Design, Synthesis and Insecticide Activity of Novel Acetylcholinesterase Inhibitors: Triazolinone and Phthalimide Heterodimers

Abstract

Based on the "cluster effect" and the structure characters of acetylcholinesterase (AChE; EC 3.1.1.7), a new series of 1,2,4-triazolin-3-one and phthalimide heterodimers were designed, synthesized, and evaluated as potent dual acetylcholinesterase inhibitors (AChEIs). Most of the synthesized compounds showed good in vitro inhibitory activities towards both Drosophila melanogaster acetylcholinesterase (DmAChE) and Musca domestica acetylcholinesterase (MdAChE). Among them, 5g was found to be the most potent anti-AChE derivate (5g, IC 50 8.07 µM to DmAChE, IC 50 32.24 µM to MdAChE). It was 2.31-and 1.35-fold more active than the positive control ethion (CP, IC 50 18.62 µM to DmAChE, IC 50 43.56 µM to MdAChE). The docking model study revealed that 5g possessed the fitted spatial structure and bound to the central pocket and peripheral site of DmAChE. Moreover, most compounds demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnabarinus at the concentration of 300 mg/L.

A structural analysis of 2,5‐diaryl‐4H‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones: NMR in the solid state, X‐ray crystallography, and GIPAW calculations

“…Due to its biological properties, many other triazol‐3‐ones, not necessarily having a 2,5‐diaryl pattern, have previously been described; they are Ca 2+ conductance openers activated potassium channels, [ 2 ] antimicrobials, [ 3 ] antifungals, [ 4,5 ] TNF‐α inhibitors, [ 6 ] selective CB1 receptor antagonists, [ 7 ] angiotensin II AT1 receptor antagonists, [ 8,9 ] antioxidants, [ 10 ] and AChE inhibitors. [ 11 ]…”

“…Due to its biological properties, many other triazol-3-ones, not necessarily having a 2,5-diaryl pattern, have previously been described; they are Ca 2+ conductance openers activated potassium channels, [2] antimicrobials, [3] antifungals, [4,5] TNF-α inhibitors, [6] selective CB1 receptor antagonists, [7] angiotensin II AT1 receptor antagonists, [8,9] antioxidants, [10] and AChE inhibitors. [11] A thorough understanding of biological properties requires information about the structure of molecules, among them tautomerism [1] and conformational isomerism. Conformational data are usually obtained in solution by nuclear magnetic resonance (NMR) [12,13] and quantum chemical calculations [14,15] and in the solidstate by NMR, [16,17] crystallography, [18,19] and again by quantum calculations.…”

Target-Based Design, Synthesis, and Biological Evaluation of Novel 1,2,4-Triazolone Derivatives as Potential nAChR Modulators

“…1,2,4-Triazolone, an important nitrogen-containing heterocycle, can form strong interactions with proteins thanks to its four polar atoms, namely, three nitrogens and one oxygen. The derivatives of 1,2,4-triazolone (Figure ), exhibit excellent biological activities as pharmaceuticals − and agrochemicals such as herbicides and insecticides . Therefore, the functional 1,2,4-triazolone fragment was added to the central part of the model (red portion; Figure a).…”

“…The derivatives of 1,2,4-triazolone (Figure 4), exhibit excellent biological activities as pharmaceuticals 45−48 and agrochemicals such as herbicides 49 and insecticides. 50 Therefore, the functional 1,2,4triazolone fragment was added to the central part of the model (red portion; Figure 5a). Based on the derived pharmacological model, a series of chloropyridine-containing 1,2,4triazolone derivatives were rationally designed by considering the key interactions between the target protein and the structural characteristics of the 11 nAChR modulators.…”

Toward the cholinesterase inhibition potential of TADDOL derivatives: Seminal biological and computational studies

“…[49][50][51] Thiazole derivatives, [52] different chalcones and flavones, [53] triazolinones, benzimidazoles, piperidines, saccharin, and phthalimide derivatives, are considered promising candidates for Alzheimer's treatment. [54][55][56][57][58][59][60][61][62] Moreover, several studies focused on the development of ester derivatives of different scaffolds to increase enzyme interactions. [63][64][65][66] Remarkably, TADDOL derivatives were never studied for their AChE inhibition potential and antioxidant activities, although they are structurally highly interesting.…”