Synthesis of bicyclic 1,4-thiazepines as novel anti-Trypanosoma brucei brucei agents.

1,4-Thiazepines derivatives are pharmacologically important heterocycles with different applications in medicinal chemistry. In the present work, we describe the preparation of new bicyclic thiazolidinyl-1,4-thiazepines 3 by reaction between azadithiane compounds and Michael acceptors. The reaction scope was explored and the yields were optimized. The activity of the new compounds was evaluated against Nippostrongylus brasiliensis and Caenorhabditis elegans as anthelmintic models and Trypanosoma brucei brucei. The most active compound was 3l, showing an EC50 = 2.8 ± 0.7 μM against T. b. brucei and a selectivity index >71.

[1]  Elias S. J. Arnér,et al.  Preparation and assay of mammalian thioredoxin and thioredoxin reductase. , 1999, Methods in enzymology.

[2]  L. Goupil,et al.  Introduction: drug discovery and development for neglected diseases. , 2014, Chemical reviews.

[3]  L. M. Lima,et al.  Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates. , 2013, European journal of medicinal chemistry.

[4]  C. Saiz,et al.  Imine Domino Reactions Generate Novel Scaffolds: Fused Bisthiazolidines or Bisthiiranes , 2012 .

[5]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[6]  G. Salinas,et al.  Discovering Echinococcus granulosus thioredoxin glutathione reductase inhibitors through site-specific dynamic combinatorial chemistry , 2013, Molecular Diversity.

[7]  Karen Perelmuter,et al.  In vitro activity and mode of action of distamycin analogues against African trypanosomes. , 2017, European journal of medicinal chemistry.

[8]  Terry K. Smith,et al.  Development of Simplified Heterocyclic Acetogenin Analogues as Potent and Selective Trypanosoma brucei Inhibitors , 2016, ChemMedChem.

[9]  R. Loddo,et al.  Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives. , 2009, European journal of medicinal chemistry.

[10]  Anuj Sharma,et al.  Thia‐Michael Addition: An Emerging Strategy in Organic Synthesis , 2018 .

[11]  D. Maloney,et al.  Synthesis of Oxadiazole-2-oxide Analogues as Potential Antischistosomal Agents. , 2009, Tetrahedron letters.

[12]  V. Moreno,et al.  New organoruthenium complexes with bioactive thiosemicarbazones as co-ligands: potential anti-trypanosomal agents. , 2012, Dalton transactions.

[13]  Allan M Jordan,et al.  The medicinal chemist's toolbox: an analysis of reactions used in the pursuit of drug candidates. , 2011, Journal of medicinal chemistry.

[14]  Anuj Sharma,et al.  Benzothiazepines: chemistry of a privileged scaffold , 2015 .

[15]  P. Wipf,et al.  Selenosemicarbazones as potent cruzipain inhibitors and their antiparasitic properties against Trypanosoma cruzi , 2012 .

[16]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[17]  V. Gladyshev,et al.  Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites , 2012, PloS one.

[18]  Tyler E. Benedum,et al.  A practical method for oxazole synthesis by cycloisomerization of propargyl amides. , 2004, Organic letters.

[19]  L. Suescun,et al.  Synthesis and in vitro anthelmintic activity against Nippostrongylus brasiliensis of new 2-amino-4-hydroxy-delta-valerolactam derivatives. , 1997, Farmaco.

[20]  Adam R Renslo,et al.  Drug discovery and development for neglected parasitic diseases , 2006, Nature chemical biology.

[21]  M. Tyers,et al.  Caenorhabditis elegans is a useful model for anthelmintic discovery , 2015, Nature Communications.

[22]  R. Bonomo,et al.  Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase. , 2015, ACS infectious diseases.

[23]  J. Baldwin,et al.  Rules for ring closure. , 1977, Ciba Foundation symposium.

[24]  G. Sheldrick.  A short history of SHELX. , 2008, Acta crystallographica. Section A, Foundations of crystallography.

[25]  N. Trippodo,et al.  Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. , 1997, Journal of medicinal chemistry.

[26]  David R Spring,et al.  Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. , 2010, Nature communications.

[27]  E. Ferreira,et al.  Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity. , 2014, European journal of medicinal chemistry.

[28]  Chuan-Xin Yu,et al.  Thioredoxin Glutathione Reductase as a Novel Drug Target: Evidence from Schistosoma japonicum , 2012, PloS one.

[29]  George M. Sheldrick,et al.  ShelXle: a Qt graphical user interface for SHELXL , 2011, Journal of applied crystallography.

[30]  L. Domínguez,et al.  Use of L4 larvae of Nippostrongylus brasiliensis for the in vivo screening of anthelmintic drugs. , 2000, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[31]  Mahmoud Labib,et al.  Synthesis and Surface Investigations of N-Substituted 2,5-Dithio-7-azabicyclo[2.2.1]heptanes on Gold Surfaces , 2012 .

[32]  D. Moerman,et al.  Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity , 2016, PLoS neglected tropical diseases.

[33]  E. Davioud‐Charvet,et al.  Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target , 2007, PLoS medicine.

[34]  L. Suescun,et al.  Enantioselective synthesis of new oxazolidinylthiazolidines as enzyme inhibitors. , 2017, Tetrahedron, asymmetry.

[35]  F. Lovering,et al.  Escape from Flatland 2: complexity and promiscuity , 2013 .

[36]  Y. Pommier,et al.  Thiazolothiazepine inhibitors of HIV-1 integrase. , 1999, Journal of medicinal chemistry.

[37]  H. Alper,et al.  Remarkable synthesis of 2-(Z)-6-(E)-4H-[1,4]-thiazepin-5-ones by zwitteronic rhodium-catalyzed chemo- and regioselective cyclohyrocarbonylative ring expansion of acetylenic thiazoles. , 2001, Journal of the American Chemical Society.