The docking analysis suggest that selected N-(substituted-1,3-benzothiazol-2-yl)benzamide derivatives, particularly Cp1, Cp3, Cp7, Cp10, Cp12, Cp13, and Cp14 were identified as the most promising lead candidates, with significant potential for anticonvulsant activity.
Abstract
Amides represent a class of organic compounds with a variety of biological potential and anticonvulsant properties.This study aimed to evaluate the pharmacokinetic properties and molecular interactions of 15 N-(substituted-1,3-benzothiazol-2-yl)benzamide derivatives with two key epilepsy-related targets, γ-aminobutyric acid aminotransferase (GABA-AT) and activated open sodium ion channel proteins, in order to assess their potential anticonvulsant activity. Crystal structures of GABA-AT (PDB ID: 1OHW) and the sodium ion channel (PDB ID: 5HVX) were obtained from the RCSB Protein Data Bank. Molecular docking was performed using AutoDock Vina following protein preparation in Chimera v1.11.2. Post-docking analysis was conducted using Chimera and Discovery Studio Visualizer. ADME properties were also predicted. ADME analysis showed high gastrointestinal absorption for all compounds except compound 5. Docking results revealed that seven compounds (Cp1, Cp3, Cp7, Cp10, Cp12, Cp13, and Cp14) exhibited interaction profiles similar to vigabatrin, while three (Cp10, Cp13, and Cp14) aligned with lamotrigine. These compounds demonstrated favorable binding interactions with both targets. The docking analysis suggest that selected N-(substituted-1,3-benzothiazol-2-yl)benzamide derivatives, particularly Cp1, Cp3, Cp7, Cp10, Cp12, Cp13, and Cp14 were identified as the most promising lead candidates, with significant potential for anticonvulsant activity.
Molecular docking simulation of 3 molecules of N-(1H-benzo[d]imidazol-2-yl)-7-chloro-6-fluorobenzo[d]thiazol2-amine with the target receptor aromatase was carried out so as to evaluate their theoretical binding affinities. The
chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density
functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**)
basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx
virtual screening software. Three compounds were developed by fusion of a benzothiazole and benzimidazole
ring system targeting the treatment of breast cancer. The marketed drug Exemestane which is also an aromatase
inhibitor was used as a reference molecule for docking. The highest docking score from all three molecules was
-8.6 kcal/mol which is very near to the standard drug score -9.5 kcal/mol which suggests that the compound
exhibited favorable protein–ligand interactions, indicating its potential as a lead candidate for further
investigation. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic
properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present
research strengthens the relevance of these compounds as promising lead candidates for the treatment of breast
cancer which could help the medicinal chemists and pharmaceutical professionals in further designing and
synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro
evaluation study for the proposed designed compounds to validate the computational findings.
Khyati Bhagdev, Chintankumar J. Tank· International Journal of Dru...· 0 citations
In this study, due to the side effect profiles and low efficacy of currently used inhibitors, novel benzimidazole-oxadiazole derivatives (6a–6e, 7a–7e) were synthesized as dual inhibitors of α-GLY and AR. Their structures were elucidated using 13C-NMR and 1H-NMR techniques. Their binding properties were investigated by molecular docking studies, and their ADME properties were screened in silico. AR and α-GLY inhibitory effects of the synthesized compounds were examined. The compounds were observed to exhibit partially similar inhibitory effects to the reference drug epalrestate (IC50: 0.78 nM; KI: 0.74 ± 0.0 nM) on AR inhibition. Among them, compounds 6a, 6b, and 6c showed the highest activity with KI values of 8.6 ± 0.4, 3.5 ± 0.3 and 6.3 ± 0.5 nM, respectively. Compounds 6a and 7e were found to have higher inhibitory activity against the α-GLY enzyme than the reference drug Acarbose (IC50: 128.4 µM; KI: 96.2 ± 5.7 µM) with KI values of 5.8 ± 0.4 and 7.9 ± 0.8 µM, respectively. Overall, the newly synthesized compounds demonstrated pronounced AR inhibitory activity and notable α-GLY inhibition. Nevertheless, further pharmacological and toxicity evaluations are required to confirm their therapeutic potential. Among the tested molecules, compounds 6a and 7e may therefore be considered potential candidates for further investigation as anti-diabetic agents.
Mesut Işık, Abdüllatif Karakaya, U. A. Çevik et al.· Molecules· 0 citations
This study investigated the therapeutic potential of novel 1,2,4-triazole- and 1,3,4-oxadiazole-based acetamide derivatives as dual-target inhibitors of urease and α-glucosidase, two enzymes implicated in gastrointestinal disorders and type 2 diabetes, respectively. An integrated approach combining multistep organic synthesis, in vitro biological evaluation, molecular docking, in silico ADME prediction, and density functional theory (DFT) analysis was employed to identify potent lead compounds with favorable pharmacokinetic properties. Starting from benzoic acid, a series of 1,2,4-triazole derivatives (8a-c) and 1,3,4-oxadiazole derivatives (9d-f) bearing substituted acetamide moieties were successfully synthesized. All compounds exhibited inhibitory activity against both target enzymes. Compound 8c was the most potent urease inhibitor (IC₅₀ = 6.14 ± 1.06 µM), while compound 9e showed the strongest α-glucosidase inhibition (IC₅₀ = 27.29 ± 0.41 µM), surpassing the reference inhibitor acarbose (IC₅₀ = 38.25 ± 0.12 µM). Computational analyses supported the experimental findings: ADME predictions indicated favorable drug-like properties, and molecular docking demonstrated strong binding interactions, with compound 8a exhibiting the highest affinity for α-glucosidase (-7.165 kcal/mol) and compound 9e showing the strongest binding to urease (-7.30 kcal/mol). DFT calculations further correlated biological activity with electronic properties, revealing relatively small HOMO-LUMO energy gaps for the most active compounds, 8c (0.14831 a.u.) and 9e (0.14302 a.u.). Collectively, these findings identify compounds 8c and 9e as promising lead scaffolds for the development of next-generation inhibitors of urease and α-glucosidase.
Mohammad A. Alrofaidi· Journal of Visualized Experi...· 0 citations
Findings suggest that PR1 and PR2 are promising candidates for advanced antidiabetic drug development, exhibiting predicted enhanced inhibitory activities and favorable pharmacokinetic and toxicological profiles.
L. Naanaai, Ikram Hanout, Md. Al-Amin et al.· Journal of the Iranian Chemi...· 0 citations
A novel hydrazone incorporating the 4-(4-aminophenoxy)-N-methylpicolinamide pharmacophore is designed and syn-thesized to achieve selective kinase inhibition and confirmed lig-and–protein complex stability, minimal RMSD fluctuations, and consistent hydro-gen bond occupancy under physiological conditions.
T. Yeşil, Ömer Dilek, Tahir Tilki· Sakarya University Journal o...· 0 citations
Reactive oxygen species and endogenous antioxidants are essential for
normal cellular metabolism; however, an imbalance between them causes oxidative stress,
which significantly contributes to the onset and progression of various diseases, including neurodegenerative,
cancer, and cardiovascular disorders. Thus, designing new antioxidant scaffolds
is an important research priority. Among the many heterocycles, 3,4-dihydropyrimidin-2(1H)-
one (DHPM) derivatives are particularly appealing because of their structural diversity and simple
synthesis route through the Biginelli reaction. This study aimed to identify potent antioxidant
DHPM derivatives using a structure-based computational approach.
The target protein (PDB ID: 4IQK) was prepared and optimised for docking studies.
Standard antioxidant drugs were retrieved from the PubChem database. The generated compounds
were subjected to molecular modeling to evaluate their binding affinities with the target
protein. In addition, the pharmacokinetic and ADME/T properties of the compounds were assessed
using pkCSM.
Among the thirty DHPM derivatives evaluated, six derivatives had strong binding affinities,
with values between -7.9 and -8.0 kcal/mol. Compound DHPM 22 was the most powerful
lead among them. It exhibited a better binding affinity of -8.0 kcal/mol because it formed
hydrogen bonds, π-π stacking, and hydrophobic interactions with the protein's active site. Furthermore,
ADME/T analysis confirmed the favorable drug-likeness and pharmacokinetic properties
of the selected compounds.
The docking and ADME/T studies of the 3,4-dihydropyrimidin-2(1H)-one derivatives
showed favorable antioxidant activity against the Keap protein with PDB ID: 4IQK.
Amongst the designed compounds, compound DHPM 22 showed the highest binding affinity (-
8.0 kcal/mol), which was comparable to the standard 4-bromoflavone (-8.5 kcal/mol). This enhanced
binding affinity can be attributed to the formation of conventional hydrogen bonds with
Gly367A, Val465A, and Gly464A, hydrophobic interactions with Val418A, Ile416A, Ala366A,
Leu557A, Leu365A, Val604A, and Val606A, as well as a π-alkyl interaction with Ile559A, collectively
contributing to the stabilization of the ligand within the active site. Compounds DHPM
3 and DHPM 29 also showed favorable binding scores of -7.9 and -7.8 kcal/mol, respectively.
The structure-activity relationship suggests that the electron-withdrawing groups like fluoro and
bromo enhanced binding affinity, whereas bulky polar substituents reduced the antioxidant activity.
Overall, the present study demonstrates that DHPM derivatives, specifically
DHPM 22, may represent a promising lead for the development of new antioxidant derivatives.
Further experimental studies are recommended to confirm their biological activities and therapeutic
potential.
Chanda Ranjan, A. Mahesh, B. C. et al.· Current Computer - Aided Dru...· 0 citations