Affiliations 

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan
  • 2 Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan; Department of Chemistry, The Women University Multan, 60000 Multan, Pakistan
  • 3 Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan. Electronic address: zahidshafiq@bzu.edu.pk
  • 4 Department of Biotechnology, Faculty of Science, Bartin University, 74100 Bartin, Turkey
  • 5 Department of Chemistry, Faculty of Science, Ataturk University, 25240 Erzurum, Turkey
  • 6 Interdisciplinary Research Center in Biomedical Materials (IRCBM), COMSATS Institute of Information Technology, Lahore, Pakistan
  • 7 Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
  • 8 Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
Bioorg Chem, 2021 02;107:104554.
PMID: 33383322 DOI: 10.1016/j.bioorg.2020.104554

Abstract

With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.