Synthesis and biological evaluation of benzothiazin-4-ones: a possible new class of acetylcholinesterase inhibitors

Abstract A series of nineteen benzothiazin-4-ones from N-(3-aminopropyl) piperidine, 4-(2-aminoethyl)morpholine or 1-(2-aminoethyl)piperidine, aliphatic or aromatic aldehyde and thiosalicylic acid, were synthesized in good yields by multicomponent one-pot reactions. The solvent was toluene and this efficient procedure afforded the desired heterocycles in 5 h. Identification and characterization were achieved by NMR and GC–MS techniques. In vitro AChE activities of all compounds were evaluated in cerebral cortex and hippocampus of rats and in general, the results in cortex were more promising than hippocampus. The benzothiazinone 5Bd showed the best AChE inhibition activity IC50 8.48 μM (cortex) and IC50 39.80 μM (hippocampus). The cytotoxicity of seven compounds in MCR-5 human fibroblast cell by SRB test in 24 h were evaluated and 5Bd suggest preliminary safety, showing no cytotoxicity at 100 µM. Finally, these important findings could be a starting point for the development of new AChE inhibitors agents and will provide the basis for new studies.

[1]  C. Supuran,et al.  The synthesis of novel sulfamides derived from β-benzylphenethylamines as acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase enzymes inhibitors. , 2017, Bioorganic chemistry.

[2]  N. Herrmann,et al.  Acetylcholinesterase inhibitors for treating dementia symptoms - a safety evaluation , 2017, Expert opinion on drug safety.

[3]  W. Almeida,et al.  2-Aryl-3-(2-morpholinoethyl)thiazolidin-4-ones: Synthesis, anti-inflammatory in vivo, cytotoxicity in vitro and molecular docking studies. , 2016, European journal of medicinal chemistry.

[4]  V. Khedkar,et al.  Synthesis and bioactivity of novel triazole incorporated benzothiazinone derivatives as antitubercular and antioxidant agent. , 2016, Bioorganic & medicinal chemistry letters.

[5]  A. Lagalante,et al.  Synthesis and Spectroscopic Properties of 2,3-Diphenyl-1,3-thiaza-4-one Heterocycles , 2015 .

[6]  Q. Lei,et al.  Synthesis and antitubercular evaluation of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives. , 2015, Bioorganic & medicinal chemistry letters.

[7]  M. Maheshwari,et al.  A REVIEW: SYNTHESIS AND MEDICINAL IMPORTANCE OF 1,4-BENZOTHIAZINE ANALOGUES , 2015 .

[8]  J. Sangshetti,et al.  Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents. , 2014, Bioorganic & medicinal chemistry letters.

[9]  W. Unsworth,et al.  Substrate scope in the direct imine acylation of ortho-substituted benzoic acid derivatives: the total synthesis (±)-cavidine , 2014 .

[10]  Stefan Teipel,et al.  Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease , 2014, Neurobiology of Aging.

[11]  Sai-Sai Xie,et al.  Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease. , 2013, European journal of medicinal chemistry.

[12]  Baldev Singh,et al.  A review on cholinesterase inhibitors for Alzheimer’s disease , 2013, Archives of pharmacal research.

[13]  Subhash Chander,et al.  Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease. , 2012, Bioorganic & medicinal chemistry.

[14]  J. Justino,et al.  Facile synthesis of oxo-/thioxopyrimidines and tetrazoles C-C linked to sugars as novel non-toxic antioxidant acetylcholinesterase inhibitors. , 2012, Carbohydrate research.

[15]  Jian Zhang,et al.  Discovery of non-glucoside SGLT2 inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[16]  Hamed I. Ali,et al.  Synthesis, antitumor activity and molecular docking study of novel sulfonamide-Schiff's bases, thiazolidinones, benzothiazinones and their C-nucleoside derivatives. , 2010, European journal of medicinal chemistry.

[17]  A. Zarghi,et al.  Design and synthesis of new 1,3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors. , 2009, Bioorganic & medicinal chemistry.

[18]  P. Falaschi,et al.  Current Strategies of Therapy in Alzheimer`s Disease , 2008 .

[19]  J. Sussman,et al.  Acetylcholinesterase: how is structure related to function? , 2008, Chemico-biological interactions.

[20]  M. Goedert,et al.  A Century of Alzheimer's Disease , 2006, Science.

[21]  V. Talesa.  Acetylcholinesterase in Alzheimer's disease , 2001, Mechanisms of Ageing and Development.

[22]  F. Vallette,et al.  Molecular and cellular biology of cholinesterases , 1993, Progress in Neurobiology.

[23]  D. Scudiero,et al.  New colorimetric cytotoxicity assay for anticancer-drug screening. , 1990, Journal of the National Cancer Institute.

[24]  K. Courtney,et al.  A new and rapid colorimetric determination of acetylcholinesterase activity. , 1961, Biochemical pharmacology.

[25]  I. Gulcin,et al.  Novel eugenol derivatives: Potent acetylcholinesterase and carbonic anhydrase inhibitors. , 2017, International journal of biological macromolecules.