A number of substituted benzopentathiepin-6-amines and their analogues without a polysulfur ring were synthesized and evaluated in vitro for antimicrobial activity against a panel of reference bacterial and fungal strains. Trifluoroacetamide 14 demonstrated high antibacterial activity against Staphylococcus aureus (MRSA strain) with a MIC of 4 μg/mL, which was four-fold higher than the activity of a reference drug amoxicillin. This compound was also most active against the Candida albicans fungus (MIC of 1 μg ml−1), whereas amide 17 containing a morpholine substituent was most active against the Cryptococcus neoformans fungus (MIC of 2 μg ml−1). These compounds have no hemolytic activity and are low cytotoxic. Replacement of the pentathiepine ring with 1,3-dithiolan-2-one or 1,3-dithiolane moieties leads to loss of antimicrobial activity. Based on the QSAR analysis and molecular docking data, bacterial DNA ligase might be one of the targets for the antibacterial activity of substituted benzopentathiepin-6-amines against S. aureus.
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Brown ED, Wright GD. Antibacterial drug discovery in the resistance era. Nature. 2016;529:336–43.
WHO. Antibiotic resistance. 2017. http://www.who.int/mediacentre/factsheets/antibiotic-resistance/en/.
World Health Organization. Antibacterial agents in clinical development. 2017. WHO/EMP/IAU/2017.11.
Aminov R. History of antimicrobial drug discovery: major classes and health impact. Biochem Pharm. 2017;133:4–19.
Rossiter SE, Fletcher MH, Wuest WM. Natural products as platforms to overcome antibiotic resistance. Chem Rev. 2017;117:12415–74.
Konstantinova LS, Amelichev SA, Rakitin OA. 1,2,3,4,5-Pentathiepines and 1,2,3,4,5-pentathiepanes. Russ Chem Rev. 2007;76:195–211.
Davison EK, Sperry J. Natural products with heteroatom-rich ring systems. J Nat Prod. 2017;80:3060–79.
Litaudon M, Trigalo F, Martin M, Frappier F, Guyot M. Lissoclinotoxins: antibiotic polysulfur derivatives from the tunicate Lissoclinum perforatum. Revised structure of lissoclinotoxin A. Tetrahedron. 1994;50:5323–34.
Litaudon M, Guyot M. Lissoclinotoxin A, an antibiotic 1,2,3-trithiane derivative from the tunicate Lissoclinum perforatum. Tetrahedron Lett. 1991;32:911–4.
Davidson BS, Molinski TF, Barrows LR, Ireland CM. Varacin: a novel benzopentathiepin from Lissoclinum vareau that is cytotoxic toward a human colon tumor. J Am Chem Soc. 1991;113:4709–10.
Makarieva TN, Stonik VA, Dmitrenok AS, Grebnev BB, Isakov VV, Rebachyk NM, et al. Varacin and three new marine antimicrobial polysulfides from the far-eastern ascidian Polycitor sp. J Nat Prod. 1995;58:254–8.
Liu H, Fujiwara T, Nishikawa T, Mishima Y, Nagai H, Shida T, et al. Lissoclibadins 1–3, three new polysulfur alkaloids, from the ascidian Lissoclinum cf. badium. Tetrahedron. 2005;61:8611–5.
Ford PW, Davidson BS. Synthesis of varacin, a cytotoxic naturally occurring benzopentathiepin isolated from a marine ascidian. J Org Chem. 1993;58:4522–3.
Chenard BL. Substituted benzopentathiepins, process therefor and intermediates. Patent WO1984004921, 1984.
Khomenko TM, Tolstikova TG, Bolkunov AV, Dolgikh MP, Pavlova AV, Korchagina DV, et al. 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine: novel aminobenzopentathiepine having in vivo anticonvulsant and anxiolytic activities. Lett Drug Des Discov. 2009;6:464–7.
Khomenko TM, Korchagina DV, Komarova NI, Volcho KP, Salakhutdinov NF. Synthesis of 6-Amino-benzopentathiepines by reactions of 4-nitro-benzyldithiol-2-ones with NaHS. Lett Org Chem. 2011;8:193–7.
Kulikov AV, Tikhonova MA, Kulikova EA, Volcho KP, Khomenko TM, Salakhutdinov NF, et al. A new synthetic varacin analogue, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), decreased hereditary catalepsy and increased the BDNF gene expression in the hippocampus in mice. Psychopharmacology. 2012;221:469–78.
Kulikova EA, Volcho KP, Salakhutdinov NF, Kulikov AV. Benzopentathiepine derivative, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), as a promising antidepressant of new generation. Lett Drug Des Discov. 2017;14:974–84.
Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, et al. Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer’s disease. PLoS Biol. 2014;12:e1001923.
Zakharenko A, Khomenko T, Zhukova S, Koval O, Zakharova O, Anarbaev R, et al. Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase I inhibitors with a benzopentathiepine moiety. Bioorg Med Chem. 2015;23:2044–52.
Kuzmich AS, Khomenko TM, Fedorov SN, Makarieva TN, Shubina LK, Komarova NI, et al. Cytotoxic and cancer preventive activity of benzotrithioles and benzotrithiole oxides, synthetic analogues of varacins. Med Chem Res. 2017;26:397–404.
Baguley TD, Nairn AC, Lombroso PJ, Ellman JA. Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP. Bioorg Med Chem Lett. 2015;25:1044–6.
Blaskovich MA, Zuegg J, Elliott AG, Cooper MA. Helping chemists discover new antibiotics. ACS Infect Dis. 2015;1:285–7.
WHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 2017. http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/.
Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007;20:133–63. https://doi.org/10.1128/CMR.00029-06.
Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis. 2001;7:375–81.
Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS—100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8:515–48.
Lee SH. Disulfide and multisulfide antitumor agents and their modes of action. Arch Pharm Res. 2009;32:299–315.
ChEMBL: ChEMBL is a manually curated database of bioactive molecules with drug-like properties. 'Official site of the European Bioinformatics Institute of the European Molecular Biology Laboratory (EMBL-EBI). Hinxton, Cambridgeshire, UK. 2017. https://www.ebi.ac.uk/chembl/.
BindingDB: The Binding Database. BindingDB is a public web-accessible database of measured binding affinities. Official site of Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California. San Diego, La Jolla, CA, USA. 2017. https://www.bindingdb.org/.
PubChem. PubChem is world’s largest collection of freely accessible chemical information. Official site of National Library of Medicine of National Center for Biotechnology Information of National Institutes of Health. Rockville Pike, Bethesda, MD, USA. 2017. https://pubchem.ncbi.nlm.nih.gov.
Vassiliev PM, Spasov AA, Kosolapov VA, Kucheryavenko AF, Gurova NA, Anisimova VA. Consensus Drug Design Using IT Microcosm. In: Application of Computational Techniques in Pharmacy and Medicine; Eds. L. Gorb, V. Kuz'min, E. Muratov. Series: Challenges and Advances in Computational Chemistry and Physics, vol. 17; Ed. J. Leszczynski. Dordrecht (Netherlands): Springer Science + Business Media. 2014;369–431
UniProtKB. 2017. http://www.uniprot.org/uniprot/.
Howard S, Amin N, Benowitz AB, Chiarparin E, Cui H, Deng X, et al. Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase. ACS Med Chem Lett. 2013;4:1208–12.
Streker K, Schäfer T, Freiberg C, Brötz-Oesterhelt H, Hacker J, Labischinski H, et al. In vitro and in vivo validation of ligA and tarI as essential targets in Staphylococcus aureus. Antimicrob Agents Chemother. 2008;52:4470–74.
Small-Molecule Drug Discovery Suite 2017-1, New York: Schrödinger, Inc.; 2017. https://www.schrodinger.com/citations.
Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, et al. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput. 2016;12:281–96.
Surivet JP, et al. Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity. Bioorg Med Chem Lett. 2012;22:6705–11.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes. J Med Chem. 2006;49:6177–96.
Stokes SS, Gowravaram M, Huynh H, Lu M, Mullen GB, Chen B, et al. Discovery of bacterial NAD+-dependent DNA ligase inhibitors: improvements in clearance of adenosine series. Bioorg Med Chem Lett. 2012;22:85–9.
Ludlow RF, Verdonk ML, Saini HK, Tickle IJ, Jhoti H. Detection of secondary binding sites in proteins using fragment screening. PNAS. 2015;112:15910–5.
Tian W, Chen C, Lei X, Zhao J, Liang J. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res. 2018;46:W363–W367. https://doi.org/10.1093/nar/gky473.
The antimicrobial screening performed by CO-ADD (The Community for Antimicrobial Drug Discovery) was funded by the Wellcome Trust (UK) and The University of Queensland (Australia). We would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. This work was supported by SB RAS integration project (N 0302–2018–0010).