Design,synthesis and biological evaluation of benzamide derivatives as novel NTCP inhibitors that induce apoptosis in HepG2 cells

Sodium taurocholate cotransport polypeptide (NTCP) plays an important role in the development of hepatitis and acts as a switch to allow hepatitis virus to enter hepatic cells. As the entry receptor protein of hepatitis virus, NTCP is also an effective target for the treatment of hepatocellular carcinoma. Herein, twenty-five benzamide analogues were synthesized based on the virtual screening design and their anti-proliferative activities against HepG2 cells were evaluated in vitro. Compound 35 was found to be promising, with an IC₅₀ value of 2.8 μM. The apoptosis induced by 35 was characterized by the regulation of markers, including an increase in Bax, cleaved-caspase 3, and cleaved-PARP proteins, and a decrease in Bcl-2 protein. Molecular docking and molecular dynamics (MD) simulation confirmed that compound 35 can bind tightly to NTCP. Western blot analysis also showed that NTCP was inhibited. Altogether, these results indicate that compound 35 acts as a novel NTCP inhibitor to induce apoptosis in HepG2 cells.     

Design,synthesis and biological evaluation of pyrimidine derivatives as novel CDK2 inhibitors that induce apoptosis and cell cycle arrest in breast cancer cells

Cyclin-dependent kinase 2 (CDK2) plays a key role in eukaryotic cell cycle progression which could facilitate the transition from G1 to S phase. The dysregulation of CDK2 is closely related to many cancers. CDK2 is utilized as one of the most studied kinase targets in oncology. In this article, 24 benzamide derivatives were designed, synthesized and investigated for the inhibition activity against CDK2. Our results revealed that the compound 25 is a potent CDK2 inhibitor exhibiting a broad spectrum anti-proliferative activity against several human breast cancer cells. Additionally, compound 25 could block cell cycle at G0 or G1 and induce significant apoptosis in MDA-MB-468 cells. These findings highlight a rationale for further development of CDK2 inhibitors to treat human breast cancer.     

Design, synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2 inhibitors

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. A series of quinoline amide derivatives were prepared and found to be good inhibitors of VEGFR-2. The inhibitory activities were investigated against VEGFR-2 kinase and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 6 (5-chloro-2-hydroxy-N-(quinolin-8-yl)benzamide) exhibited the most potent inhibitory activity (IC(50)=3.8 and 5.5 nM for VEGFR-2 kinase and HUVEC, respectively). Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further researching.     

Design, synthesis and biological evaluation of N-phenylsulfonylnicotinamide derivatives as novel antitumor inhibitors

A series of novel N-phenylsulfonylnicotinamide derivatives (1-24) have been synthesized and evaluated as potential EGFR tyrosine kinase (TK) inhibitors. Among all the compounds, compound 10 (5-bromo-N-(4-chlorophenylsulfonyl)nicotinamide) showed the most potent growth inhibitory activity against EGFR TK and antiproliferative activity of MCF-7 cancer cell line in vitro, with IC(50) value of 0.09 and 0.07 μM. Docking simulation was performed to insert compound 10 into the EGFR TK active site to determine the probable binding model. Based on the preliminary results, compound 10 with potent inhibitory activity to tumor growth may be a potential anticancer agent.     

Design,synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.     

Design,synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer’s disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC₅₀ 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.     

Design, synthesis and biological evaluation of pyridine acyl sulfonamide derivatives as novel COX-2 inhibitors

A series of pyridine acyl sulfonamide derivatives (1-24) have been designed and synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among all the compounds, compound 23 displayed the most potent COX-2 inhibitory activity with an IC(50) of 0.8 μM. Antitumor and anti-inflammatory assays indicated that compound 23 owned high antiproliferative activity against B16-F10, HepG2 and MCF-7 cancer cell lines as well as COX-2-derived prostaglandin E(2) (PGE(2)) inhibitory activity of murine macrophage RAW 264.7 cell line with IC(50) values of 2.8, 1.2, 1.8 and 0.15 μM, respectively. Docking simulation was performed to position compound 23 into the COX-2 active site to determine the probable binding model.     

Design,synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

A novel series of chalcone derivatives (4a–8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC₅₀: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC₅₀: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.     

Design, synthesis, and evaluation of 2-phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors

A series of 2-phenoxy-indan-1-one derivatives have been designed, synthesized, and tested as acetylcholinesterase inhibitors. The most potent compound exhibited high AChE inhibitory activity (IC50 = 50 nM), and the molecular docking study indicated that it was nicely accommodated by AChE.     

Design,synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase

Rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), has been approved by U.S. Food and Drug Administration to treat Alzheimer’s disease (AD) and Parkinson’s disease (PD) dementia. In the current work, a bambuterol derivative lacking one of the carbamoyloxy groups on the benzene ring (BMC-1) and its analogues were synthesized using 1-(3-hydroxyphenyl) ethan-1-one and 1-(4-hydroxyphenyl) ethan-1-one as starting materials. In-vitro cholinesterase assay established that nine compounds were more potent to inhibit both electric eel AChE and equine serum BChE than rivastigmine under the same experimental conditions. Further study confirmed that among the nine carbamates, BMC-3 (IC_50(AChE) = 792 nM, IC_50(BChE) = 2.2 nM) and BMC-16 (IC_50(AChE) = 266 nM, IC_50(BChE) = 10.6 nM) were excellent cholinesterase inhibitors with potential of permeating through the blood-brain barrier. These carbamates could be used as potential dual inhibitors of AChE and BChE and to discover novel drugs for the treatment of AD and PD dementia.     

Design,synthesis and biological evaluation of novel thiazole derivatives as potent FabH inhibitors

Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram positive and negative bacteria. Three series of Schiff bases containing thiazole template were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 11 and 18 were potent inhibitors of E. coli FabH.     

Design,synthesis and biological evaluation of novel oseltamivir derivatives as potent neuraminidase inhibitors

Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r²) and cross-validation coefficient (q²) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r² and q² of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme-inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC₅₀ value of 39.6?μM against NA, while IC₅₀ value for oseltamivir is 61.1?μM. This compound may be further investigated for the treatment of infection by the new type influenza virus.     

Design,synthesis and biological evaluation of novel zanamivir derivatives as potent neuraminidase inhibitors

Neuraminidase (NA) is an important antiviral drug target. Zanamivir is one of the most potent NA inhibitors. In this paper, a series of zanamivir derivatives as potential NA inhibitors were studied by combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q²?=?0.728 and r²?=?0.988, and the best CoMSIA (comparative molecular similarity indices analysis) model has q²?=?0.750 and r²?=?0.981, respectively. The built 3D-QSAR models show significant statistical quality and excellent predictive ability. Seven new NA inhibitors were designed and predicted. 20?ns of MD simulations were carried out and their binding free energies were calculated. Two designed compounds were selected to be synthesized and biologically evaluated by NA inhibition and virus inhibition assays. One compound (IC₅₀?=?0.670?µM, SI?>?149) exhibits excellent antiviral activity against A/WSN/33 H1N1, which is superior to the reference drug zanamivir (IC₅₀?=?0.873?µM, SI?>?115). The theoretical and experimental results may provide reference for development of new anti-influenza drugs.     

Design,synthesis and biological evaluation of novel dithiocarbamate-substituted diphenylaminopyrimidine derivatives as BTK inhibitors

Bruton’s tyrosine kinase (BTK) has emerged as an attractive target related to B-lymphocytes dysfunctions, especially hematologic malignancies and autoimmune diseases. In our study, a series of diphenylaminopyrimidine derivatives bearing dithiocarbamate moieties were designed and synthesized as novel BTK inhibitors for treatment of B-cell lymphoma. Among all these compounds, 30ab (IC₅₀ = 1.15 ± 0.19 nM) displays similar or more potent inhibitory activity against BTK than spebrutinib (IC₅₀ = 2.12 ± 0.32 nM) and FDA approved drug ibrutinib (IC₅₀ = 3.89 ± 0.57 nM), which is attributed to close binding of 30ab with BTK predicted by molecular docking. In particular, 30ab exhibits enhanced anti-proliferative activity against B-lymphoma cell lines at the IC₅₀ concentration of 0.357 ± 0.02 μM (Ramos) and 0.706 ± 0.05 μM (Raji), respectively, almost 10-fold better than ibrutinib and spebrutinib. In addition, 30ab displays stronger selectivity on B-cell lymphoma over other cancer cell lines than spebrutinib. Furthermore, 30ab efficiently blocks BTK downstream pathways and results in apoptosis of cancer cells. In vivo xenograft model evaluation demonstrates the significant efficacy and broad safety margin of 30ab in treatment of B-cell lymphoma. We propose that compound 30ab is a candidate for further study and development based on our current findings.     

Design,synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors

A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC₅₀ values of 64.47?nM, 188.7?nM and 65.36?nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure–activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.     

Design,synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors

New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC₅₀ value of 43?nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.     

Design,synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors

A series of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized, Furthermore, their inhibitory activities against acetylcholinesterase in vitro were tested by Ellman spectrophotometry, and the results of inhibitory activity test showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro. Moreover, the IC₅₀ value of compound 4f was to 0.66 μM, which was higher than that of Rivastigmine and Huperzine-A as reference compounds, and it had a weak inhibitory effect on butyrylcholinesterase. The potential binding mode of compound 4f with AChE was investigated by the molecular docking, and the results showed that 4f was strongly bound up with AChE with the optimal conformation, in addition, their binding energy reached −11.27 Kcal*mol⁻¹. At last, in silico molecular property of the synthesized compounds were predicted by using Molinspiration online servers. It can be concluded that the lead AChEIs compound 4f presented satisfactory drug-like characteristics.     

Design, synthesis and evaluation of isaindigotone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors

A series of isaindigotone derivatives 5a-d and 6a-d were designed, synthesized and evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors. Results showed that the novel class of isaindigotone derivatives could inhibit both cholinesterases and the selectivity of AChE over BuChE inhibition was related to the aromatic, the species and length of the alkyl amino side chain of compounds. The structure-activity relationships were discussed and their multiple binding modes were further clarified in the molecular docking studies.     

Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: Design,synthesis and biological evaluation

A series of novel biphenyl urea derivates were synthesized and investigated for their potential to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2). In particular, A7, B3 and B4 displayed significant enzymatic inhibitory activities, with IC₅₀ values of 4.06, 4.55 and 5.26 nM. Compound A7 exhibited potent antiproliferative activity on several cell lines. SAR study suggested that the introduction of methyl at ortho-position of the biphenyl urea and tertiary amine moiety could improve VEGFR-2 inhibitory activity and antitumor effects. Molecular docking indicated that the urea moiety formed four hydrogen bonds with DFG residue. These biphenyl ureas could serve as promising lead compounds for further optimization.     

Design,synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors

Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.