Design and synthesis of 2‐phenyl benzimidazole derivatives as VEGFR‐2 inhibitors with anti‐breast cancer activity

Three new series of 2‐phenyl benzimidazole‐based derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activity against breast cancer (MCF‐7) cell lines. Three compounds 8 , 9 , and 15 showed high cytotoxic activities, with IC₅₀ values of 3.37, 6.30, and 5.84 μM, respectively, while they showed comparable cytotoxicity to the standard drug doxorubicin against human normal cells, including nontumorigenic breast epithelial cell line (MCF‐10F), skin fibroblast cell line (BJ), and lung fibroblast cell line (MRC‐5). Six of the synthesized compounds were screened against vascular endothelial growth factor receptor 2 (VEGFR‐2) where compounds 8 , 9 , 12 , and 15 exhibited an outstanding potency in comparison with sorafenib, with IC₅₀ values of 6.7–8.9 nM. Molecular docking study assessed the good binding patterns of the most potent compounds with the reported conserved amino acids of VEGFR‐2 active site.     

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q²), conventional coefficient (r²), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC₅₀ values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.     

Synthesis and structure–activity relationships of pyrazolo‐[3,4‐b]pyridine derivatives as adenosine 5'‐monophosphate‐activated protein kinase activators

A series of pyrazolo[3,4‐b]pyridine derivatives were designed, synthesized, and evaluated for their activation activity toward adenosine 5'‐monophosphate‐activated protein kinase (AMPK). According to the enzyme activity, the pyrazole N?H exposure and para substitution on the diphenyl group were proved to be essential for the activation potency. Compound 17f showed equal activation compared with A‐769662. In the molecular modeling study, compound 17f exhibited important hydrogen bond interaction with Lys29, Asp88, and Arg83. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays on the NRK‐49F cell line showed that potent enzyme activators could effectively inhibit cell proliferation, especially for 17f (EC₅₀ [AMPKα1γ1β1] = 0.42 μM, efficacy = 79%; IC₅₀ [NRK‐49F cell line] = 0.78 μM). These results might provide new insights to explore novel AMPK activators.     

Structure‐based approaches for the design of benzimidazole‐2‐carbamate derivatives as tubulin polymerization inhibitors

Microtubules are highly dynamic assemblies of α/β‐tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (βI) and class III (βIII) β‐tubulin isotypes in breast and lung cancers and the highly expressed class VI (βVI) β‐tubulin isotype in normal blood cells have increased the interest for designing specific tubulin‐binding anticancer therapies. To this end, we employed our previously proposed model of the β‐tubulin–nocodazole complex, supported by the recently determined X‐ray structure, to identify the fundamental structural differences between β‐tubulin isotypes. Moreover, we employed docking and molecular dynamics (MD) simulations to determine the binding mode of a series of benzimidazole‐2‐carbamete (BzC) derivatives in the βI‐, βIII‐, and βVI‐tubulin isotypes. Our results demonstrate that Ala198 in the βVI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between βI‐ and βIII‐BzC complexes were observed; however, Ser239 in the βIII isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the β‐tubulin–BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics.     

Novel 3‐substituted N‐methylcarbazole–imidazolium salt derivatives: Synthesis and cytotoxic activity

A series of novel 3‐substituted N‐methylcarbazole–imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G‐2, Hela and PC12). The results suggest that the presence of substituted 2‐methyl‐imidazole or imidazole ring and substitution of the imidazolyl‐3‐position with a naphthylacyl or 4‐bromophenacyl group were important for improving cytotoxic activity. Compounds 17 , 18 , 27, and 28 with 4‐bromophenacyl and naphthylacyl groups displayed good activities with IC₅₀ values of 0.09–7.20 μm against three tumor cell lines investigated and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell.     

Quinazoline based 1,3,5‐triazine derivatives as cancer inhibitors by impeding the phosphorylated RET tyrosine kinase pathway: Design,synthesis, docking,and QSAR study

The present research focused on designing a quinazoline skeleton, framed via 1,3,5‐triazine derivatives (QBT) through field mapping and alignment studies. The QBT derivatives were synthesized via time‐ and cost‐effective protocol. The 3D‐QSAR study, computational physicochemical properties, and ADME calculation of the derivatives were performed to establish the affinity towards the biological system. Molecular docking in the adenosine triphosphate binding site of the RET tyrosine kinase domain (PDB ID: 7IVU) was studied to elucidate vital structural residues necessary for bioactivity. The derivatives were evaluated for anticancer potency against TPC‐1 cells (thyroid cancer), MCF‐7 cells (breast cancer), and one normal cell line (human foreskin fibroblasts) via 3‐(4,5‐dimethylthiazol‐2‐y1)‐2,5‐diphenyltetrazolium bromide assay followed by an in ovo CAM assay. The entire series of derivatives ( 8a–o ) showed mild to significant anticancer potency against the selected cancer cell lines.     

Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease

A library of substituted tetrahydroacridin‐9‐amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC₅₀ = 20 nm ; AChE IC₅₀ = 2.2 μm ) and was able to inhibit amyloid aggregation (40% inhibition at 25 μm ). Compounds 9e (6‐chloro‐N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.8 μm ; BuChE IC₅₀ = 1.4 μm ; Aβ‐aggregation inhibition = 75.7% inhibition at 25 μm ) and 11b (6‐chloro‐N‐(3,4‐dimethoxyphenethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.6 μm ; BuChE IC₅₀ = 1.9 μm ; Aβ‐aggregation inhibition = 85.9% inhibition at 25 μm ) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine‐substituted compound 12c (6‐chloro‐N‐(pyridin‐2‐ylmethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was the most potent AChE inhibitor (IC₅₀ = 90 nm ). These investigations demonstrate the utility of 3,4‐dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti‐Aβ‐aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.     

Mannosylated N‐Aryl Substituted 3‐Hydroxypyridine‐4‐Ones: Synthesis,Hemagglutination Inhibitory Properties,and Molecular Modeling

Structural alterations of the aglycon portions of α‐mannosides influence their inhibitory potency toward type 1‐fimbriated Escherichia coli. The aim of our work was to prepare and explore inhibitory properties of novel mannosylated N‐aryl‐substituted 3‐hydroxypyridine‐4‐ones because they possess needed structural characteristics as possible FimH antagonists. Hemagglutination inhibitory tests showed that the examined 3‐hydroxypyridine‐4‐one α‐mannosides exhibited better inhibitory activity than methyl α‐d ‐mannopyranoside used as a reference compound. Molecular modeling studies revealed the specific interactions responsible for the observed binding activities toward the mannose‐specific FimH lectin. The activity depends on the substituent in p‐position on the aglycon aromatic ring.     

Synthesis,docking, in vitro and in vivo antidiabetic activity of pyrazole‐based 2,4‐thiazolidinedione derivatives as PPAR‐γ modulators

The design, synthesis, structure–activity relationship, and biological activity of 2,4‐thiazolidinedione derivatives as peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) modulators for antidiabetic activity are reported. Fifteen 2,4‐thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR‐γ by the Glide XP module of Schrodinger. Eight derivatives ( 5a , 5b , 5d , 5f , 5i , 5l , 5n , 5o ) having Glide XP scores > ?8 as compared to the standard drug, rosiglitazone (Glide XP score = ?9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR‐γ transactivation and in vivo blood glucose lowering activity in the streptozotocin‐induced diabetic rat model. Compounds 5o , 5n , 5a , 5i , and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR‐γ transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o , 5n , and 5a (140.1 ± 4.36, 141.4 ± 6.15, and 150.7 ± 4.15, respectively), along with reference drugs pioglitazone (135.2 ± 4.91) and rosiglitazone (141.1 ± 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR‐γ gene expression by 2.35‐fold as compared to rosiglitazone (1.27‐fold) and pioglitazone (1.6‐fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver.

     

Design,synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin‐dependent protein kinase IV

Calcium/calmodulin‐dependent protein kinase IV (CAMKIV ) is a multifunctional Ser/Thr kinase, associated with cerebral hypoxia, cancer, and neurodegenerative diseases. Here, we report design, synthesis, and biological evaluation of seven pyrimidine‐substituted novel inhibitors of CAMKIV . We successfully synthesized and extensively characterized (ESI ‐MS , ¹H NMR , and ¹³C NMR studies) seven compounds that are showing appreciable binding affinity to the CAMKIV . Molecular docking and fluorescence binding studies revealed that compound 1 is showing very high binding free energy (ΔG  = ?11.52 kcal/mol) and binding affinity (K  =  9.2 × 10¹⁰ m ^?1) to the CAMKIV . We further performed MTT assay to check the cytotoxicity and anticancer activity of these compounds. An appreciable IC ₅₀ (39 μm ) value of compound 1 was observed on human hepatoma cell line and nontoxic till the 400 μm on human embryonic kidney cells. To ensure anticancer activity of all these compounds, we further performed propidium iodide assay to evaluate cell viability and DNA content during the cell cycle. We found that compound 1 is again showing a better anticancer activity on both human hepatoma and human embryonic kidney cell lines.     

Synthesis,biological evaluation,and molecular docking studies of new pyrazol‐3‐one derivatives with aromatase inhibition activities

A new series derived from 4‐(2‐chloroacetyl)‐1,2‐dihydro‐1,5‐dimethyl‐2‐phenyl‐3H‐pyrazol‐3‐one was synthesized, characterized and its pharmacological activity toward aromatase enzyme inhibition was screened and compared to the reference native ligand letrozole. The most active compound of the series was 16 , showing IC₅₀ value of 0.0023 ± 0.0002 μm compared to letrozole with IC₅₀ of 0.0028 ± 0.0006 μm . In addition, compounds 26 and 36 exhibit good inhibition activities close to letrozole with IC₅₀ values 0.0033 ± 0.0001 and 0.0032 ± 0.0003 μm , respectively. Moreover, molecular docking studies were conducted to support the findings.     

An expedient synthesis of N‐(1‐(5‐mercapto‐4‐((substituted benzylidene)amino)‐4H‐1,2,4‐triazol‐3‐yl)‐2‐phenylethyl)benzamides as jack bean urease inhibitors and free radical scavengers: Kinetic mechanism and molecular docking studies

In this study, some new azomethine‐triazole hybrids 5a–5l derived from N‐benzoyl‐L‐phenylalanine were synthesized and characterized. The synthesized compounds showed first‐rate, urease inhibition, and compounds 5c and 5e were found to be most effective inhibitors with 0.0137 ± 0.00082 μm and 0.0183 ± 0.00068 μm , respectively (thiourea 15.151 ± 1.27 μm ). The kinetic mechanism of urease inhibition revealed the compounds 5c and 5e to be non‐competitive inhibitors, whereas compounds 5d and 5j were found to be of mixed‐type inhibitors. Docking studies also indicated better interaction patterns with urease enzyme. The results of enzyme inhibition, kinetic mechanism and molecular docking suggest that these compounds can serve as lead compounds in the design of more effective urease inhibitors.     

Synthesis,in vitro evaluation and molecular docking studies of novel coumarin‐isatin derivatives as α‐glucosidase inhibitors

This study synthesized a series of novel coumarin‐isatin derivatives and evaluated them for α‐glucosidase inhibitory activity. The majority of the screened compounds exhibited excellent inhibition activities with IC₅₀ values of 2.56 ± 0.08–268.79 ± 3.04 μm , when compared to acarbose. Among the newly derivatives, compound 5p was found to be the most active compound in the library of coumarin‐isatin derivatives. Furthermore, enzyme kinetic studies showed that compound 5p is a non‐competitive inhibitor with a K_i of 2.14 μm . Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α‐glucosidase. Our results indicate that coumarin‐isatin derivatives as a new class of α‐glucosidase inhibitors.     

Synthesis,p38α MAP kinase inhibition,anti‐inflammatory activity,and molecular docking studies of 1,2,4‐triazole‐based benzothiazole‐2‐amines

Recent studies have demonstrated that inhibition of p38α MAP kinase could effectively inhibit pro‐inflammatory cytokines including TNF‐α and interleukins. Thus, inhibition of this enzyme can prove greatly beneficial in the therapy of chronic inflammatory diseases. A new series of N‐[3‐(substituted‐4H‐1,2,4‐triazol‐4‐yl)]‐benzo[d]thiazol‐2‐amines ( 4a–n ) were synthesized and subjected to in vitro evaluation for anti‐inflammatory activity (BSA anti‐denaturation assay) and p38α MAPK inhibition. Among the compounds selected for in vivo screening of anti‐inflammatory activity ( 4b , 4c , 4f , 4g , 4j , 4m , and 4n ), compound 4f was found to be the most active with an in vivo anti‐inflammatory efficacy of 85.31% when compared to diclofenac sodium (83.68%). It was also found to have a low ulcerogenic risk and a protective effect on lipid peroxidation. The p38α MAP kinase inhibition of this compound (IC₅₀ = 0.036 ± 0.12 μM) was also found to be superior to the standard SB203580 (IC₅₀ = 0.043 ± 0.27 μM). Furthermore, the in silico binding mode of the compound on docking against p38α MAP kinase exemplified stronger interactions than those of SB203580.

     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

(Z)‐2‐(3‐Chlorobenzylidene)‐3,4‐dihydro‐N‐(2‐methoxyethyl)‐3‐oxo‐2H‐benzo[b][1,4]oxazine‐6‐carboxamide as GSK‐3β inhibitor: Identification by virtual screening and its validation in enzyme‐ and cell‐based assay

Glycogen synthase kinase 3β (GSK‐3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. The present study was aimed to discover new scaffolds for GSK‐3β inhibition, through protein structure‐guided virtual screening approach. With the availability of large number of GSK‐3β crystal structures with varying degree of RMSD in protein backbone and RMSF in side chain geometry, herein appropriate crystal structures were selected based on the characteristic ROC curve and percentage enrichment of actives. The validated docking protocol was employed to screen a library of 50,000 small molecules using molecular docking and binding affinity calculations. Based on the GLIDE docking score, Prime MMGB/SA binding affinity, and interaction pattern analysis, the top 50 ligands were selected for GSK‐3β inhibition. (Z)‐2‐(3‐chlorobenzylidene)‐3,4‐dihydro‐N‐(2‐methoxyethyl)‐3‐oxo‐2H‐benzo[b][1,4]oxazine‐6‐carboxamide (F389‐0663, 7 ) was identified as a potent inhibitor of GSK‐3β with an IC₅₀ value of 1.6 μm . Further, GSK‐3β inhibition activity was then investigated in cell‐based assay. The treatment of neuroblastoma N2a cells with 12.5 μm of F389‐0663 resulted in the significant increase in GSK‐3β Ser9 levels, which is indicative of the GSK‐3β inhibitory activity of a compound. The molecular dynamic simulations were carried out to understand the interactions of F389‐0663 with GSK‐3β protein.