Design,modification and 3D QSAR studies of novel 2,3-dihydrobenzo[b][1,4]dioxin-containing 4,5-dihydro-1H-pyrazole derivatives as inhibitors of B-Raf kinase

Two series of novel 2,3-dihydrobenzo[b][1,4]dioxin-containing 4,5-dihydro-1H-pyrazole derivatives C1–C15 and D1–D15 have been synthesized and evaluated for their B-Raf inhibitory and anti-proliferation activities. Compound C14 ((3-(4-bromophenyl)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone) showed the most potent biological activity against B-Raf^V600E (IC₅₀ = 0.11 μM) and WM266.4 human melanoma cell line (GI₅₀ = 0.58 μM), being comparable with the positive control Erlotinib and more potent than our previous best compound, while D10 ((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(5-(3-fluorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone) performed the best in the D series (IC₅₀ = 1.70 μM; GI₅₀ = 1.45 μM). The docking simulation was performed to analyze the probable binding models and poses and the QSAR model was built for reasonable design of B-Raf inhibitors in future. The introduction of 2,3-dihydrobenzo[b][1,4]dioxin structure reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity.     

Design,synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors

Two series of thiazolidinone derivatives designing for potential EGFR and HER-2 kinase inhibitors have been discovered. Some of them exhibited significant EGFR and HER-2 inhibitory activity. Compound 2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)thiazol-4(5H)-one (12) displayed the most potent inhibitory activity (IC₅₀ = 0.09 μM for EGFR and IC₅₀ = 0.42 μM for HER-2), comparable to the positive control erlotinib. Docking simulation was performed to position compound 12 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the thiazolidinone derivatives own high antiproliferative activity against MCF-7. Compound 12 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.     

Synthesis and biological evaluation of 1,2,4-trisubstituted imidazoles as inhibitors of transforming growth factor-β type I receptor (ALK5)

A series of 2-(6-methylpyridin-2-yl)-1H-imidazoles were synthesized and evaluated for ALK5 inhibitory activity in cell-based luciferase reporter assays. The compound 4-(((1-(benzo[d][1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)benzenesulfonamide (27a) exhibited slightly higher inhibition (IC₅₀ = 0.24 μM) than SB431542 (IC₅₀ = 0.35 μM), a well known potent ALK5 inhibitor. The binding mode of 27a generated by flexible docking study shows that it fits well into the site cavity of ALK5 by forming several tight interactions.     

Synthesis,molecular docking studies of coumarinyl-pyrazolinyl substituted thiazoles as non-competitive inhibitors of mushroom tyrosinase

A series of coumarinyl-pyrazolinyl substituted thiazoles derivatives were synthesized and their inhibitory effects on the DPPH and mushroom tyrosinase were evaluated. The results showed that all of the synthesized compounds exhibited significant mushroom tyrosinase inhibitory activities. In particular, 3-(5-(4-(benzyloxy)-3-methoxyphenyl)-1-(4-(4-bromophenyl)thiazol-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (7j) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value 0.00458 ± 0.00022 μM compared with the IC₅₀ value of kojic acid is 16.84 ± 0.052 μM. The inhibition mechanism analyzed by Lineweaver–Burk plots revealed that the type of inhibition of compound 7j on tyrosinase was noncompetitive. The docking study against tyrosinase enzyme was also performed to determine the binding affinity of the compounds. The compound 7a showed the highest binding affinity (−10.20 kcal/mol) with active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that compound 7j may serve as a structural template for the design and development of novel tyrosinase inhibitors.     

Synthesis and structure–activity relationships of N-benzyl-N-(X-2-hydroxybenzyl)-N′-phenylureas and thioureas as antitumor agents

Two series of novel N-benzyl-N-(X-2-hydroxybenzyl)-N′-phenylureas and thioureas (1a–18a; 1b–18b) as potential EGFR and HER-2 kinase inhibitors have been discovered. These compounds displayed good EGFR and HER-2 inhibitory activity and the SARs are also been studied. Especially compound 7b demonstrated significant EGFR and HER-2 inhibitory activity (IC₅₀ = 0.08 μM for EGFR and IC₅₀ = 0.35 μM for HER-2). Docking simulation was performed to position compound 7b into the EGFR active site to determine the probable binding conformation and antiproliferative assay results indicating that these series of urea and thioureas own high antiproliferative activity against MCF-7. Above all, thiourea 7b would be a potential anticancer agent deserves further research.     

Synthesis,molecular modeling,and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents

A series of novel cinnamic acid metronidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Compound 3h showed the most potent biological activity (IC₅₀ = 0.62 μM for EGFR and IC₅₀ = 2.15 μM for HER-2). Docking simulation was performed to position compound 3h into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against MCF-7. Compound 3h with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent.     

Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment

Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure–activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC₅₀ = 0.019 μM, rat IC₅₀ = 0.0051 μM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.     

Synthesis,biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors

A series of novel 4,5-dihydropyrazole derivatives (3a–3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF^V600E) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF^V600E to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF^V600E, MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC₅₀ value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC₅₀ = 1.31 μM for MCF-7 and IC₅₀ = 0.45 μM for WM266.5, IC₅₀ = 0.22 μM for BRAF^V600E, 3m: IC₅₀ = 0.97 μM for MCF-7 and IC₅₀ = 0.72 μM for WM266.5, IC₅₀ = 0.46 μM for BRAF^V600E, which were comparable with the positive control Erlotinib.     

5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors

A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC₅₀ = 5.5 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC₅₀ = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).     

Evaluation of pyrrolin-2-one derivatives synthesized by a new practical method as inhibitors of plasminogen activator inhibitor-1 (PAI-1)

We describe in this Letter a new synthetic method for pyrrolin-2-ones as potent plasminogen activator inhibitor-1 (PAI-1) inhibitors. Pyrrolin-2-one derivatives synthesized from N-2-oxoethylamides and aldehydes in aqueous NaOH by one-pot were evaluated for their PAI-1 inhibitory activity. Among these derivatives, compounds 16 and 18 were found to possess potent PAI-1 inhibitory activity (compound 16: IC₅₀: 0.69 μM, compound 18: IC₅₀: 0.65 μM).     

Coumarin-thiazole and -oxadiazole derivatives: Synthesis,bioactivity and docking studies for aldose/aldehyde reductase inhibitors

In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a–o) and coumarin-oxadiazole 11(a–h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC₅₀ value of 0.16 ± 0.06 μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC₅₀ = 2.94 ± 1.23 μM for ARL1 and 0.12 ± 0.05 μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC₅₀ = 1.71 ± 0.01 μM for ARL1 and 0.11 ± 0.001 μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC₅₀ = 0.459 ± 0.001 μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors.     

Studies on depigmenting activities of dihydroxyl benzamide derivatives containing adamantane moiety

Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4-n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a–e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC₅₀ = 1.25 μM and 0.73 μM, respectively) as compared to 4-n-butyl resorcinol (IC₅₀ = 21.64 μM) and hydroquinone (IC₅₀ = 3.97 μM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition.     

Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors

Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N′-substituted phenylthiourea derivatives (3a–i, 6a–k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a–i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a–k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC₅₀ = 6.13 μM) is significantly higher than kojic acid (IC₅₀ = 33.3 μM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor.     

Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR–TK inhibitory activity. Especially, N⁶-((5-bromothiophen-2-yl)methyl)-N⁴-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC₅₀ = 3.11 μM for Hep G2, IC₅₀ = 0.82 μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.     

Design,synthesis and molecular modeling of biquinoline–pyridine hybrids as a new class of potential EGFR and HER-2 kinase inhibitors

A new series of biquinoline–pyridine hybrids were designed and synthesized by a base-catalyzed cyclocondensation through one-pot multicomponent reaction. All compounds were tested for in vitro anticancer activities against two cancer cell lines A549 (adenocarcinomic human alveolar basal epithelial) and Hep G2 (liver cancer). Enzyme inhibitory activities of all compounds were carried out against EGFR and HER-2 kinase. Of the compounds studied, majority of the compounds showed effective anticancer activity against used cancer cell lines. Compound 9i (IC₅₀ = 0.09 μM) against EGFR and (IC₅₀ = 0.2 μM) against HER-2 kinase displayed the most potent inhibitory activity as compared to other member of the series. In the molecular modelling study, compound 9i was bound in to the active pocket of EGFR with four hydrogen bonds and two π–cation interactions having minimum binding energy ΔG_b = −54.4 kcal/mol.     

Rational design,synthesis and biological evaluation of 1,3,4-oxadiazole pyrimidine derivatives as novel pyruvate dehydrogenase complex E1 inhibitors

On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4-triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC₅₀ 0.97–19.21 μM) and obvious inhibitory activity against cyanobacteria (EC₅₀ 0.83–9.86 μM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC₅₀ < 6.62 μM) and cyanobacteria (EC₅₀ < 1.63 μM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC₅₀ = 0.97 μM) and cyanobacteria (EC₅₀ = 0.83 μM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1.     

Design of novel nicotinamides as potent and selective monoamine oxidase a inhibitors

A series of N-(2-morpholinoethyl)nicotinamide (1–13) and N-(3-morpholinopropyl)nicotinamide derivatives (14–26) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. Most of these synthesized compounds proved to be potent, and selective inhibitors of MAO-A rather than of MAO-B. 5-Chloro-6-hydroxy-N-(2-morpholinoethyl)nicotinamide (13) displayed the highest MAO-A inhibitory potency (IC₅₀ = 0.045 μM) and a good selectivity. 2-Bromo-N-(2-morpholinoethyl)nicotinamide (3) was the most potent MAO-B inhibitor with the IC₅₀ value of 0.32 μM, but it was not selective. Molecular dockings of compound 13 were performed in order to give structural insights regarding the MAO-A selectivity.     

Synthesis and biological evaluation of pyrazole derivatives containing thiourea skeleton as anticancer agents

Two series of pyrazole derivatives designing for potential EGFR kinase inhibitors have been discovered. Some of them exhibited significant EGFR inhibitory activity. Compound 3-(3,4-dimethylphenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (C5) displayed the most potent EGFR inhibitory activity with IC₅₀ of 0.07 μM, which was comparable to the positive control erlotinib. Docking simulation was performed to position compound C5 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the pyrazole derivatives own high antiproliferative activity against MCF-7. Compound C5 showed significant antiproliferative activity against MCF-7 with IC₅₀ of 0.08 μM. Therefore, compound C5 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.     

Design and synthesis of novel chloramphenicol amine derivatives as potent aminopeptidase N (APN/CD13) inhibitors

Herein we report a series of novel chloramphenicol amine derivatives as aminopeptidase N (APN)/CD13 inhibitors. All compounds were synthesized starting from commercially available (1S,2S)-2-amino-1-(4-nitrophenyl) propane-1,3-diol. The preliminary biological screening showed that some compounds exhibited potent inhibitory activity against APN. It should be noted that one compound, 13b (IC₅₀ = 7.1 μM), possess similar APN inhibitory activity compared with Bestatin (IC₅₀ = 3.0 μM).     

Design and synthesis of novel anti-Alzheimer’s agents: Acridine-chromenone and quinoline-chromenone hybrids

A novel series of acridine-chromenone and quinoline-chromenone hybrids were designed, synthesized, and evaluated as anti-Alzheimer’s agents. All synthesized compounds were evaluated as cholinesterases (ChEs) inhibitors and among them, 7-(4-(6-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)phenoxy)-4-methyl-2H-chromen-2-one (8e) exhibited the most potent anti-acetylcholinesterase (AChE) inhibitory activity (IC₅₀ = 16.17 μM) comparing with rivastigmine (IC₅₀ = 11.07 μM) as the reference drug. Also, compound 8e was assessed for its β-secretase (BACE1) inhibitory and neuroprotective activities which demonstrated satisfactory results. It should be noted that both kinetic study on the inhibition of AChE and molecular modeling revealed that compound 8e interacted simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.