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New 4-Phenylpiperazine-Carbodithioate-N-Phenylacetamide Hybrids: Synthesis, in Vitro and in Silico Evaluations Against Cholinesterase and Α-Glucosidase Enzymes Publisher Pubmed



Mohammadikhanaposhtani M1 ; Nori M2 ; Valizadeh Y2 ; Javanshir S3 ; Dastyafteh N2 ; Moaazam A2 ; Hosseini S4 ; Larijani B2 ; Adibi H2 ; Biglar M2 ; Hamedifar H5 ; Mahdavi M2 ; Kamci H6 ; Karakus A6 Show All Authors
Authors
  1. Mohammadikhanaposhtani M1
  2. Nori M2
  3. Valizadeh Y2
  4. Javanshir S3
  5. Dastyafteh N2
  6. Moaazam A2
  7. Hosseini S4
  8. Larijani B2
  9. Adibi H2
  10. Biglar M2
  11. Hamedifar H5
  12. Mahdavi M2
  13. Kamci H6
  14. Karakus A6
  15. Taslimi P6
Show Affiliations
Authors Affiliations
  1. 1. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
  2. 2. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
  4. 4. Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
  6. 6. Department of Biotechnology, Faculty of Science, Bartin University, Bartin, Turkey

Source: Archiv der Pharmazie Published:2022


Abstract

A series of novel 4-phenylpiperazine-carbodithioate-N-phenylacetamide hybrids (6a–n) was designed, synthesized, and evaluated for their in vitro inhibitory activity against the metabolic enzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The obtained results showed that most of the synthesized compounds exhibited high to good anti-AChE and anti-BChE activity in the range of nanomolar concentrations in comparison to tacrine as a positive control. Molecular modeling of the most potent compounds 6e and 6i demonstrated that these compounds interacted with important residues of the AChE and BChE active sites. Moreover, all the newly synthesized compounds 6a–n had significant Ki values against α-glucosidase when compared with the positive control acarbose. Representatively, N-2-fluorophenylacetamide derivative 6l, with a Ki value of 0.98 nM as the most potent compound, was 126 times more potent than acarbose with a Ki value of 123.70 nM. This compound also fitted in the α-glucosidase active site and interacted with key residues. An in silico study of the druglikeness/absorption, distribution, metabolism, and excretion (ADME)/toxicity profile of the selected compounds 6e, 6i, and 6l predicts that these compounds are drug-like and have the appropriate properties in terms of ADME and toxicity. © 2022 Deutsche Pharmazeutische Gesellschaft.