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

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.

Synthesis, In Vitro Biological Evaluation and Molecular Modeling of Benzimidazole-Based Pyrrole/Piperidine Hybrids Derivatives as Potential Anti-Alzheimer Agents

“…The enzyme inhibition activities for acetylcholinesterase and butyrylcholinesterase were determined using the method of Ellman et al [ 36 ] with slight modifications. The 62.0 mM sodium phosphate buffer (pH 8.0, 880 μL) used contained 0.002 M of DTNB (5,5′-dithiobis-2-nitrobenzoic acid).…”

In Vitro and In Silico Investigation of Polyacetylenes from Launaea capitata (Spreng.) Dandy as Potential COX-2, 5-LOX, and BchE Inhibitors

“…Hence, the highest in vitro enzyme inhibition activity of compound 4 IC 50 (14.77 ± 1.55 µM) could be attributed to its interaction with these residues. Compound 3 displayed three H-bonding interactions with Tyr-128, Trp-82, and His-438 residues (Figure S29h) in the active site of BchE [39,40]. It showed a lower docking score (−7.018 kcal/mol, Table 4) and a higher IC 50 (48.81 ± 6.34 µM) than compound 4 against the BchE enzyme.…”

4‐Furfuryloxymethyl‐1,2,3‐triazol‐1‐yl‐acetohydrazide Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors: Synthesis, Characterization and Comprehensive Biological Activity Studies

“…In addition to 1,2,3-triazoles, hydrazide-hydrazone derivatives synthesized from substituted-acetohydrazid also have various biological activities such as anti-bacterial, [10] antiinflammatory, [11] antifungal, [12] analgesic, [13] anticonvulsant, [14] antimalarial [15] and antitubercular, [16,17] anticancer, [18,19] antioxidant [20] and anticholinergic. [21] Some examples were given in Scheme 2.…”