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. 2022 Dec 20;28(1):21.
doi: 10.3390/molecules28010021.

Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer's Disease Candidates: Evidence-Based In Vitro Study

Fazal Rahim  1 , Hayat Ullah  2 , Muhammad Taha  3 , Rafaqat Hussain  1 , Maliha Sarfraz  4 , Rashid Iqbal  5 , Naveed Iqbal  6 , Shoaib Khan  1 , Syed Adnan Ali Shah  7   8 , Marzough Aziz Albalawi  9 , Mahmoud A Abdelaziz  10 , Fatema Suliman Alatawi  11 , Abdulrahman Alasmari  12 , Mohamed I Sakran  11   13 , Nahla Zidan  14   15 , Ibrahim Jafri  16 , Khalid Mohammed Khan  17
Affiliations

Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer's Disease Candidates: Evidence-Based In Vitro Study

Fazal Rahim et al. Molecules. .

Abstract

Triazole-based thiosemicarbazone derivatives (6a-u) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except 6c and 6d, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue 6i (IC50 = 0.10 ± 0.050 for AChE and IC50 = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue 6b (IC50 = 0.20 ± 0.10 µM for AChE and IC50 = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO2 groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.

Keywords: acetylcholinesterase; butyrylcholinesterase; molecular docking study; structure activity relationship; thiosemicarbazone; triazole.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Available drugs for Alzheimer’s disease.
Figure 2
Figure 2
Bioactive drugs with triazole moiety.
Figure 3
Figure 3
Rationale of the current study.
Scheme 1
Scheme 1
Synthesis of triazole-based thiosemicarbazone derivatives (6a–u).
Figure 4
Figure 4
Summary of SAR studies of triazole-based thiosemicarbazone derivatives (6a–u).
Figure 5
Figure 5
Protein–ligand interaction (PLI) profile of analogue 6i against acetylcholinesterase (AChE): (A) 2D; (B) 3D.
Figure 6
Figure 6
Protein–ligand interaction (PLI) profile of analogue 6i against butyrylcholinesterase (BuChE): (A) 2D; (B) 3D.
Figure 7
Figure 7
Protein–ligand interaction (PLI) profile of analogue 6b against acetylcholinesterase (AChE): (A) 2D; (B) 3D.
Figure 8
Figure 8
Protein–ligand interactions (PLI) profile of analogue 6b against butyrylcholinesterase (BuChE): (A) 2D; (B) 3D.
Figure 9
Figure 9
Protein–ligand interaction (PLI) profile of analogue 6q against acetylcholinesterase (AChE): (A) 2D; (B) 3D.
Figure 10
Figure 10
Protein–ligand interaction (PLI) profile of analogue 6q against butyrylcholinesterase (BuChE): (A) 2D; (B) 3D.
See this image and copyright information in PMC

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