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In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including 1 H NMR, 13 C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 ± 0.10 μM to 20.50 ± 0.20 μM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 μM to 20.70 ± 0.50 μM when compared with the standard drug Donepezil having IC 50  = 6.70 ± 0.20 μM for AChE and 7.90 ± 0.10 μM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC 50  = 3.20 ± 0.10 μM for AChE and 4.30 ± 0.50 μM for BuChE), analog-4 (IC 50  = 4.30 ± 0.30 μM for AChE and 5.50 ± 0.20 μM for BuChE) and analog-5 (IC 50  = 4.10 ± 0.30 μM for AChE and 4.60 ± 0.40 μM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively., Competing Interests: Declaration of competing interest It is declared that there is no conflict of interest between the authors of the current manuscripts and it is only submitting to Biochemical and Biophysical Research Communication and not submitted elsewhere., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As a springboard to explore novel potent inhibitors of cholinesterase enzymes (AChE and BChE) responsible for causing Alzheimer disorder, the current study was conducted to synthesize pyrrole derived triazole based Schiff base scaffolds by facile synthetic route. These compounds were validated by 1HNMR, 13CNMR and HREI-MS. All these scaffolds (1–16) were examined for their inhibitory activity against AChE and BChE in contrast to Donepezil (10.20 ± 0.10 and 10.80 ± 0.20 µM) and Allanzanthone (12.40 ± 0.10 and 13.10 ± 0.10 µM). All pyrrole derived triazole based Schiff base scaffolds (1–16) showed varied range of inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes with lowest inhibition concentration values ranging from 5.10 ± 0.40–27.10 ± 0.10 µM (for AChE) and 5.60 ± 0.30–28.40 ± 0.30 µM (for BChE). SAR analysis of these derivatives revealed analog 7 as lead molecule against targeted enzyme, while analog 6 and 11 were ranked as second and third most potent scaffolds. Binding affinity and selectivity of potent molecules against targeted enzymes were examined by molecular docking and obtained results showed that potent molecule have versatile significant binding interactions with stated enzymes. Furthermore, safety profiles of potent analogues were predicted via ADMET protocols. [ABSTRACT FROM AUTHOR]

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1–17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives 1–17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure–activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurological illness that is distinguished clinically by cognitive and memory decline and adversely affects the people of old age. The treatments for this disease gained much attention and have prompted increased interest among researchers in this field. As a springboard to explore new anti-Alzheimer's chemical prototypes, the present study was carried out for the synthesis of benzoxazole-oxadiazole analogues as effective Alzheimer's inhibitors. In this research work, we have focused our efforts to synthesize a series of benzoxazole-oxadiazole (1–19) and evaluating their anti-Alzheimer properties. In addition, the precise structures of synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H-NMR, 13C-NMR and HREI-MS. To find the anti-Alzheimer potentials of the synthesized compounds (1–19), in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), inhibitory activities were performed using Donepezil as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes were due to different substitution patterns of substituent(s) at the variable position of both acetophenone aryl and oxadiazole aryl rings. The results of the anti-Alzheimer assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values ranging from 5.80 ± 2.18 to 40.80 ± 5.90 µM (against AChE) and 7.20 ± 2.30 to 42.60 ± 6.10 µM (against BuChE) as compared to standard Donepezil drug (IC50 = 33.65 ± 3.50 µM (for AChE) and 35.80 ± 4.60 µM (for BuChE), respectively. Specifically, analogues 2, 15 and 16 were identified to be significantly active, even found to be more potent than standard inhibitors with IC50 values of 6.40 ± 1.10, 5.80 ± 2.18 and 6.90 ± 1.20 (against AChE) and 7.50 ± 1.20, 7.20 ± 2.30 and 7.60 ± 2.10 (against BuChE). The results obtained were compared to standard drugs. These findings reveal that benzoxazole-oxadiazole analogues act as AChE and BuChE inhibitors to develop novel therapeutics for treating Alzheimer's disease and can act as lead molecules in drug discovery as potential anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

Twenty-one analogs were synthesized based on benzimidazole, incorporating a substituted benzaldehyde moiety (1–21). These were then screened for their acetylcholinesterase and butyrylcholinesterase inhibition profiles. All the derivatives except 13, 14, and 20 showed various inhibitory potentials, ranging from IC50 values of 0.050 ± 0.001 µM to 25.30 ± 0.40 µM against acetylcholinesterase, and 0.080 ± 0.001 µM to 25.80 ± 0.40 µM against butyrylcholinesterase, when compared with the standard drug donepezil (0.016 ± 0.12 µM and 0.30 ± 0.010 µM, against acetylcholinesterase and butyrylcholinesterase, respectively). Compound 3 in both cases was found to be the most potent compound due to the presence of chloro groups at the 3 and 4 positions of the phenyl ring. A structure-activity relationship study was performed for all the analogs except 13, 14, and 20, further, molecular dynamics simulations were performed for the top two compounds as well as the reference compound in a complex with acetylcholinesterase and butyrylcholinesterase. The molecular dynamics simulation analysis revealed that compound 3 formed the most stable complex with both acetylcholinesterase and butyrylcholinesterase, followed by compound 10. As compared to the standard inhibitor donepezil both compounds revealed greater stabilities and higher binding affinities for both acetylcholinesterase and butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

• Synthesis and spectroscopic characterization of oxadiazole/thiadiazole-fused 1,3,4-Thiadiazole hybrids derivatives. • Isolated compounds were evaluated for in vitro anti-cholinesterase inhibition. • A number of the compounds exhibited excellent activity, some better than the reference standards. • A molecular docking study was used to determine the binding interactions of the potent compounds with the enzymes. The present study aims to synthesize new thiadiazole/oxadiazole fused thiadiazole derivatives, incorporating pyridine moiety as effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) to treat Alzheimer disease. Initially, pyridine based thiosemicarbazone was synthesized by treating pyridine 2,6-dicarboxaldehyde with thiosemicarbazide. Thiosemicarbazone was cyclized into bis-thiadiazole, which further react with different isothiocyanates to give pyridine-based bis-(thiadiazole-fused-thiadiazole) derivatives (4a-h). Next pyridine based semicarbazone was synthesized by treating pyridine 2,6-dicarboxaldehyde with semicarbazide. Then semicarbazone was cyclized into bis-oxadiazole which further react with different isothiocyanates to give pyridine-based bis-(oxadiazole-fused-thiadiazole) derivatives (7a-h).The synthetic analogs were structurally elucidated through 1H NMR,13C NMR and HRMS (EI) analysis and assessed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potential. All synthetic analogues showed varying degrees of inhibitory effects on AChE and BuChE, with IC 50 value ranging from 12.89 ± 1.10 µM - 61.76 ± 2.40 µM for AChE and 14.79 ± 1.20 µM - 56.87 ± 2.50 µM for BuChE in comparison of standard inhibitor Galantamine (IC 50 = 37.40 ± 1.20 µM for AChE and IC 50 = 41.20 ± 1.90 µM for BuChE). Among the series, analogues 4c IC 50 = 13.32 ± 1.30 μM (against AChE), and 15.17 ± 1.40 μM (against BuChE), and 7c IC 50 = 12.89 ± 1.10 μM (against AChE) and 14.79 ± 1.20 μM (against BuChE) exhibited notable inhibitory activity against AChE and BuChE enzymes, Moreover, molecular docking studies were conducted on potential analogues to investigate their binding interactions with the targeted enzyme's active sites. [ABSTRACT FROM AUTHOR]

• Synthesis and spectroscopic characterization of bis-thiazole based thiazolidinone derivatives. • Isolated compounds were evaluated for in vitro anti-cholinesterase inhibition. • A number of the compounds exhibited excellent activity, some better than the reference standards. • A molecular docking study was used to determine the binding interactions of the potent compounds with the enzymes. A total of sixteen new derivatives of the bis-thiazole-thiazolidinone skeletal structure were synthesized and examined for their potential as inhibitors of cholinesterase in the context of Alzheimer's disease (AD) therapy. The compounds with the numerical designations 6, 14 , and 16 exhibited superior activities in the inhibition of acetylcholinesterase (AChE), while compounds designated as 2, 7, and 10 were found to show remarkable potency against butyrylcholinesterase (BuChE). Furthermore, these drugs had the most minimal IC 50 values and demonstrated relative potencies above 50 percent when compared to the efficacious cholinesterase inhibitor, donepezil. The docking experiments performed within the active site of cholinesterase revealed that compounds 6, 14, and 16 with their IC 50 values 2.81 ± 0.34 μM, 2.45 ± 0.58 μM and 1.33 ± 0.10 μM exhibited favorable binding orientations against AChE, while compounds 2, 7, and 10 with their IC 50 values of 3.19 ± 0.42 μM, 3.40 ± 0.34 μM and 1.83 ± 0.14 μM displayed comparable binding orientations against BuChE. These compounds demonstrated critical interactions similar to that of donepezil, which can account for their potent cholinesterase activity. It has been shown that the thiazole-thiazolidinone molecule's active site gorge has significant interactions with its amino acid residues. According to the study's results, it is suggested that the novel thiazole-thiazolidinone derivatives, namely compounds 6, 14, and 16 for AChE inhibition and compounds 2, 7, and 10 for BuChE inhibition, have the potential to be used as promising lead compounds in the synthesis of potent thiazole-based thiazolidinone inhibitors targeting these enzymes. [Display omitted] [ABSTRACT FROM AUTHOR]

• Benzoxazole based thiazolidinone analogues were designed and synthesized. • These analogues were further evaluated for in vitro AChE and BuChE activities. • Most of analogues were found be potent. • The most potent analogues were further subjected to molecular docking studies for exploring binding mode of interaction with the active sites of targeted enzymes. Alzheimer's disease (AD) is a brain disorder medically defined as loss of memory and analytical reasoning abilities of an infected person. The adult or aged peoples are more likely to be adversely affected by this disease. Following this prospect, this study is conducted to synthesize a novel class of (Z)-2-(((Z)-2-(benzo[d]oxazol-2-ylthio)-1-phenylethylidene)hydrazono)-3-phenylthiazolidin-4-one based derivatives and evaluate its performance towards the treatment of AD. This study showed the better results when compared to the inhibition potential of the standard drug Donepezil against AChE (IC 50 = 4.10 ± 1.05 µM) and against BuChE (IC 50 =6.59 ± 1.63 µM), the inhibition potential shown by benzimidazole based thiadiazole scaffolds against the targeted enzymes is of wide range. The inhibition potential of all the scaffolds against AChE ranged from 2.89 ± 0.65 µM to 19.04 ± 0.49 µM and against BuChE ranged from 3.70 ± 0.98 µM to 23.19 ± 0.71 µM. Moreover, to investigate the binding interaction of effective scaffolds against the active sites of AChE and BuChE, molecular docking studies were carried out and the analysis data evaluated the substantial binding interaction of scaffolds against the targeted enzymes. The structural characteristic of each scaffold is determined by using different spectroscopic techniques. In this work only three analogues found to be the most active having the observed IC 50 values 7d, 3.05 ± 0.19 µM, 2.90 ± 0.87 µM(for BuChE), 7g, 3.88 ± 0.32 µM(for AChE), 4.98 ± 0.54 µM(for BuChE), 7k 2.89 ± 0.65 µM(for AChE), 3.70 ± 0.98 µM(for BuChE). Furthermore, the selected analogues considered for In-Vivo and cytotoxic study as well as structure modification carried out in search of more active analogues. [ABSTRACT FROM AUTHOR]

• Synthesis and spectroscopic characterization of benzoxazole-based thiazolidinone derivatives. • Isolated compounds were tested for in vitro anti-cholinesterase inhibition. • A number of the compounds demonstrated excellent activity, some better than the reference standards. • A molecular docking study was used to determine the binding interactions of the potent compounds with the enzymes. Benzoxazole-based thiazolidinone hybrids derivatives (1–19) were afforded and further subjected to in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition studies for the first time. All these analogues were found to display good inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)enzymes with IC 50 values 4.20 ± 1.10 µM to 43.20 ± 4.50 µM (against AChE) and 3.80 ± 1.20 µM to 34.50 ± 3.30 µM (against BuChE) as compared to standard donepezil having IC 50 values of 21.86 ± 0.40 µM (against AChE) and 32.47 ± 2.30 µM (against BuChE) respectively. Specifically, compound 16, characterized by a 3,4-dichloro substitution on ring B and 2–OH and 4-CF3 substitutions on ring C, along with compound 13, having 2,4-diCl on ring B and 2-OH and 4-CF 3 on ring C, were identified as the most potent inhibitors of the targeted AChE and BuChE enzymes, even manifolds more potent than standard donepezil drug. The structures of all synthesized analogues were verified through the utilization of multiple spectroscopic techniques, including HREI-MS and NMR (1H NMR and 13C NMR). The structure-activity relationship (SAR) demonstrated that analogs bearing electron withdrawing groups such as –CF 3 , –Cl and -NO 2 groups displayed superior AChE and BuChE activities. In the molecular docking analysis of the most potent analogs, a favorable protein-ligand interaction (PLI) profile was observed with the respective targets (AChE and BuChE). These interactions encompassed crucial bonding types such as hydrogen bonding, π-π interactions, π-π stacking, and hydrophobic interactions. [ABSTRACT FROM AUTHOR]

• Synthesis of benzimidazole-based thiadiazole derivatives. • Exploring in vitro acetylcholinesterase and butyrylcholinesterase inhibition profile of the synthesized compounds. • To find out the binding mode of interactions of most active compounds with targeted enzymes using molecular docking approach. A new series of benzimidazole-based thiadiazole hybrids analogues (6a–p) as effective Alzheimer's inhibitors were synthesized and then evaluated for their inhibition profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes as compared to Donepezil as standard drug. All the synthesized benzimidazole-based thiadiazole analogues showed varied range of inhibitory potentials against targeted AChE & BuChE enzymes with IC 50 values ranging from 1.32 ± 0.10 µM to 19.26 ± 0.60 µM (for AChE) and 1.94 ± 0.10 µM to 21.33 ± 0.70 µM (for BuChE) when compared to standard Donepezil (IC 50 = 2.16 ± 0.050 µM for AChE) & 4.50 ± 0.10 µM for BuChE). As structure-activity relationship (SAR) studies revealed that the analogues 4d (bearing ortho ‑hydroxy and para -NO 2 on N -aryl ring along with ortho -NO 2 substitution on another aryl ring) and 6k (that holds ortho ‑hydroxy & para -NO 2 substitutions on N -aryl ring and 3,4-diCl moieties on another aryl ring) were emerged as the most potent analogues of AChE & BuChE enzymes having IC 50 values of 1.32 ± 0.10 µM & 1.84 ± 0.20 µM (against AChE) and 1.94 ± 0.10 µM & 2.23 ± 0.20 µM (against BuChE) respectively. Furthermore, the active analogues were subjected to molecular docking studies in order to explore the binding interactions possess by potent analogues with the active sites of amino acids of targeted AChE & BuChE enzymes and result obtained shows that these active analogues furnished that several key interactions with targeted enzymes active sites. Additionally, all the synthesized analogues were elucidated structurally using variety of spectroscopic (1H NMR & 13C NMR) and spectrometric (HREI-MS) analysis. [ABSTRACT FROM AUTHOR]

• Synthesis of thiosemicarbazone-based isatin/bis-Schiff base hybrid analogues. • Identification of a new class of acetylcholinesterase and butyrylcholinesterase inhibitors. • Analogue 1 proved to be most active acetylcholinesterase and butyrylcholinesterase inhibitors. • Docking study was conducted to interpret the obtained results. Analogues of isatin/bis-Schiff bases based on thiocarbohydrazone (1–16) were synthesized, characterised using various methods like NMR and HR-ESI-MS, and then tested against the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All analogues showed good inhibitory potentials ranging from 0.20 ± 0.05 to 7.40 ± 0.20 M (for AChE) and 0.50 ± 0.05 to 9.40 ± 0.10 M (for BuChE) as compared to the reference drug Donepezil (IC50 = 2.16 ± 0.12 & 4.5 ± 0.11 M respectively). Analogue 1 was shown to be the most effective inhibitor of the AChE and BuChE enzymes among the synthesised analogues. The reason for Analogue 1 may be due to the role played by oxygen and the nitro motif in H-bonding with the active sites of AChE and BuChE enzymes. A structure–activity relationship (SAR) was developed based on nature, position, number, and the electron-donating and -withdrawing effects of substitution(s) on phenyl rings. Molecular docking studies were used to describe the binding interactions of the most active inhibitors with the active sites of AChE and BuChE. [ABSTRACT FROM AUTHOR]