Search

Alzheimer's disease (AD), a neurodegenerative condition is expected to affect 152 million in 2050. The current study comprises the evaluation of thiazole based thiadiazole bearing sulfonamide derivatives to treat Alzheimer's disease. A series of compounds (1‐15) were synthesized and were studied for their anti‐Alzheimer's potential. Their IC50 values lie in the range between (19.20±0.20 nM–2.50±0.20 nM) for AChE and (19.80±0.20 nM–3.30±0.50 nM) for AChE. Among all of them, analog 2, 7, 9, and 15 were reported to possess significant activity. Among all the members of series, compound 15 having IC50=2.50±0.20 nM and 3.30±0.50 nM for AChE and BuChE, respectively, emerged as the most promising candidate due to the presence of two electronegative fluorine (F) atoms. The small and highly electronegative fluorine atoms have the ability to block the enzyme's activity by forming strong hydrogen bonds with the amino acids of the target enzymes, thereby inhibiting their function. The efficacy of these novel compounds was studied in comparison to the standard drug donepezil having IC50=5.80±0.30 nM for AChE and IC50=6.30±0.81 nM BuChE. For further assessment of inhibition potential and mode of inhibition, molecular docking study of all the potent compounds was carried out. Further, the structural identity of the synthesized compounds was confirmed using various spectroscopic techniques, including 1H‐NMR, 13C‐NMR, and High‐Resolution Electron Impact (HREI) Mass spectrometry, which provided detailed information about their molecular structure. ADME analysis of all the synthesized compounds confirmed their potential as drugs, indicating favorable pharmacokinetic properties and a promising drug profile. [ABSTRACT FROM AUTHOR]

A series of benzimidazole-based Schiff base derivatives (1–18) were synthesized and structurally elucidated through 1H NMR, 13C NMR and HREI-MS analysis. Subsequently, these synthetic derivatives were subjected to evaluation for their inhibitory capabilities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). All these derivatives showed significant inhibition against AChE with an IC50 value in the range of 123.9 ± 10.20 to 342.60 ± 10.60 µM and BuChE in the range of 131.30 ± 9.70 to 375.80 ± 12.80 µM in comparison with standard Donepezil, which has IC50 values of 243.76 ± 5.70 µM (AChE) and 276.60 ± 6.50 µM (BuChE), respectively. Compounds 3, 5 and 9 exhibited potent inhibition against both AChE and BuChE. Molecular docking studies were used to validate and establish the structure–activity relationship of the synthesized derivatives. [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 techniques of hybrid benzothiazole derived fused triazole/thiazole derivatives. • Isolated compounds were evaluated for in vitro anti-Alzheimer activity. • A number of the compounds exhibited excellent activity, some better than the reference standards. • A molecular docking and ADMET studies were used to determine the binding interactions of the potent compounds with the enzymes active sites and their toxicity respectively. Alzheimer's disease, as per reports, 50 million people worldwide suffer from dementia and an increase of 152 million is expected by 2050. This study reports a novel synthetic approach to designing and synthesizing a series of benzothiazole-based fused 1,3,4-triazole/1,3,4-thiadiazole hybrid derivatives (1–19), which show promising potential as therapeutic agents for the treatment of Alzheimer's disease. These derivatives were structurally confirmed through spectroscopic analytical techniques, including 13C NMR, 1H NMR and HREI-MS. All the analogs were subjected to biological inhibitory evaluation against AChE and BuChE, in which analog 2 ((IC 50 = 3.30 ± 0.20 and 3.70 ± 0.40 µM), 7 (2.70 ± 0.10 and 3.240 ± 0.10 µM), 12 (4.80 ± 0.30 and 5.40 ± 0.20 µM), 15 (2.10 ± 0.20 and 3.10 ± 0.50 µM) and 19 (4.40 ± 0.20 and 5.10 ± 0.10 µM)) exhibited spellbinding potency in contrast to standard Donepezil (IC 50 = 4.60 ± 0.10 µM for AChE and 5.20 ± 0.71 µM for BuChE). The surpassing potential of the analogs is elaborated in SAR analysis, based on number, position and nature of the substituents. In this regard, analog 15 having two flouro groups, was found as the top ranking candidate, inhibiting the enzymes through hydrogen bonding. Additionally, molecular docking study was also performed to investigate the binding modes and interactions between the ligands and the target protein. Furthermore, the drug-likeness of the compounds was evaluated through in silico ADME analysis, which assessed their pharmacokinetic properties and potential to become a successful drug candidate. [ABSTRACT FROM AUTHOR]

• Synthesis and spectroscopic characterization of new triazole derived Schiff base bearing sulfonamide derivatives. • Isolated compounds were evaluated for in vitro anti-Alzheimer agents. • A number of the compounds exhibited excellent activity, whereas few of them show better activity than the reference standards. • A molecular docking and ADMET studies were conducted to determine the binding interactions of the potent compounds with the enzymes active sites and their drug likeness respectively. Alzheimer's disease (AD), a chronic neurodegenerative disorder is reported with its high prevalence and increasing at a disturbing level across the world. Due to no availability of therapeutic drugs permanently treating AD, it became imperative to develop potent therapeutic anti-Alzheimer's agent with spellbinding efficacy and minimal side effects. With this objective, herein current study we had efficiently synthesized a novel library of triazole derived Schiff base bearing sulfonamide scaffolds (1–16). The in vitro efficacy of these compounds as anti-Alzheimer was evaluated in contrast to Donepezil (IC 50 = 5.10 ± 0.20 µM, 5.70 ± 0.30 µM for AChE BuChE, respectively). These synthesized compounds displayed moderate to excellent inhibition potential with inhibitory concentration ranging between 1.90 ± 0.40 µM to 14.50 ± 0.20 µM against AChE and 2.10 ± 0.10 µM to 14.80 ± 0.40 µM against BuChE. Among the synthesized compounds, analog 4 (IC 50 =1.90 ± 0.40 µM and 2.10 ± 0.10 µM) having –CF 3 at para -position exhibited promising biological potency. For structural confirmation of these compounds HREI-MS and 1HNMR, 13CNMR techniques were employed. The binding affinity of all the lead candidates with different amino acids of targeted enzymes was studied in silico under molecular docking. Moreover, ADMET analysis was also conducted to predict the drug likeness characteristics of all the active compounds. [Display omitted] [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]

• This study presents a novel route for the synthesis of thiazole-thiadiazole based schiff base derivatives. • These derivatives were biological investigated for their anti-Alzheimer's potential. • The structural confirmation of the synthesized compounds was achieved via spectroscopic analysis. • These derivatives were subjected to in silico molecular docking study to gain insight into the binding interactions with target enzymes. • These derivatives were also investigated for their pharmacokinetic properties through ADME analysis to study their drug likeness attributes. A novel series of thiazole-thiadiazole based schiff base derivatives (1–16) were synthesized and examined for their inhibitory profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). All the compounds exhibited excellent inhibitory activity ranging from IC 50 = 1.87 ± 1.47 to 27.4 ± 2.45 µ M for AChE and 1.72 ± 1.43 to 29.4 ± 1.87 µ M for BuChE when compared with the standard drug donepezil (IC 50 = 3.87 ± 1.14 µ M and 3.56 ± 2.52 µ M for AChE and BuChE, respectively). Among the members of the whole series, compounds- 6 (IC 50 = 3.49 ± 1.20 µ M, 3.18 ± 0.27 µ M) , 7 (IC 50 = 3.20 ± 1.14 µ M, 3.21 ± 0.49 µ M), 8 (IC 50 =1.87 ± 1.47 µ M, IC 50 = 1.72 ± 1.43) and 9 (IC 50 = 2.18 ± 1.02 µ M, IC 50 = 2.02 ± 0.49 µ M), showed remarkable potency against AChE and BuChE and emerged as anti-alzheimer's agents. Molecular docking study revealed the excellent binding interactions of ligands with different amino acids of the target enzymes. Structure activity relationship (SAR) study was also conducted to evaluate inhibitory potency of all the derivatives that depends on the position, number and nature of the substituents. Furthermore, ADME outcomes authenticate the drug likeness of the potent analogs. Structural confirmation of the derivatives was achieved through different spectroscopic techniques, including 13C NMR, 1H NMR and HREI-MS. [ABSTRACT FROM AUTHOR]

• Design and target synthesis of novel imidazothiazole derived Schiff base hybrid derivatives (1–17). • Isolated compounds were evaluated for in vitro acetylcholinesterase and butyrylcholinesterase. • A number of the compounds exhibited excellent activity, some better than the reference standards. • A molecular docking and ADMET study was used to determine the binding interactions of the potent compounds with the enzymes active sites and their toxicity respectively. The current study aims to develop synthetic route and biological evaluation regarding a series of fused imidazothiazole derived Schiff base hybrid derivatives (1–17), synthesized by treating imidazothiazole bearing ester with hydrazine. The first intermediate imidazothiazole bearing hydrazide upon treating with ammonium thiocyanate was cyclized in the presence of 1,2-dioxane and potassium carbonate to second intermediate fused imidazothiazole bearing 2-aminothiadiazole. This intermediate was then mixed substituted benzaldehyde to afford fused imidazothiazole derived Schiff base hybrid derivatives. The current study revealed that the synthesized derivatives were examined and found with high inhibition profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in-comparison with marketed drug donepezil (IC 50 = 7.20 ± 0.10 and 7.80 ± 0.20 µM for AChE and BuChE). Among all the derivatives, analog 11 (IC 50 = 2.10 ± 0.30 and 2.80 ± 0.20 µM) was the one having highest inhibitory profile against both enzymes due to attachment of highly active tri-fluoromethyl group and hence regarded as potent analog. Furthermore, analog 7, 8, 9, 12 and 14 were also studied to exhibit excellent activity due to the attachment of electron donating groups and were found modest in contrast with the standard marketed drug. Protein-ligand interactions were observed through in-silico docking studies and their drug likeness properties were studied through ADMET analysis. [ABSTRACT FROM AUTHOR]

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 1H NMR, 13C 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. • Design and target synthesis of novel benzimidazole based thiadiazole derivatives. • Isolated compounds were evaluated for in vitro anti-Alzheimer. • A number of the compounds exhibited excellent activity, few of them shows better than the reference drug. • A molecular docking and ADMET study was used to determine the binding interactions and their toxicity respectively. [ABSTRACT FROM AUTHOR]

• Synthesis and spectroscopic characterization of benzimidazole-based indole/thiazole hybrids derivatives. • Isolated compounds were evaluated for in vitro anti-diabetics and anti-Alzheimer's 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 targeted enzymes. Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are common in developed countries and their incidence is increasing. The research is mostly concentrated on the exploration of novel therapies to remedy or avert these ailments. AD and T2DM have several molecular pathways in common that contributes to their degenerative development. A novel series of ten hybrid analogues (1–10) based on benzimidazole bearing indole analogues were synthesized and these scaffolds were characterized by spectroscopic techniques like HR-EIMS, 13CNMR and 1HNMR. Furthermore, the synthesized moieties were screened for α-amylase and α-glucosidase inhibitory activities. All these synthesized analogues showed good to moderate α-amylase and α-glucosidase inhibition potency ranging (4.90 ± 0.10 to 15.30 ± 0.60 µM) and (5.30 ± 0.10 to 16.10 ± 0.60 µM) while acarbose was used as a reference standard (IC 50 = 10 0.30 ± 0.20 µM), (IC50 = 9.80 ± 0.20 µM). Another series of ten hybrid analogues (11–20) based on benzimidazole bearing thiazole moieties were synthesized and were evaluated for AChE and BuChE inhibition activities. All these newly afforded analogues showed good to moderate AChE and BuChE inhibitory potential ranging of (IC 50 = 0.20 ± 0.01 µM), (IC 50 = 0.15 ± 0.01 µM) to (IC 50 = 3.90 ± 0.20 µM), (IC 50 = 3.80 ± 0.10 µM) while Donepezil was taken as a reference standard with (IC 50 = 0.016 ± 0.01 µM), (IC 50 = 0.30 ± 0.010 µM).The scaffolds were also characterized using spectroscopic techniques such as HR-EIMS, 13CNMR and 1HNMR for a better understanding of their structure. SAR was done for all synthesized analogues for substituents.In addition, docking research was conducted to determine the binding mode of interaction between the active site of analogues and targeted enzymes. This work aims to estimate the potential of the synthesized scaffolds as competitors to existing drugs. Incorporating molecular docking analysis with in vitro activities improves the accuracy of predictions and validates the possibility of these compounds as options for treating type-2 diabetes and Alzheimer's disease. [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]