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Design, synthesis, and biological evaluation of pyrimidine analogs as SecA inhibitors

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Abstract

SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. We have previously reported pyrimidine analogs as SecA inhibitors. Herein, we report an extension of the earlier work in the synthesis and evaluation of a series of 15 5-cyanothiouracil derivatives as SecA inhibitors. All the compounds have been evaluated for their inhibition of SecA ATPase (EcSecAN68) and for their antimicrobial activity against Escherichia coli NR698 (a leaky mutant) and Bacillus anthracis Sterne. Twelve compounds showed IC50 of less than 6.3 μM when tested against EcSecAN68. In antimicrobial studies against E. coli NR698, six compounds showed MIC of <12.5 μM with three being less than 6.3 μM. Against B. anthracis Sterne, three compounds showed MIC of <6.3 μM.

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References

  1. Levy SB, Marshall B. Antibacterial resistance worldwide: causes, challenges and responses. Nat Med. 2004;10:S122–9. https://doi.org/10.1038/nm1145.

    Article  CAS  PubMed  Google Scholar 

  2. Smets D, Loos MS, Karamanou S, Economou A. Protein transport across the bacterial plasma membrane by the Sec pathway. Protein J. 2019;38:262–73. https://doi.org/10.1007/s10930-019-09841-8.

    Article  CAS  PubMed  Google Scholar 

  3. Catipovic MA, Bauer BW, Loparo JJ, Rapoport TA. Protein translocation by the SecA ATPase occurs by a power-stroke mechanism. Embo J. 2019;38. https://doi.org/10.15252/embj.2018101140.

  4. Chaudhary AS, Chen W, Jin J, Tai PC, Wang B. SecA: a potential antimicrobial target. Future Med Chem. 2015;7:989–1007. https://doi.org/10.4155/fmc.15.42.

    Article  CAS  PubMed  Google Scholar 

  5. Kusters I, Driessen AJ. SecA, a remarkable nanomachine. Cell Mol Life Sci. 2011;68:2053–66. https://doi.org/10.1007/s00018-011-0681-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hsieh YH, Zhang H, Lin BR, Cui N, Na B, Yang H, et al. SecA alone can promote protein translocation and ion channel activity: SecYEG increases efficiency and signal peptide specificity. J Biol Chem. 2011;286:44702–9. https://doi.org/10.1074/jbc.M111.300111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Banerjee T, Zheng Z, Abolafia J, Harper S, Oliver D. The SecA protein deeply penetrates into the SecYEG channel during insertion, contacting most channel transmembrane helices and periplasmic regions. J Biol Chem. 2017;292:19693–707. https://doi.org/10.1074/jbc.RA117.000130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Findik BT, Smith VF, Randall LL. Penetration into membrane of amino-terminal region of SecA when associated with SecYEG in active complexes. Protein Sci. 2018;27:681–91. https://doi.org/10.1002/pro.3362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cranford-Smith T, Huber D. The way is the goal: how SecA transports proteins across the cytoplasmic membrane in bacteria. FEMS Microbiol Lett. 2018;365. https://doi.org/10.1093/femsle/fny093.

  10. Ma C, Wu X, Sun D, Park E, Catipovic MA, Rapoport TA, et al. Structure of the substrate-engaged SecA-SecY protein translocation machine. Nat Commun. 2019;10:2872 https://doi.org/10.1038/s41467-019-10918-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gupta R, Toptygin D, Kaiser CM. The SecA motor generates mechanical force during protein translocation. Nat Commun. 2020;11:3802 https://doi.org/10.1038/s41467-020-17561-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cui J, Jin J, Hsieh YH, Yang H, Ke B, Damera K, et al. Design, synthesis and biological evaluation of rose bengal analogues as SecA inhibitors. ChemMedChem. 2013;8:1384–93. https://doi.org/10.1002/cmdc.201300216.

    Article  CAS  PubMed  Google Scholar 

  13. Chen W, Huang YJ, Gundala SR, Yang H, Li M, Tai PC, et al. The first low microM SecA inhibitors. Bioorg Med Chem. 2010;18:1617–25.

    Article  CAS  Google Scholar 

  14. Li M, Huang YJ, Tai PC, Wang B. Discovery of the first SecA inhibitors using structure-based virtual screening. Biochem Biophys Res Commun. 2008;368:839–45. https://doi.org/10.1016/j.bbrc.2008.01.135.

    Article  CAS  PubMed  Google Scholar 

  15. Chaudhary AS, Jin J, Chen W, Tai PC, Wang B. Design, syntheses and evaluation of 4-oxo-5-cyano thiouracils as SecA inhibitors. Bioorg Med Chem. 2015;23:105–17. https://doi.org/10.1016/j.bmc.2014.11.017.

    Article  CAS  PubMed  Google Scholar 

  16. Jang MY, De Jonghe S, Segers K, Anné J, Herdewijn P. Synthesis of novel 5-amino-thiazolo[4,5-d]pyrimidines as E. coli and S. aureus SecA inhibitors. Bioorg Med Chem. 2011;19:702–14. https://doi.org/10.1016/j.bmc.2010.10.027.

    Article  CAS  PubMed  Google Scholar 

  17. Akula N, Trivedi P, Han FQ, Wang N. Identification of small molecule inhibitors against SecA of Candidatus Liberibacter asiaticus by structure based design. Eur J Med Chem. 2012;54:919–24. https://doi.org/10.1016/j.ejmech.2012.05.035.

    Article  CAS  PubMed  Google Scholar 

  18. Akula N, Zheng H, Han FQ, Wang N. Discovery of novel SecA inhibitors of Candidatus Liberibacter asiaticus by structure based design. Bioorg Med Chem Lett. 2011;21:4183–8. https://doi.org/10.1016/j.bmcl.2011.05.086.

    Article  CAS  PubMed  Google Scholar 

  19. Bamba F, Jinn J, Tai PC, Wang B. Synthesis and biological evaluation of novel 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors. Heterocyc Commun. 2020;26. https://doi.org/10.1515/hc-2020-0100.

  20. Kondoh A, Yorimitsu H, Oshima K. Nucleophilic aromatic substitution reaction of nitroarenes with alkyl- or arylthio groups in dimethyl sulfoxide by means of cesium carbonate. Tetrahedron. 2006;62:2357–60. https://doi.org/10.1016/j.tet.2005.11.073.

    Article  CAS  Google Scholar 

  21. Rao PJ, Gopal MV, Shaheen SM, Chakrathi B. Synthesis characterization and biological activity of some pyrimidine derivatives. World J Pham Pharm Sci. 2015;4:896.

    CAS  Google Scholar 

  22. Wang W, Yang Q, Zhou R, Fu H-Y, Li R-X, Chen H, et al. Palladium nanoparticles generated from allylpalladium chloride in situ: a simple and highly efficient catalytic system for Mizoroki–Heck reactions. J Organomet Chem. 2012;697:1–5. https://doi.org/10.1016/j.jorganchem.2011.10.002.

    Article  CAS  Google Scholar 

  23. Yi T, Mo M, Fu H-Y, Li R-X, Chen H, Li X-J. Highly efficient Pd/tetraphosphine catalytic system for copper-free sonogashira reactions of aryl bromides with terminal alkynes. Catal Lett. 2012;142:594–600. https://doi.org/10.1007/s10562-012-0796-2.

    Article  CAS  Google Scholar 

  24. Arienti KL, Brunmark A, Axe FU, McClure K, Lee A, Blevitt J, et al. Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles. J Med Chem. 2005;48:1873–85. https://doi.org/10.1021/jm0495935.

    Article  CAS  PubMed  Google Scholar 

  25. Ruiz N, Falcone B, Kahne D, Silhavy TJ. Chemical conditionality: a genetic strategy to probe organelle assembly. Cell. 2005;121:307–17. https://doi.org/10.1016/j.cell.2005.02.014.

    Article  CAS  PubMed  Google Scholar 

  26. Hanaki H, Labischinski H, Sasaki K, Kuwahara-Arai K, Inaba Y, Hiramatsu K. Mechanism of vancomycin resistance in MRSA strain Mu50. Jpn J Antibiot. 1998;51:237–47.

    CAS  PubMed  Google Scholar 

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Acknowledgements

FB was a visiting scholar at GSU when conducting the lab research with partial financial support from the Islamic Development Bank (IDB) under a merit scholarship program. We also acknowledge the partial financial support to PCT and BW (AI104168) by the National Institutes of Health. JJ and ASC were supported by the Molecular Basis of Diseases Fellowship of Georgia State University.

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Author notes

  1. Jinshan Jin

    Present address: US Food and Drug Administration, National Center of Toxicological Research, 3900 NCTR Road, Jefferson, AR, 72079, USA

  2. Arpana S. Chaudhary

    Present address: Bayer Corporation, 800N. Lindbergh Blvd, St. Louis, MO, 63141, USA

Authors and Affiliations

  1. Departments of Chemistry, Georgia State University, Atlanta, GA, 30303, USA

    Fante Bamba, Arpana S. Chaudhary & Binghe Wang

  2. Laboratoire de Chimie Organique et des Substances Naturelles, Université Félix Houphouët-Boigny, 22Bp 582, Abidjan, Côte d’Ivoire

    Fante Bamba

  3. Departments of Biology, Georgia State University, Atlanta, GA, 30303, USA

    Jinshan Jin & Phang C. Tai

  4. Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA

    Binghe Wang

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  1. Fante Bamba
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Correspondence to Phang C. Tai or Binghe Wang.

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Bamba, F., Jin, J., Chaudhary, A.S. et al. Design, synthesis, and biological evaluation of pyrimidine analogs as SecA inhibitors. Med Chem Res 30, 1334–1340 (2021). https://doi.org/10.1007/s00044-021-02717-6

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