Design,synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors

STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC₅₀ values as low as 7.71 μM and 1.38 μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC₅₀ value of 9.61 μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration.     

Identification of novel quinazolin-4(3H)-ones as inhibitors of thermolysin,the prototype of the M4 family of proteinases

A combinatorial series of novel quinazolin-4(3H)-ones were synthesised and their structures were established based on spectroscopic data (IR, NMR, EI-MS, and FAB-MS). The compounds were tested for inhibition of the zinc metalloproteinase thermolysin (TLN) utilizing a chemical array-based approach. Some of the compounds were found to inhibit TLN, with IC₅₀ values ranging from 0.0115 μM (compound 3) to 122,637 μM (compound 29). Compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3H)-one] (IC₅₀ = 0.0115 μM) and compound 35 [3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4 (1H)-one] (IC₅₀ = 0.2477 μM) were found to be the most potent inhibitors.     

Synthesis and biological activity of 4-substituted benzoxazolone derivatives as a new class of sEH inhibitors with high anti-inflammatory activity in vivo

A series of novel 4-substituted benzoxazolone derivatives was synthesized, characterized and evaluated as human soluble epoxide hydrolase (sEH) inhibitors and anti-inflammatory agents. Some compounds showed moderate sEH inhibitory activities in vitro, and two novel compounds, 3g and 4j, exhibited the highest activities with IC₅₀ values of 1.72 and 1.07 μM, respectively. Structure–activity relationships (SARs) revealed that introduction of a lipophilic amino acid resulted in an obvious increase in the sEH inhibitory activity, especially for derivatives containing a phenyl (3d, IC₅₀ = 2.67 μM), pyrrolidine (3g, IC₅₀ = 1.72 μM), or sulfhydryl group (3e, IC₅₀ = 3.02 μM). Several compounds (3a–3g) were tested in vivo using a xylene-induced ear edema mouse model. Three compounds (3d, 3f, and 3g) showed strong anti-inflammatory activities in vivo which were higher than that of Chlorzoxazone, a reference drug widely used in the clinic. Our investigation provided a novel type of sEH inhibitor and anti-inflammatory agent that may lead to the discovery of a potential candidate for clinical use.     

Synthesis and biological evaluation of novel γ-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists

Synthesis, biological evaluation and structure–activity relationships for a series of novel γ-carboline analogues of Dimebon^? are described. Among the studied compounds, γ-carbolines 3{8} and 3{14} have been identified as potent small molecule antagonists of histamine H₁ (IC₅₀ = 0.1 μM) and serotonin 5-HT₆ (IC₅₀ = 0.37 μM) receptors, respectively.     

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.     

Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides

A series of N-substituted 1-aminomethyl-β-d-glucopyranoside derivatives was prepared. These novel synthetic compounds were assessed in vitro for inhibitory activity against yeast α-glucosidase and both rat intestinal α-glucosidases maltase and sucrase. Most of the compounds displayed α-glucosidase inhibitory activity, with IC₅₀ values covering the wide range from 2.3 μM to 2.0 mM. Compounds 19a (IC₅₀ = 2.3 μM) and 19b (IC₅₀ = 5.6 μM) were identified as the most potent inhibitors for yeast α-glucosidase, while compounds 16 (IC₅₀ = 7.7 and 15.6 μM) and 19e (IC₅₀ = 5.1 and 10.4 μM) were the strongest inhibitors of rat intestinal maltase and sucrase. Analysis of the kinetics of enzyme inhibition indicated that 19e inhibited maltase and sucrase in a competitive manner. The results suggest that the aminomethyl-β-d-glucopyranoside moiety can mimic the substrates of α-glucosidase in the enzyme catalytic site, leading to competitive enzyme inhibition. Moreover, the nature of the N-substituent has considerable influence on inhibitory potency.     

Discovery of small molecules that inhibit melanogenesis via regulation of tyrosinase expression

5,6,7,8-Tetrahydro-4H-cyclohepta[d]isoxazole derivatives were synthesized and evaluated as a novel class of inhibitors for α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis in a mouse melanoma B16F10 cell line. Compound 8e (IC₅₀ = 0.67 μM), 8h (IC₅₀ = 1.01 μM) and 9b (IC₅₀ = 0.99 μM) exhibited a potent inhibitory activity approximately 85- to 126-fold greater than kojic acid, a well-known potent inhibitor. A biochemical study indicates that the activity of this series should be displayed via down-regulation of the expression of tyrosinase.     

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC₅₀: 0.68 ± 0.13 μM) with strong DPPH and ABTS radical scavenging activity (IC₅₀: 13.77 ± 0.25 μM and IC₅₀: 12.59 ± 0.21 μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC₅₀: 0.74 ± 0.09 μM) and with DPPH and ABTS radical scavenging activity (IC₅₀: 13.52 ± 0.62 μM and IC₅₀: 13.13 ± 0.85 μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.     

Synthesis,characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors

Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as ¹H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC₅₀ < 10 μM. The highest inhibitory activity (IC₅₀ = 5.12 μM for AChE and IC₅₀ = 8.63 μM for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure–activity relationship was discussed.     

Thymidine esters as substrate analogue inhibitors of angiogenic enzyme thymidine phosphorylase in vitro

Thymidine phosphorylase (TP) catalyzes the cleavage of thymidine into thymine and 2-deoxy-α-d-ribose-1-phosphate. Elevated activity of TP prevents apoptosis, and induces angiogenesis which ultimately leads to tumor growth and metastasis. Critical role of TP in cancer progression makes it a valid target in anti-cancer research. Discovery of small molecules as TP inhibitors is vigorously pursued in cancer therapy. In the present study, we functionalized thymidine as benzoyl ester to synthesize compounds 3–16. In vitro evaluation of thymidine esters for their thymidine phosphorylase inhibition activity was subsequently carried out. Compounds 4, 10, 14, and 15 showed good activities with lower IC₅₀ values than the standard, 7-deazaxanthine (IC₅₀ = 41.0 ± 1.63 μM). Among them, compound 14 showed five folds higher activity (IC₅₀ = 7.5 ± 0.8 μM), while 4 (IC₅₀ = 18.5 ± 1.0 μM) and 10 (IC₅₀ = 18.8 ± 1.2 μM) showed two folds higher activity than the standard. Compound 15 showed slightly better activity (IC₅₀ = 33.3 ± 1.5 μM) to the standard. Potent compounds were further subjected to kinetic and molecular docking studies to identify their mode of inhibition, and to study their interactions with the protein at atomic level, respectively. All active compounds were non-cytotoxic to mouse fibroblast 3T3 cell line. These results identify thymidine esters as substrate analogue (substrate-like) inhibitors of angiogenic enzyme thymidine phosphorylase for further studies.     

Terpenoids with cytotoxic activity from the branches and leaves of Pyrus pashia

Twenty terpenoids, including a new triterpenoid (1) and a new monoterpenoid (20), were isolated from the branches and leaves of Pyrus pashia. The structures of two new compounds were determined to be 2α, 3β, 27-trihydroxyolean-12-en-28-oic acid (1) and (4α)-3-(5,5-dimethyltetrahydrofuranyl)-1-buten-3-ol 3-O-β-d-glucopyranoside (20) on the basis of spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and chemical method. Some of the isolated compounds were evaluated for their cytotoxic activity against a panel of human cancer cell lines by MTT assay, using cisplatin as a positive control. Compound 14 exhibited cytotoxic activities against A549 (IC₅₀ = 19.18 ± 4.26 μM), Hela (IC₅₀ = 12.56 ± 3.89 μM), SGC7901 (IC₅₀ = 10.48 ± 1.95 μM) and NHI-1975 (IC₅₀ = 7.38 ± 2.31 μM) cell lines as well as compound 12 displayed cytotoxic activities against A549 (IC₅₀ = 14.71 ± 1.47 μM) and Hela (IC₅₀ = 12.22 ± 1.88 μM) cell lines.     

Synthesis,biological evaluation,and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors

Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC₅₀ = 0.061 μM and COX-2 IC₅₀ = 0.325 μM; selectivity index (SI) = 0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC₅₀ = 0.011 μM and 0.398 μM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC₅₀ = 1 μM, COX-2 IC₅₀ = 0.011 μM; SI = ～92). Molecular docking studies of compounds 6b and 11b–d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.     

Inhibition of tyrosinase activity by polyphenol compounds from Flemingia philippinensis roots

Flemingia philippinensis is used as a foodstuff or medicinal plant in the tropical regions of China. The methanol (95%) extract of the roots of this plant showed potent tyrosinase inhibition (80% inhibition at 30 μg/ml). Activity-guided isolation yielded six polyphenols that inhibited both the monophenolase (IC₅₀ = 1.01–18.4 μM) and diphenolase (IC₅₀ = 5.22–84.1 μM) actions of tyrosinase. Compounds 1–6 emerged to be three new polyphenols and three known flavanones, flemichin D, lupinifolin and khonklonginol H. The new compounds (1–3) were identified as dihydrochalcones which we named fleminchalcones (A–C), respectively. The most potent inhibitor, dihydrochalcone (3) showed significant inhibitions against both the monophenolase (IC₅₀ = 1.28 μM) and diphenolase (IC₅₀ = 5.22 μM) activities of tyrosinase. Flavanone (4) possessing a resorcinol group also inhibited monophenolase (IC₅₀ = 1.79 μM) and diphenolase (IC₅₀ = 7.48 μM) significantly. In kinetic studies, all isolated compounds behaved as competitive inhibitors. Fleminchalcone A was found to have simple reversible slow-binding inhibition against monophenolase.     

Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design,synthesis, biological evaluation,COX-1,2/5-LOX inhibition and docking study

A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data and elemental analysis. IC₅₀ values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC₅₀ = 0.67 μM) and 4b (IC₅₀ = 0.58 μM) showed better COX-2 inhibitory activity than celecoxib (IC₅₀ = 0.87 μM) with selectivity index (SI = 8.41, 10.55 in sequent) relative to celecoxib (SI = 8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC₅₀ = 1.92, 2.31 μM) higher than zileuton (IC₅₀ = 2.43 μM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition = 15–20%) at all doses when compared to reference drug celecoxib (% edema inhibition = 15.7–17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site.     

Synthesis of 6-chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives: Antidiabetic,antioxidant, β-glucuronidase inhibiton and their molecular docking studies

6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1–26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC₅₀ = 240.10 ± 2.50 μM) and 4 (IC₅₀ = 240.30 ± 2.90 μM) was found to be most active compound of this series, while compounds 3 (IC₅₀ = 260.10 ± 2.50 μM), 6 (IC₅₀ = 290.60 ± 3.60 μM), 13 (IC₅₀ = 288.20 ± 3.00 μM) and 26 (IC₅₀ = 292.10 ± 3.20 μM) also showed better activities than the standard rutin (IC₅₀ = 294.50 ± 1.50 μM). In antioxidant assay, compound 1 (IC₅₀ = 69.45 ± 0.25 μM), 2 (IC₅₀ = 58.10 ± 2.50 μM), 3 (IC₅₀ = 74.25 ± 1.10 μM), and 4 (IC₅₀ = 72.50 ± 3.30 μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC₅₀ = 29.25 ± 0.50 μM), compound 1 (IC₅₀ = 30.10 ± 0.60 μM) and compound 4 (IC₅₀ = 46.10 ± 1.10 μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC₅₀ = 48.50 ± 1.25 μM) and their interaction with the enzyme was confirm by docking studies.     

Kojic acid derived hydroxypyridinone–chloroquine hybrids: Synthesis,crystal structure,antiplasmodial activity and β-haematin inhibition

Aminochloroquinoline–kojic acid hybrids were synthesized and evaluated for β-haematin inhibition and antiplasmodial activity against drug resistant (K1) and sensitive (3D7) strains of Plasmodium falciparum. Compound 7j was the most potent compound in both strains (IC₅₀^3D7 = 0.004 μM; IC₅₀^K1 = 0.03 μM) and had the best β-haematin inhibition activity (0.07 IC₅₀ equiv vs 1.91 IC₅₀ equiv for chloroquine). One compound 8c was found to be equipotent in both strains (IC₅₀ = 0.04 μM).     

Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase

Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC₅₀ of 6 μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC₅₀ of 2.27 μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC₅₀ = 10.01 μM and IC₉₀ = 13.53 μM.     

Unsymmetrically disubstituted urea derivatives: A potent class of antiglycating agents

A series of unsymmetrically disubstituted urea derivatives 1–28 has been synthesized and screened for their antiglycation activity in vitro. Compounds 26 (IC₅₀ = 4.26 ± 0.25 μM), 1 (IC₅₀ = 5.8 ± 0.08 μM), 22 (IC₅₀ = 4.26 ± 0.25 μM), 6 (IC₅₀ = 6.4 ± 0.02 μM), 5 (IC₅₀ = 6.6 ± 0.26 μM), 2 (IC₅₀ = 7.02 ± 0.31 μM), 3 (IC₅₀ = 7.14 ± 0.84 μM), 27 (IC₅₀ = 7.27 ± 0.36 μM), 4 (IC₅₀ = 8.16 ± 1.04 μM), 21 (IC₅₀ = 8.4 ± 0.15 μM), 23 (IC₅₀ = 9.0 ± 0.35 μM) and 13 (IC₅₀ = 15.22 ± 6.7 μM) showed an excellent antiglycation activity far better than the standard (rutin, IC₅₀ = 41.9 ± 2.3 μM). This study thus provides a series of potential molecules for further studies of antiglycation agents.     

Synthesis,in vitro α-glucosidase inhibitory activity and molecular docking studies of new thiazole derivatives

Current study based on the synthesis of new thiazole derivatives via “one pot” multicomponent reaction, evaluation of their in vitro α-glucosidase inhibitory activities, and in silico studies. All synthetic compounds were fully characterized by ¹H NMR, ¹³C NMR and EIMS. CHN analysis was also performed. These newly synthesized compounds showed activities in the range of IC₅₀ = 9.06 ± 0.10–82.50 ± 1.70 μM as compared to standard acarbose (IC₅₀ = 38.25 ± 0.12 μM). It is worth mentioning that most of the compounds such as 1 (IC₅₀ = 23.60 ± 0.39 μM), 2 (IC₅₀ = 22.70 ± 0.60 μM), 3 (IC₅₀ = 22.40 ± 0.32 μM), 4 (IC₅₀ = 26.5 ± 0.40 μM), 6 (IC₅₀ = 34.60 ± 0.60 μM), 7 (IC₅₀ = 26.20 ± 0.43 μM), 8 (IC₅₀ = 14.06 ± 0.18 μM), 9 (IC₅₀ = 17.60 ± 0.28 μM), 10 (IC₅₀ = 27.16 ± 0.41 μM), 11 (IC₅₀ = 19.16 ± 0.19 μM), 12 (IC₅₀ = 9.06 ± 0.10 μM), 13 (IC₅₀ = 12.80 ± 0.21 μM), 14 (IC₅₀ = 11.94 ± 0.18 μM), 15 (IC₅₀ = 16.90 ± 0.20 μM), 16 (IC₅₀ = 12.60 ± 0.14 μM), 17 (IC₅₀ = 16.30 ± 0.29 μM), and 18 (IC₅₀ = 32.60 ± 0.61 μM) exhibited potent inhibitory potential. Molecular docking study was performed in order to understand the molecular interactions between the molecule and enzyme. Newly identified α-glucosidase inhibitors except few were found to be completely non-toxic.