Design, Synthesis, In Silico ADME, Toxicity Prediction and Molecular Docking Studies of Benzimidazole-Oxadiazole Derivatives for α-Glucosidase and Aldose Reductase Pathways as Potent Anti-Diabetic Agents
Overall, the newly synthesized compounds demonstrated pronounced AR inhibitory activity and notable α-GLY inhibition and may therefore be considered potential candidates for further investigation as anti-diabetic agents.
Abstract
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.
Experimental 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
INTRODUCTION
Inflammation and oxidative stress play important roles in the development of various chronic diseases, necessitating compounds with dual therapeutic potential.
METHODS
A series of (E)-7-hydroxy-4-methyl-6-(3-(substituted phenyl)acryloyl)-2H-chromen-2-one (7a-m) were synthesized starting from 7-hydroxy-4-methyl coumarin. The synthesized compounds were evaluated for their in vitro antioxidant and anti-inflammatory activity Results: Compound 7a exhibited the most potent antioxidant activity with an IC50 value of 83.39 μM. Compound 7b was found to be nearly 1.5-fold more potent in inhibiting albumin protein denaturation than ibuprofen and diclofenac at 100 μg/ml. Compound 7b displayed the most potent inhibitory activity against TNF-α and weak inhibition against the COX-2 enzyme with an IC50 value of 4.32 and 419.04 μM, compared to standard ibuprofen (IC50 value of 5.0 μM against COX-2) and diclofenac (IC50 value of 21.0 μM against TNF-α). Molecular docking studies of compound 7b showed the highest docking score against TNF-α and COX-2 enzymes, compared to the standard celecoxib.
DISCUSSION
It was found that chloro at the 2nd position or methoxy at the 3rd position led to promising anti-inflammatory activity. Removal of the chloro group led to a decrease in COX-2 and TNF-α inhibitory activity. In the molecular docking studies, compound 7b shows a similar binding interaction against TNF-α and COX-2 as the standard celecoxib. The DFT studies showed favorable interactions, good stability, and moderate reactivity within the biological targets.
CONCLUSION
Based on the results of the present study, it is suggested that coumarin-chalcone derivatives may act as a lead for the synthesis of more potent antioxidants and anti-inflammatory compounds.
Dalaa Ali El-Jadayel, Husna Khalifa Al-Busaidi, Zainab Hamood Al-Balushi et al.· Anti-Inflammatory & Anti-All...· 0 citations
Quinazoline scaffolds are widely recognized in drug discovery for their diverse pharmacological profiles, and several quinazoline derivatives have been reported as phosphodiesterase 7A (PDE7A) inhibitors with potential anti-inflammatory effects. This study aimed to synthesize novel quinazoline derivatives, evaluate their anti-inflammatory activity and investigate their computationally predicted binding to PDE7A. A series of quinazoline hydrazone (6a–j) and benzylthioquinazolinone (7a–c, 8a,b) derivatives were synthesized and structurally characterized using IR, 1H/13C NMR, mass spectrometry, and elemental analysis. Anti-inflammatory activity was evaluated in vivo using the carrageenan-induced rat paw edema model. An acute oral toxicity assessment identified the highest tested doses without observed mortality or overt clinical toxicity of 1000–1200 mg/kg, from which anti-inflammatory test doses of 100–120 mg/kg were selected. Compound 6f produced the highest numerical inhibition among the synthesized derivatives, with 79.39% inhibition at 100 mg/kg. Compounds 6a, 6b, and 8a produced 61.85%, 61.65%, and 60.12% inhibition, respectively, at 120 mg/kg, whereas diclofenac produced 68.21% inhibition at 7.5 mg/kg. Molecular docking, Prime MM–GBSA calculations, and 100-ns molecular dynamics simulations were used to evaluate predicted PDE7A interactions and comparative dynamic behavior. Compound 6f showed the most favorable Glide GScore and IFDScore, persistent Tyr211 and Gln413 hydrogen bonds, and the clearest apparent late-stage stationary root-mean-square deviation regime. In silico ADMET analysis indicated acceptable predicted drug-likeness and absorption-related properties, although moderate-to-low aqueous solubility and predicted hERG liability require experimental evaluation. Overall, compound 6f was prioritized as the leading anti-inflammatory candidate within the evaluated series; however, PDE7A involvement remains computationally inferred and requires direct biochemical and selectivity validation.
Majed A. Alharbi, Ashwaq A. Almagati, M. M. Gineinah et al.· Frontiers in Pharmacology· 0 citations
A new series of pyrazolo[3,4-d]pyrimidine scaffolds, namely, 4a–l, were designed, synthesized, and tested for anti-inflammatory and anti-proliferative activities. Compounds 4f and 4g displayed advanced COX-2 selectivity (SI = 4.95 and 16.22) in comparison to celecoxib (SI = 7.61). In addition, all compounds were evaluated for their cytotoxic activity against three cancer cells using a reference drug (staurosporine). Compounds 4f and 4g showed the most potent anti-proliferative activity against MCF-7 (IC50 = 0.259 and 0.292 µM, respectively), MDA-MB-231 (IC50 = 0.258 and 0.327 µM, respectively), and Caco-2 (IC50 = 0.228 and 0.178 µM, respectively) cell lines and were more potent than staurosporine (IC50 = 0.401, 0.411, and 0.224 µM, respectively). Moreover, both derivatives were less toxic with comparable selectivity to the normal breast cell line (MCF-10) (SI values of 1.13–4.43) compared to staurosporine (SI values of 1.10–2.02). Further assessment of the CDK2 inhibitory activity of the most cytotoxic candidates 4f and 4g revealed their higher potency (IC50 = 0.324 and 0.215 µM, respectively) than that of the reference drug ribociclib (IC50 = 0.496 µM). Additionally, compound 4g revealed cell cycle arrest at the G2/M phase in Caco-2 cells, resulting in cell apoptosis. Furthermore, molecular docking and dynamics simulations revealed that derivatives 4f and 4g form stable and tighter complexes with the CDK2 kinase domain, as confirmed by their lower RMSD values, superior interaction stability, and stronger hinge and catalytic site binding. Finally, ADME profiling demonstrated that compound 4f satisfies all major drug-likeness criteria without any violations, while compound 4g fully adheres to the Veber's, Lipinski's, Egan's, and Ghose's drug-likeness guidelines. Consequently, these compounds represent promising starting candidates for the development of future CDK2 kinase and COX-2 inhibitors.
Sara Y. Ewieda, Laila Ziko, Ahmed Elshewy et al.· RSC Advances· 0 citations
This study involved the synthesis, characterization, and toxicity prediction of nine novel pyridazine‐hydrazone analogs
(
3a–i
)
to investigate their inhibitory activity against α‐amylase and α‐glucosidase enzymes as potential antidiabetic agents using in vitro assays. In addition, in silico molecular docking was conducted to evaluate the binding interactions of these analogs with the target enzymes, while physicochemical and pharmacokinetic properties were predicted using the ADMET2.0 web server. The in vitro assays demonstrated significant α‐amylase inhibitory activity (except for compounds
3a
and
3b
), with IC
50
values ranging from 61.21 ± 0.78 to 209.40 ± 2.98 µM, compared with the standard drug acarbose (IC
50
= 126.5 ± 0.02 µM). All compounds also exhibited significant α‐glucosidase inhibitory activity, with IC
50
values ranging from 19.91 ± 0.12 to 204.3 ± 1.76 µM, compared with acarbose (IC
50
= 98.12 ± 0.01 µM). Notably, compounds
3e
and
3h
showed the strongest α‐amylase inhibition, whereas
3c
,
3g
, and
3i
were the most potent α‐glucosidase inhibitors. Molecular docking revealed binding energies ranging from −7.6 to −9.2 kcal/mol for α‐amylase (PDB ID: 4GQR) and −6.0 to −8.0 kcal/mol for α‐glucosidase (PDB ID: 5NN5), supporting their potential as promising α‐amylase and α‐glucosidase inhibitors.
Hamza Assila, S. Mortada, I. A. El Hassani et al.· ChemistrySelect· 0 citations
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.
A. Rufa'i, A. Idris, A. Musa et al.· Molecular Modeling Connect· 0 citations
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