Article 2021 · 80 citations

Probing 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones as multi-target directed ligands against cholinesterases, carbonic anhydrases and α-glycosidase enzymes

Hashmi, Sadaf, Khan, Samra, Shafiq, Zahid, Taslimi, Parham, Ishaq, Muhamamd, Sadeghian, Nastaran, Karaman, Halide Sedef, Akhtar, Naeem, Islam, Muhamamd, Asari, Asnuzilawati, Mohamad, Habsah, Gulcin, Ilhami

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 alpha-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 K(i)s 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 alpha-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 mglycosidase 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 alpha-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.

Keywords

Thiosemicarbazones 4-(Diethylamino)-salicylaldehyde Multi-target-directed ligands Molecular docking Cholinesterase DRUG DISCOVERY GLUCOSIDASE INHIBITORS CRYSTAL-STRUCTURE IRON CHELATORS HCA I DESIGN DERIVATIVES ANTICANCER DOCKING

WoS Categories

Biochemistry & Molecular Biology Chemistry, Organic

Sustainable Development Goals

Good Health and Well-being

Citation

Journal: BIOORGANIC CHEMISTRY
Year: 2021
Volume: 107
ISSN: 0045-2068
eISSN: 1090-2120
DOI: 10.1016/j.bioorg.2020.104554
WoS UID: WOS:000618103400005

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