; Wakchaure, Y.B. Design, synthesis, in vitro antimicrobial, antioxidant evaluation, and molecular docking study of novel benzimidazole and benzoxazole derivatives. J. Heterocycl. Chem.,  2019, 56(3), 895.
[http://dx.doi.org/10.1002/jhet.3467] 
[21] 
Mashayekhi, V.; Tehrani, K.H.M.E.; Amidi, S.; Kobarfard, F. Synthesis of novel indole hydrazone derivatives and evaluation of their antiplatelet aggregation activity. Chem. Pharm. Bull. (Tokyo),  2013, 61(2), 144-150.
[PMID: 23154304] 
[22] 
(a) Azéma, J.; Guidetti, B.; Korolyov, A.; Kiss, R.; Roques, C.; Constant, P.; Daffé, M.; Malet-Martino, M. Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents. Eur. J. Med. Chem.,  2011, 46(12), 6025-6038.
[http://dx.doi.org/10.1016/j.ejmech.2011.10.014] [PMID: 22036229] 
(b) Durgesh, R.; Reddymasu, S. Ramesh. R., Rudraraju Synthesis and antitumor evaluation of indole-substituted indole-fused keto hydrazide hydrazones. J. Pharm. Res.,  2018, 12(I), 42.
[23] 
(a) Siddiqui, S.M.; Salahuddin, A.; Azam, A. Synthesis, characterization and antiamoebic activity of some hydrazone and azole derivatives bearing pyridyl moiety as a promising heterocyclic scaffold. Eur. J. Med. Chem.,  2012, 49, 411-416.
[http://dx.doi.org/10.1016/j.ejmech.2012.01.030] [PMID:  22309914] 
(b) Gerpe, A.; Alvarez, G.; Benítez, D.; Boiani, L.; Quiroga, M.; Hernández, P.; Sortino, M.; Zacchino, S.; González, M.; Cerecetto, H. 5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi activity and ability to accumulate squalene. Bioorg. Med. Chem.,  2009, 17(21), 7500-7509.
[http://dx.doi.org/10.1016/j.bmc.2009.09.013] [PMID:  19811923] 
[24] 
Belkheiri, N.; Bouguerne, B.; Bedos-Belval, F.; Duran, H.; Bernis, C.; Salvayre, R.; Nègre-Salvayre, A.; Baltas, M. Synthesis and antioxidant activity evaluation of a syringic hydrazones family. Eur. J. Med. Chem.,  2010, 45(7), 3019-3026.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.031] [PMID:  20403645] 
[25] 
(a) Dimmock, J.R.; Vashishtha, S.C.; Stables, J.P. Anticonvulsant properties of various acetylhydrazones, oxamoylhydrazones and semicarbazones derived from aromatic and unsaturated carbonyl compounds Eur. J. Med. Chem,  2000, 35(2), 241-248.
[http://dx.doi.org/10.1016/S0223-5234(00)00123-9] [PMID:  10758285] 
(b) Ragavendran, J.V.; Sriram, D.; Patel, S.K.; Reddy, I.V.; Bharathwajan, N.; Stables, J.; Yogeeswari, P. Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore. Eur. J. Med. Chem.,  2007, 42(2), 146-151.
[http://dx.doi.org/10.1016/j.ejmech.2006.08.010] [PMID:  17011080] 
[26] 
(a) Todeschini, A.R.; de Miranda, A.L.P.; Da Silva, K.C.M.; Parrini, S.C.; Barreiro, E.J. Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2- pyridylarylhydrazone derivatives. Eur. J. Med. Chem.,,  1998, 33(3), 189.
[http://dx.doi.org/10.1016/S0223-5234(98)80008-1] 
(b) Reddy, A.K.; Kathale, N.E. Synthesis and anti-inflammatory activity of hydrazones bearing biphenyl moiety and vanillin based hybrids. Orient. J. Chem.,  2017, 33(2), 971.
[http://dx.doi.org/10.13005/ojc/330250] 
[27] 
(a) Hauser-Davis, R.A.; de Freitas, L.V.; Cukierman, D.S.; Cruz, W.S.; Miotto, M.C.; Landeira-Fernandez, J.; Valiente-Gabioud, A.A.; Fernández, C.O.; Rey, N.A. Disruption of zinc and copper interactions with Aβ(1-40) by a non-toxic, isoniazid-derived, hydrazone: a novel biometal homeostasis restoring agent in Alzheimer’s disease therapy? Metallomics,  2015, 7(5), 743-747.
[http://dx.doi.org/10.1039/C5MT00003C] [PMID:  25860559] 
(b) Cukierman, D.S.; Pinheiro, A.B.; Castiñeiras-Filho, S.L.; da Silva, A.S.P.; Miotto, M.C.; De Falco, A. de P Ribeiro, T.; Maisonette, S.; da Cunha, A.L.; Hauser-Davis, R.A.; Landeira- Fernandez, J.; Aucélio, R.Q.; Outeiro, T.F.; Pereira, M.D.; Fernández, C.O.; Rey, N.A. A moderate metal-binding hydrazone meets the criteria for a bioinorganic approach towards Parkinson’s disease: Therapeutic potential, blood-brain barrier crossing evaluation and preliminary toxicological studies. J. Inorg. Biochem.,  2017, 170, 160-168.
[http://dx.doi.org/10.1016/j.jinorgbio.2017.02.020] [PMID:  28249224] 
(c) Cukierman, D.S.; Bodnár, N.; Evangelista, B.N.; Nagy, L.; Kállay, C.; Rey, N.A. Impact of pyridine-2-carboxaldehyde-derived aroylhydrazones on the copper-catalyzed oxidation of the M112A PrP103-112 mutant fragment. J. Biol. Inorg. Chem.,  2019, 24(8), 1231-1244.
[http://dx.doi.org/10.1007/s00775-019-01700-2] [PMID:  31401689] 
[28] 
(a) Lehn, J.M. From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry. Chem. Soc. Rev.,  2007, 36(2), 151-160.
[http://dx.doi.org/10.1039/B616752G] [PMID:  17264919] 
(b) Uribe-Romo, F.J.; Doonan, C.J.; Furukawa, H.; Oisaki, K.; Yaghi, O.M. Crystalline covalent organic frameworks with hydrazone linkages. J. Am. Chem. Soc.,  2011, 133(30), 11478- 11481.
[http://dx.doi.org/10.1021/ja204728y] [PMID:  21721558] 
(c) Jin, Y.; Yu, C.; Denman, R.J.; Zhang, W. Recent advances in dynamic covalent chemistry. Chem. Soc. Rev.,  2013, 42(16), 6634-6654.
[http://dx.doi.org/10.1039/c3cs60044k] [PMID:  23749182] 
[29] 
Rao, D.; Dwivedi, S.; Sreenivasulu, P.; Sahu, A.; Trinadhachari, G. Process for the Preparation of Levofloxacin Hemihydrate. US
0244318A1, 2007.
[30] 
(a) Hamzi, I. BarhoumiSlimi, T.M.; Abidi, R. Synthesis,
characterization, and conformational study of acylhydrazones of
α, β - unsaturated aldehydes. Heteroatom Chem,  2016, 27(3), 139.
[http://dx.doi.org/10.1002/hc.21310] 
(b) Syakaev, V.V.; Podyachev, S.N.; Buzykin, B.I.; Latypov, S.K.; Habicher, W.D.; Konovalov, A.I. NMR study of conformation and
isomerization of aryl-and heteroarylaldehyde 4-tertbutylphenoxyacetylhydrazones. J. Mol. Struct.,  2006, 788(1-3), 55.
[http://dx.doi.org/10.1016/j.molstruc.2005.11.018] 
(c) Podyachev, S.N.; Litvinov, I.A.; Shagidullin, R.R.; Buzykin, B.I.; Bauer, I.; Osyanina, D.V.; Avvakumova, L.V.; Sudakova, S.N.; Habicher, W.D.; Konovalov, A.I. Structure and
spectroscopic characteristics of 4-tertbutylphenoxyacetylhydrazones
of arylaldehydes. Spectrochim.
Acta A Mol. Biomol. Spectrosc.,  2007, 66(2), 250-261.
[http://dx.doi.org/10.1016/j.saa.2006.02.049] [PMID:  16876469] 
(d) Sarıgöl, D.; Yüksel, D.; Okay, G.; Uzgören-Baran, A. Synthesis and structural studies of acyl hydrazone derivatives having tetrahydrocarbazole moiety. J. Mol. Struct.,  2015, 1086, 146.
[http://dx.doi.org/10.1016/j.molstruc.2014.12.092] 
[31] 
Eswaran, S.; Adhikari, A.V.; Chowdhury, I.H.; Pal, N.K.; Thomas, K.D. New quinoline derivatives: synthesis and investigation of antibacterial and antituberculosis properties. Eur. J. Med. Chem.,  2010, 45(8), 3374-3383.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.022] [PMID:  20537437] 
[32] 
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem.,  2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID:  15027865] 
[33] 
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem.,  2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID:  15027866] 
[34] 
Forbes, L.V.; Sjögren, T.; Auchère, F.; Jenkins, D.W.; Thong, B.; Laughton, D.; Hemsley, P.; Pairaudeau, G.; Turner, R.; Eriksson, H.; Unitt, J.F.; Kettle, A.J. Potent reversible inhibition of myeloperoxidase by aromatic hydroxamates. J. Biol. Chem.,  2013, 288(51), 36636-36647.
[http://dx.doi.org/10.1074/jbc.M113.507756] [PMID:  24194519] 
[35] 
Collins, L.; Franzblau, S.G. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother.,  1997, 41(5), 1004-1009.
[http://dx.doi.org/10.1128/AAC.41.5.1004] [PMID:  9145860] 
[36] 
 Drug-likeness and molecular property prediction, http://www.molsoft.com/mprop/
[37] 
Zhao, Y.H.; Abraham, M.H.; Le, J.; Hersey, A.; Luscombe, C.N.; Beck, G.; Sherborne, B.; Cooper, I. Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res.,  2002, 19(10), 1446-1457.
[http://dx.doi.org/10.1023/A:1020444330011] [PMID:  12425461] 
[38] 
Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem.,  2000, 43(20), 3714-3717.
[http://dx.doi.org/10.1021/jm000942e] [PMID:  11020286] 

Rights & Permissions Print Cite

Article Metrics

21

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207323666201229150734	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Synthesis of Novel Hydrazones of Levofloxacin Related Molecule and their In Vitro Evaluation as Antioxidant, and Molecular Docking Studies

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract