2. Academic Validation
  3. Synthesis, in vitro, and in silico studies of morpholine-based thiosemicarbazones as ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors

Synthesis, in vitro, and in silico studies of morpholine-based thiosemicarbazones as ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors

  • Int J Biol Macromol. 2024 May;266(Pt 2):131068. doi: 10.1016/j.ijbiomac.2024.131068.
Mussarat Tasleem 1,  Julie Pelletier 2,  Jean Sévigny 3,  Zahid Hussain 4,  Ajmal Khan 5,  Ahmed Al-Harrasi 6,  Attalla F El-Kott 7,  Parham Taslimi 8,  Sally Negm 9,  Zahid Shafiq 10,  Jamshed Iqbal 11
Affiliations

Affiliations

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan.
  • 2 Centre de Recherche du CHU de Québec-Université Laval, Québec G1V 4G2, Canada.
  • 3 Centre de Recherche du CHU de Québec-Université Laval, Québec G1V 4G2, Canada; Département de Microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec G1V 0A6, Canada.
  • 4 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
  • 5 Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616, Birkat Al Mauz, Nizwa, Sultanate of Oman.
  • 6 Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616, Birkat Al Mauz, Nizwa, Sultanate of Oman. Electronic address: aharrasi@unizwa.edu.om.
  • 7 Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia; Department of Zoology, College of Science, Damanhour University, Egypt.
  • 8 Department of Biotechnology, Faculty of Science, Bartin University, 74100 Bartin, Türkiye.
  • 9 Department of Life Sciences, College of Science and Art Mahyel Aseer, King Khalid University, Abha 62529, Saudi Arabia.
  • 10 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan; Department of Pharmaceutical & Medicinal Chemistry, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: zahidshafiq@bzu.edu.pk.
  • 11 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan. Electronic address: drjamshed@cuiatd.edu.pk.
PMID: 38531526 DOI: 10.1016/j.ijbiomac.2024.131068
Abstract

An extensive range of new biologically active morpholine based thiosemicarbazones derivatives 3a-r were synthesized, characterized by spectral techniques and evaluated as inhibitors of ENPP isozymes. Most of the novel thiosemicarbazones exhibit potent inhibition towards NPP1 and NPP3 isozymes. Compound 3 h was potent inhibitor of NPP1 with IC50 value of 0.55 ± 0.02. However, the most powerful inhibitor of NPP3 was 3e with an IC50 value of 0.24 ± 0.02. Furthermore, Lineweaver-Burk plot for compound 3 h against NPP1 and for compound 3e against NPP3 was devised through Enzymes kinetics studies. Molecular docking and in silico studies was also done for analysis of interaction pattern of all newly synthesized compounds. The results were further validated by molecular dynamic (MD) simulation where the stability of conformational transformation of the best protein-ligand complex (3e) were justified on the basis of RMSD and RMSF analysis.

Keywords

Ectonucleotide pyrophosphatase; Molecular docking; Thiosemicarbazones.

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