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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Synthesis and Assessment of 3-Substituted Phenazines as Novel Antichlamydial Agents

Author(s): Xiaofeng Bao, Ziyi Liu, Min Ni, Chao Xia, Shunxin Xu, Shengju Yang* and Yu Zhao*

Volume 16, Issue 3, 2020

Page: [413 - 421] Pages: 9

DOI: 10.2174/1573406415666190708145639

Price: $65

Abstract

Background: In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity.

Objective: The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents.

Methods: The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method.

Results: Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 μM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 μM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle.

Conclusion: Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.

Keywords: 3-substituted phenazine, synthesis, antichlamydial activity, Buchwald-Hartwig, 3-substituted phenazine derivatives, chlamydiae.

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[1]
Abdelrahman, Y.M.; Belland, R.J. The chlamydial developmental cycle. FEMS Microbiol. Rev., 2005, 29(5), 949-959.
[http://dx.doi.org/10.1016/j.femsre.2005.03.002] [PMID: 16043254]
[2]
Stephens, R.S.; Myers, G.; Eppinger, M.; Bavoil, P.M. Divergence without difference: phylogenetics and taxonomy of Chlamydia resolved. FEMS Immunol. Med. Microbiol., 2009, 55(2), 115-119.
[http://dx.doi.org/10.1111/j.1574-695X.2008.00516.x] [PMID: 19281563]
[3]
Banhart, S.; Saied, E.M.; Martini, A.; Koch, S.; Aeberhard, L.; Madela, K.; Arenz, C.; Heuer, D. Improved plaque assay identifies a novel anti-chlamydia ceramide derivative with altered intracellular localization. Antimicrob. Agents Chemother., 2014, 58(9), 5537-5546.
[http://dx.doi.org/10.1128/AAC.03457-14] [PMID: 25001308]
[4]
Bao, X.; Gylfe, A.; Sturdevant, G.L.; Gong, Z.; Xu, S.; Caldwell, H.D.; Elofsson, M.; Fan, H. Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner. J. Bacteriol., 2014, 196(16), 2989-3001.
[http://dx.doi.org/10.1128/JB.01677-14] [PMID: 24914180]
[5]
Fan, H. Blindness-causing trachomatous trichiasis biomarkers sighted. Invest. Ophthalmol. Vis. Sci., 2012, 53, 2560-2560.
[http://dx.doi.org/10.1167/iovs.12-9835]
[6]
Workowski, K.A. Centers for disease control and prevention sexually transmitted diseases treatment guidelines. Clin. Infect. Dis., 2015, 61(Suppl. 8), S759-S762.
[http://dx.doi.org/10.1093/cid/civ771] [PMID: 26602614]
[7]
Sandoz, K.M.; Rockey, D.D. Antibiotic resistance in Chlamydiae. Future Microbiol., 2010, 5(9), 1427-1442.
[http://dx.doi.org/10.2217/fmb.10.96] [PMID: 20860486]
[8]
Hogan, R.J.; Mathews, S.A.; Mukhopadhyay, S.; Summersgill, J.T.; Timms, P. Chlamydial persistence: beyond the biphasic paradigm. Infect. Immun., 2004, 72(4), 1843-1855.
[http://dx.doi.org/10.1128/IAI.72.4.1843-1855.2004] [PMID: 15039303]
[9]
Hybiske, K.; Stephens, R.S. Mechanisms of host cell exit by the intracellular bacterium Chlamydia. Proc. Natl. Acad. Sci. USA, 2007, 104(27), 11430-11435.
[http://dx.doi.org/10.1073/pnas.0703218104] [PMID: 17592133]
[10]
Lee, J.K.; Enciso, G.A.; Boassa, D.; Chander, C.N.; Lou, T.H.; Pairawan, S.S.; Guo, M.C.; Wan, F.Y.M.; Ellisman, M.H.; Sütterlin, C.; Tan, M. Replication-dependent size reduction precedes differentiation in Chlamydia trachomatis. Nat. Commun., 2018, 9(1), 45.
[http://dx.doi.org/10.1038/s41467-017-02432-0] [PMID: 29298975]
[11]
Li, X.H.; Wang, X.M.; Xu, C.J.; Huang, J.K.; Wang, C.N.; Wang, X.Y.; He, L.Q.; Ling, Y. Synthesis and biological evaluation of nitric oxide-releasing hybrids from gemcitabine and phenylsulfonyl furoxans as anti-tumor agents. MedChemComm, 2015, 6, 1130-1136.
[http://dx.doi.org/10.1039/C5MD00158G]
[12]
Ling, Y.; Feng, J.; Luo, L.; Guo, J.; Peng, Y.; Wang, T.; Ge, X.; Xu, Q.; Wang, X.; Dai, H.; Zhang, Y. Design and synthesis of C3-substituted β-carboline-based histone deacetylase inhibitors with potent antitumor activities. ChemMedChem, 2017, 12(9), 646-651.
[http://dx.doi.org/10.1002/cmdc.201700133] [PMID: 28425177]
[13]
Li, J.L.; Chen, D.; Huang, L.; Ni, M.; Zhao, Y.; Fan, H.; Bao, X. Antichlamydial dimeric indole derivatives from marine actinomycete Rubrobacter radiotolerans. Planta Med., 2017, 83(9), 805-811.
[http://dx.doi.org/10.1055/s-0043-100382] [PMID: 28095586]
[14]
Chen, G.T.; Yang, M.; Nong, S.J.; Yang, X.; Ling, Y.; Wang, D.G.; Wang, X.Y.; Zhang, W. Microbial transformation of 20(S)-protopanaxadiol by Absidia corymbifera. Cytotoxic activity of the metabolites against human prostate cancer cells. Fitoterapia, 2013, 84, 6-10.
[http://dx.doi.org/10.1016/j.fitote.2012.09.018] [PMID: 23022533]
[15]
Conda-Sheridan, M.; Marler, L.; Park, E.J.; Kondratyuk, T.P.; Jermihov, K.; Mesecar, A.D.; Pezzuto, J.M.; Asolkar, R.N.; Fenical, W.; Cushman, M. Potential chemopreventive agents based on the structure of the lead compound 2-bromo-1-hydroxyphenazine, isolated from Streptomyces species, strain CNS284. J. Med. Chem., 2010, 53(24), 8688-8699.
[http://dx.doi.org/10.1021/jm1011066] [PMID: 21105712]
[16]
Garrison, A.T.; Abouelhassan, Y.; Norwood, V.M., IV; Kallifidas, D.; Bai, F.; Nguyen, M.T.; Rolfe, M.; Burch, G.M.; Jin, S.; Luesch, H.; Huigens, R.W., III Structure-activity relationships of a diverse class of halogenated phenazines that targets persistent, antibiotic tolerant bacterial biofilms and mycobacterium tuberculosis. J. Med. Chem., 2016, 59(8), 3808-3825.
[http://dx.doi.org/10.1021/acs.jmedchem.5b02004] [PMID: 27018907]
[17]
Bao, X.F.; Xue, Y.; Xia, C.; Lu, Y.; Yang, N.; Zhao, Y. Synthesis and assessment of novel anti-chlamydial benzylidene acylhydrazides derivatives. Lett. Drug Des. Discov., 2018, 15, 31-36.
[18]
Bao, X.F.; Yu, X.W.; Xia, C.; Yang, N.J.; Yang, S.J.; Zhao, Y. Synthesis and antichlamydial activity of novel phenazines. Lett. Drug Des. Discov., 2019, 16, 174-181.
[http://dx.doi.org/10.2174/1570180815666180518112952]
[19]
Garrison, A.T.; Abouelhassan, Y.; Kallifidas, D.; Tan, H.; Kim, Y.S.; Jin, S.; Luesch, H.; Huigens, R.W., III An Efficient buchwald-hartwig/reductive cyclization for the scaffold diversification of halogenated phenazines: potent antibacterial targeting, biofilm eradication, and prodrug exploration. J. Med. Chem., 2018, 61(9), 3962-3983.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01903] [PMID: 29638121]
[20]
Jiang, J.; Guiza Beltran, D.; Schacht, A.; Wright, S.; Zhang, L.; Du, L. Functional and Structural analysis of phenazine o-methyltransferase laphzm from lysobacter antibioticus OH13 and one-pot enzymatic synthesis of the antibiotic myxin. ACS Chem. Biol., 2018, 13(4), 1003-1012.
[http://dx.doi.org/10.1021/acschembio.8b00062] [PMID: 29510028]
[21]
Prandina, A.; Herfindal, L.; Radix, S.; Rongved, P.; Døskeland, S.O.; Le Borgne, M.; Perret, F. Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 370-375.
[http://dx.doi.org/10.1080/14756366.2017.1421638] [PMID: 29336193]
[22]
Sletta, H.; Degnes, K.F.; Herfindal, L.; Klinkenberg, G.; Fjærvik, E.; Zahlsen, K.; Brunsvik, A.; Nygaard, G.; Aachmann, F.L.; Ellingsen, T.E.; Døskeland, S.O.; Zotchev, S.B. Anti-microbial and cytotoxic 1,6-dihydroxyphenazine-5,10-dioxide (iodinin) produced by Streptosporangium sp. DSM 45942 isolated from the fjord sediment. Appl. Microbiol. Biotechnol., 2014, 98(2), 603-610.
[http://dx.doi.org/10.1007/s00253-013-5320-0] [PMID: 24158735]
[23]
Abdelmohsen, U.R.; Cheng, C.; Reimer, A.; Kozjak-Pavlovic, V.; Ibrahim, A.K.; Rudel, T.; Hentschel, U.; Edrada-Ebel, R.; Ahmed, S.A. Antichlamydial sterol from the Red Sea sponge Callyspongia aff. implexa. Planta Med., 2015, 81(5), 382-387.
[http://dx.doi.org/10.1055/s-0035-1545721] [PMID: 25782033]

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