Login Register Cart 0
Generic placeholder image

Current Organic Chemistry

Editor-in-Chief

ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

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

Novel 7-substituted Fluoroquinolone Citrate Conjugates as Powerful Antibacterial and Anticancer Agents: Synthesis and Molecular Docking Studies

Author(s): Tejeswara R. Allaka and Jaya S. Anireddy*

Volume 23, Issue 18, 2019

Page: [1992 - 2003] Pages: 12

DOI: 10.2174/1877946809666191007125408

Price: $65

Abstract

In this study, the synthesis and evaluation of norfloxacin analogues of dimethyl citrate conjugates were described and their antibacterial and anticancer activities were assessed. The cognate 7-substituted norfloxacin citrate conjugates are active against various strains of bacteria, including MRSA (methicillin-resistant Staphylococcus aureus) with higher activity than ciprofloxacin. Screening results indicated that compound 10 possessed good antibacterial activity against several microorganisms, with MIC values in the range of 0.16-0.35 mg/mL and MBCs in the range of 0.55-0.84 mg/mL. Experiments indicated that 9 demonstrated the most significant activity towards the HCT-15 cell line with IC50 value 8.2 ± 0.139 and against the HT-29 cell line with IC50 8.9 ± 0.122. The title compounds were also evaluated for determining the molecular and pharmacokinetic properties and drug-likeness model scores by using the Molinspiration-2008 and MolSoft-2007 softwares. The region isomeric conjugates followed the Lipinski’s rule of five can be considered as potential antibacterial and anticancer bioavailable oral leads. Compounds 9 and 10 possessed maximum drug-likeness scores. The docking pose interactions of target compounds with the active site of enzyme PDB: 2ZCS of Staphylococcus aureus were estimated by using Autodock 4.2, to calculate the affinity, binding orientation of the ligand with the target protein and to explore the finest conformations. The target compounds, 7, 8, 9, 10, with protein, were loaded separately into Auto dock tools (ADT) and evaluated. The citrate conjugates, 8, 9, showed better docking scores with amino acids Lys17, Ser21, Val268, Lys273 and Arg171, Arg265, Val268, Val273 with the binding energy -5.70, -5.57 kcal/mol and dissociation constant 66.62, 82.13 µM respectively.

Keywords: Antibacterial activity, anticancer activity, dimethyl citrates, drug-likeness, molecular docking, molecular properties, Staphylococcus aureus.

« Previous
Graphical Abstract

[1]
Mugnaini, C.; Pasquini, S.; Corelli, F. The 4-quinolone-3-carboxylic acid motif as a multivalent scaffold in medicinal chemistry. Curr. Med. Chem., 2009, 16(14), 1746-1767.
[http://dx.doi.org/10.2174/092986709788186156] [PMID: 19442143]
[2]
Shen, L.L.; Chu, D.T.W. Type II DNA topoisomerases as antibacterial targets. Curr. Pharm. Des., 1996, 2, 195-208.
[3]
Marians, K.J.; Hiasa, H. Mechanism of quinolone action. A drug-induced structural perturbation of the DNA precedes strand cleavage by topoisomerase IV. J. Biol. Chem., 1997, 272(14), 9401-9409.
[http://dx.doi.org/10.1074/jbc.272.14.9401] [PMID: 9083078]
[4]
Chu, D.T.W. Recent development in antibacterial research. Annu. Rep. Med. Chem., 1998, 33, 141-150.
[http://dx.doi.org/10.1016/S0065-7743(08)61079-9]
[5]
Chai, Y.; Liu, M.L.; Lv, K.; Feng, L.S.; Li, S.J.; Sun, L.Y.; Wang, S.; Guo, H.Y. Synthesis and in vitro antibacterial activity of a series of novel gatifloxacin derivatives. Eur. J. Med. Chem., 2011, 46(9), 4267-4273.
[http://dx.doi.org/10.1016/j.ejmech.2011.06.032] [PMID: 21764484]
[6]
Ball, P. Bacterial resistance to fluoroquinolones: Lessons to be learned. Infection, 1994, 22(Suppl. 2), S140-S147.
[http://dx.doi.org/10.1007/BF01793579] [PMID: 7927833]
[7]
Ball, P.; Mandell, L.; Niki, Y.; Tillotson, G. Comparative tolerability of the newer fluoroquinolone anti-bacterials. Drug Saf., 1999, 21(5), 407-421.
[http://dx.doi.org/10.2165/00002018-199921050-00005] [PMID: 10554054]
[8]
Ball, P. Quinolone-induced QT interval prolongation: A not-so-unexpected class effect. J. Antimicrob. Chemother., 2000, 45(5), 557-559.
[http://dx.doi.org/10.1093/jac/45.5.557] [PMID: 10797074]
[9]
Yu, Z.; Shi, G.; Sun, Q.; Jin, H.; Teng, Y.; Tao, K.; Zhou, G.; Liu, W.; Wen, F.; Hou, T. Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl) quinoline-3-carboxylic acid derivatives. Eur. J. Med. Chem., 2009, 44(11), 4726-4733.
[http://dx.doi.org/10.1016/j.ejmech.2009.05.028] [PMID: 19560843]
[10]
Dang, Z.; Yang, Y.; Ji, R.; Zhang, S. Synthesis and antibacterial activity of novel fluoroquinolones containing substituted piperidines. Bioorg. Med. Chem. Lett., 2007, 17(16), 4523-4526.
[http://dx.doi.org/10.1016/j.bmcl.2007.05.093] [PMID: 17566733]
[11]
Shen, L.L.; Mitscher, L.A.; Sharma, P.N.; O’Donnell, T.J.; Chu, D.W.T.; Cooper, C.S.; Rosen, T.; Pernet, A.G. Mechanism of inhibition of DNA gyrase by quinolone antibacterials: A cooperative drug-DNA binding model. Biochemistry, 1989, 28(9), 3886-3894.
[http://dx.doi.org/10.1021/bi00435a039] [PMID: 2546585]
[12]
Wang, W.; You, Q.D.; Li, Z.Y.; Zou, Y.Q. Design, synthesis and antitumor activity of 3-substituted quinolone derivatives (I). Chin. Chem. Lett., 2008, 19, 1395-1397.
[http://dx.doi.org/10.1016/j.cclet.2008.09.034]
[13]
Nelson, J.M.; Chiller, T.M.; Powers, J.H.; Angulo, F.J. Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: A public health success story. Clin. Infect. Dis., 2007, 44(7), 977-980.
[http://dx.doi.org/10.1086/512369] [PMID: 17342653]
[14]
Ito, A.; Hirai, K.; Inoue, M.; Koga, H.; Suzue, S.; Irikura, T.; Mitsuhashi, S. In vitro antibacterial activity of AM-715, a new nalidixic acid analog. Antimicrob. Agents Chemother., 1980, 17(2), 103-108.
[http://dx.doi.org/10.1128/AAC.17.2.103] [PMID: 6446258]
[15]
King, A.; Warren, C.; Shannon, K.; Phillips, I. In vitro antibacterial activity of norfloxacin (MK-0366). Antimicrob. Agents Chemother., 1982, 21(4), 604-607.
[http://dx.doi.org/10.1128/AAC.21.4.604] [PMID: 6211139]
[16]
Drlica, K.; Zhao, X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol. Mol. Biol. Rev., 1997, 61(3), 377-392.
[PMID: 9293187]
[17]
Milner, S.J.; Seve, A.; Snelling, A.M.; Thomas, G.H.; Kerr, K.G.; Routledge, A.; Duhme-Klair, A.K. Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics. Org. Biomol. Chem., 2013, 11(21), 3461-3468.
[http://dx.doi.org/10.1039/c3ob40162f] [PMID: 23575952]
[18]
Tabarrini, O.; Massari, S.; Daelemans, D.; Stevens, M.; Manfroni, G.; Sabatini, S.; Balzarini, J.; Cecchetti, V.; Pannecouque, C.; Fravolini, A. Structure-activity relationship study on anti-HIV 6-desfluoroquinolones. J. Med. Chem., 2008, 51(17), 5454-5458.
[http://dx.doi.org/10.1021/jm701585h] [PMID: 18710207]
[19]
Emami, S.; Ghafouri, E.; Faramarzi, M.A.; Samadi, N.; Irannejad, H.; Foroumadi, A. Mannich bases of 7-piperazinylquinolones and kojic acid derivatives: Synthesis, in vitro antibacterial activity and in silico study. Eur. J. Med. Chem., 2013, 68, 185-191.
[http://dx.doi.org/10.1016/j.ejmech.2013.07.032] [PMID: 23974018]
[20]
Md-Saleh, S.R.; Chilvers, E.C.; Kerr, K.G.; Milner, S.J.; Snelling, A.M.; Weber, J.P.; Thomas, G.H.; Duhme-Klair, A.K.; Routledge, A. Synthesis of citrate-ciprofloxacin conjugates. Bioorg. Med. Chem. Lett., 2009, 19(5), 1496-1498.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.007] [PMID: 19179071]
[21]
Hooper, D.C.; Wolfson, J.S.; Souza, K.S.; Ng, E.Y.; McHugh, G.L.; Swartz, M.N. Mechanisms of quinolone resistance in Escherichia coli: Characterization of nfxB and cfxB, two mutant resistance loci decreasing norfloxacin accumulation. Antimicrob. Agents Chemother., 1989, 33(3), 283-290.
[http://dx.doi.org/10.1128/AAC.33.3.283] [PMID: 2658782]
[22]
Ferguson, A.D.; Chakraborty, R.; Smith, B.S.; Esser, L.; van der Helm, D.; Deisenhofer, J. Structural basis of gating by the outer membrane transporter FecA. Science, 2002, 295(5560), 1715-1719.
[http://dx.doi.org/10.1126/science.1067313] [PMID: 11872840]
[23]
Hirai, K.; Aoyama, H.; Irikura, T.; Iyobe, S.; Mitsuhashi, S. Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli. Antimicrob. Agents Chemother., 1986, 29(3), 535-538.
[http://dx.doi.org/10.1128/AAC.29.3.535] [PMID: 3521490]
[24]
Wencewicz, T.A.; Möllmann, U.; Long, T.E.; Miller, M.J. Is drug release necessary for antimicrobial activity of siderophore-drug conjugates? Syntheses and biological studies of the naturally occurring salmycin “Trojan Horse” antibiotics and synthetic desferridanoxamine-antibiotic conjugates. Biometals, 2009, 22(4), 633-648.
[http://dx.doi.org/10.1007/s10534-009-9218-3] [PMID: 19221879]
[25]
Guo, H.; Naser, S.A.; Ghobrial, G.; Phanstiel, O.I.V. Synthesis and biological evaluation of new citrate-based siderophores as potential probes for the mechanism of iron uptake in mycobacteria. J. Med. Chem., 2002, 45(10), 2056-2063.
[http://dx.doi.org/10.1021/jm0104522] [PMID: 11985473]
[26]
Hirota, K.; Kitagawa, H.; Shimamura, M.; Ohmori, S. A facile preparation of asym-monomethyl, sym-monomethyl and asym-dimethyl citrate. Chem. Lett., 1980, 9, 191-194.
[http://dx.doi.org/10.1246/cl.1980.191]
[27]
Persmark, M.; Pittman, P.; Buyer, J.S.; Schwyn, B.; Giel, P.R.; Nielands, J.B. Isolation and structure of rhizobactin 1021, a siderophore from alfalfa symbiont Rhizobium meliloti 1021. J. Am. Chem. Soc., 1993, 115, 3950-3956.
[http://dx.doi.org/10.1021/ja00063a014]
[28]
Dolle, R.E.; Gribble, A.; Wilkes, T.; Kruse, L.I.; Eggleston, D.; Saxty, B.A.; Wells, T.N.C.; Groot, P.H.E. Synthesis of novel thiol-containing citric acid analogues. Kinetic evaluation of these and other potential active-site-directed and mechanism-based inhibitors of ATP citrate lyase. J. Med. Chem., 1995, 38(3), 537-543.
[http://dx.doi.org/10.1021/jm00003a016] [PMID: 7853346]
[29]
Weaver, R.; Gilbert, I.H. The design and synthesis of nucleoside triphosphate isosteres as potential inhibitors of HIV reverse transcriptase. Tetrahedron, 1997, 53, 5537-5562.
[http://dx.doi.org/10.1016/S0040-4020(97)00210-X]
[30]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[31]
Molinspiration Cheminformatics. Mol-Soft; 2007.Available at. http://www.molinspiration.com (Accessed September 15, 2019).
[32]
Drechsel, H.; Metzger, J.; Freund, S.; Jung, G.; Boelaert, J.R.; Winkelmann, G. Rhizoferrin - a novel siderophore from the fungus Rhizopusmicrosporus var. rhizopodiformis. Biol. Met., 1991, 4, 238-243.
[http://dx.doi.org/10.1007/BF01141187]
[33]
Drechsel, H.; Jung, G.; Winkelmann, G. Stereochemical characterization of rhizoferrin and identification of its dehydration products. Biol. Met., 1992, 5, 141-148.
[34]
Jung, H.C.; Dong, U.L. Practical synthesis of novel citryl glycoside, the component of the rhizomes of Gastrodiaelata. Korean Chem. Soc., 2008, 29, 2051-2053.
[http://dx.doi.org/10.5012/bkcs.2008.29.10.2051]
[35]
Harris, G.H.; Turner, J.E.T.; Meinz, M.S.; Nallin, O.M.; Helms, G.L.; Bills, G.F.; Zink, D.; Wilson, K.E. Isolation and structure elucidation of viridiofungins A, B and C. Tetrahedron Lett., 1993, 34, 5235-5238.
[http://dx.doi.org/10.1016/S0040-4039(00)73961-X]
[36]
Bergeron, R.J.; Xin, M.G.; Smith, R.E.; Wollenweber, M.; McManis, J.S.; Ludin, C.; Abboud, K.A. Total synthesis of rhizoferrin, an iron chelator. Tetrahedron, 1997, 53, 427-434.
[http://dx.doi.org/10.1016/S0040-4020(96)01061-7]
[37]
Refsgaard, H.H.F.; Jensen, B.F.; Brockhoff, P.B.; Padkjaer, S.B.; Guldbrandt, M.; Christensen, M.S. In silico prediction of membrane permeability from calculated molecular parameters. J. Med. Chem., 2005, 48(3), 805-811.
[http://dx.doi.org/10.1021/jm049661n] [PMID: 15689164]
[38]
Muegge, I. Selection criteria for drug-like compounds. Med. Res. Rev., 2003, 23(3), 302-321.
[http://dx.doi.org/10.1002/med.10041] [PMID: 12647312]
[39]
Wang, R.X.; Fu, Y.; Lai, L.H. A new atom-additive method for the calculating partition coefficient. J. Chem. Inf. Comput. Sci., 1997, 37, 615-621.
[http://dx.doi.org/10.1021/ci960169p]
[40]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[41]
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]
[42]
Perez, C.; Pauli, M.; Bazevque, P. An antibiotic assay by the agar well diffusion method. Acta Biologiaeet Medicinal Experimentalis, 1990, 15, 113-115.
[43]
Satish, S.; Raveesha, K.A.; Janardhna, G.R. Antibacterial activity of plant extracts on phytopathogenic Xanthomonas campestrispathovars. Lett. Appl. Microbiol., 2002, 22, 145-147.
[44]
Senthil, K.S.; Kamaraj, M. Analysis of Phytochemical constituents and microbial activities of Cucumisanguria L. against clinical pathogens. Amer. Eur. J. Agr. Envi. Sci., 2010, 7, 176-178.
[45]
Tsyalkovsky, V.M.; Kutsyk, R.V.; Matiychuk, V.S.; Obushak, N.D.; Klyufinskaya, T.I. Recent developments and biological activities of thiazolidinone derivatives. Pharm. Chem. J., 2005, 39, 20-27.
[46]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Immunol. methods, 1983, 65, 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4]
[47]
Bose, D.S.; Idrees, M.; Jakka, N.M.; Rao, J.V. Diversity-oriented synthesis of quinolines via Friedländer annulation reaction under mild catalytic conditions. J. Comb. Chem., 2010, 12(1), 100-110.
[http://dx.doi.org/10.1021/cc900129t] [PMID: 20000618]
[48]
Crystal Structure of the C(30) Carotenoid Dehydrosqualene Synthase from Staphylococcus Aureus Complexed With Bisphosphonate BPH-700. Available at. http://www.rcsb.org/pdb/explore/explore.do?structureId=2zcs (Accessed September 14, 2019).
[49]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[50]
Goodsell, D.S.; Olson, A.J. Automated docking of substrates to proteins by simulated annealing. Proteins, 1990, 8(3), 195-202.
[http://dx.doi.org/10.1002/prot.340080302] [PMID: 2281083]

Rights & Permissions Print Cite
Article Metrics
51
4
© 2024 Bentham Science Publishers | Privacy Policy