Synthesis and biological evaluation of panaxadiol ester derivatives possessing pyrazole and pyrrole moiety as HIF-1α inibitors.

Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole (18a-j) and pyrrole (19a-n) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c, 19d, and 19n (IC50 = 8.70-10.44 µM) showed better HIF-1α inhibitory activity than PD (IC50 = 13.35 µM). None of these compounds showed cytotoxicity above 100 µM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.

Phytochemical Analysis, Antioxidant and Enzyme-Inhibitory Activities, and Multivariate Analysis of Insect Gall Extracts of Picea koraiensis Nakai.

Picea koraiensis Nakai (PK) is an evergreen tree. It plays an important role in landscaping and road greening. Insect galls of PK are formed by parasitism of the adelgid Adelges laricis. Except for phenolics, other chemical constituents and biological activity of insect gall from PK are still unknown. Thus, here, we performed phytochemical and biological activity analyses of PK insect gall extracts, aiming to turn waste into treasure and serve human health. PK insect gall extracts were prepared using seven solvents. Antioxidant activities of the extracts were examined via antioxidant assays (radical and oxidizing substance quenching, metal chelating, and reducing power). The inhibitory activities of the extracts were determined toward the key human-disease-related enzymes α-glucosidase, α-amylase, cholinesterase, tyrosinase, urease, and xanthine oxidase. The content of numerous active constituents was high in the methanol and ethanol extracts of PK insect gall, and these extracts had the highest antioxidant and enzyme-inhibitory activities. They also showed excellent stability and low toxicity. These extracts have potential for use as stabilizers of olive and sunflower seed oils.

Development of fluorine-substituted NH2-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability.

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t 1/2 = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 µmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain (EC50 = 1.8-349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 µmol/L) was 32-fold in selectivity (SI = 66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t 1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t 1/2 = 14.6 min). Also, 5t possessed good stability in both human and monkey plasma. No significant in vitro inhibition effect toward CYP enzyme and hERG was observed. The single-dose acute toxicity test did not induce mice death or obvious pathological damage. These findings pave the way for further development of 5t as a drug candidate.

Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives.

(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC50 = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents.

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol.

Based on the well-known cytotoxicity of indole compounds, we used the 'Fisher indole synthesis' method to introduce appropriately substituted indole rings into panaxadiol (PD), generating eighteen novel Panaxadiol indole derivatives. Six human cancer cell lines (A549, HepG-2, HCT-116, SGC-7901, MDA-MB-231, PC-3 cells) and one normal ovarian cell lines (IOSE144) were designed to evaluate the anti-proliferative activity of the PD derivatives. The results showed that the majority of PD derivatives showed enhanced anti-proliferative activity, when compared with PD, with P-Methylindolo-PD exhibiting the highest cytotoxicity. In A549 cells, IC50 value was 5.01±0.87 µM, which is roughly 12 times higher than the activity of PD and 5 times that of 5-FU. Moreover, cell morphology analysis and Annexin V-FITC/PI assays exhibited that P-Methylindolo-PD could induce A549 cell apoptosis (55.7 % of apoptotic cells at 20 µM). Moreover, molecular docking experiments were performed to explore the molecular mechanism underlining the binding of P-Methylindolo-PD to the active site of EGFR. The results support that P-Methylindolo-PD might be a promising lead compound for further studies.

Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability.

Adding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66, which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (EC50 = 13 nM) and various single/double mutant strains. ZLM-66 possessed acceptable cytotoxicity and selectivity index. In vivo profiling indicated that ZLM-66 exhibited excellent pharmacokinetics with significantly improved oral bioavailability (F = 140.24%) and a more favorable half-life (T1/2 = 8.45 h), compared to that of doravirine (F = 57%, T1/2 = 4.4 h). In addition, ZLM-66 did not cause significant inhibition of CYP and hERG (>200 µM), as well as acute toxicity and tissue damage at a dose of 1.2 g/kg. Therefore, ZLM-66 can be used as a lead compound to further guide the development of orally active biphenyl-containing doravirine analogs for HIV therapy.

Synthesis and Evaluation of Chiral Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors.

BACKGROUND: TGF-ß signaling pathway inhibition is considered an effective way to prevent the development of several diseases. In the design and synthesis of TGF-ß inhibitors, a rhodanine compound containing a quinoxalinyl imidazole moiety was found to have strong antimicrobial activity. OBJECTIVE: The purpose of this work was to investigate the antimicrobial activity of other chiral rhodanine TGF-ß inhibitors synthesized. METHODS: Two series of 3-substituted-5-(5-(6-methylpyridin-2-yl)-4-(quinoxalinyl-6-yl)- 1Himidazol- 2-yl)methylene)-2-thioxothiazolin-4-ones (12a-h and 13a-e) were synthesized and evaluated for their ALK5 inhibitory and antimicrobial activity. The structures were confirmed by their 1H NMR, 13C NMR and HRMS spectra. All the synthesized compounds were screened against Grampositive strains, Gram-negative strains, and fungi. RESULTS: Among the synthesized compounds, compound 12h showed the highest activity (IC50 = 0.416 µM) against ALK5 kinase. Compound 12h exhibited a good selectivity index of >24 against p38α MAP kinase and was 6.0-fold more selective than the clinical candidate, compound 2 (LY- 2157299). Nearly all the compounds displayed high selectivity toward both Gram-positive and Gram-negative bacteria. They also showed similar or 2.0-fold greater antifungal activity (minimum inhibitory concentration [MIC] = 0.5 µg/mL) compared with the positive control compounds Gatifloxacin (MIC = 0.5 µg/mL) and fluconazole (MIC = 1 µg/mL). CONCLUSION: The findings suggest that the synthesized rhodanine compounds have good ALK5 inhibitory activity, and merit further research and development as potential antifungal drugs.

Design of the naphthyl-diarylpyrimidines as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) via structure-based extension into the entrance channel.

A series of novel naphthyl-diarylpyrimidine (DAPY) derivatives were designed and synthesized to explore the entrance channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating different flexible side chains at the C-6 position. The biological evaluation results showed that all analogues possessed promising HIV-1 inhibitory activity at the nanomolar concentration range. Three compounds (7, 9 and 39) displayed excellent potency against WT HIV-1 strain with EC50 values ranging from 5 to 10 nM and high selectivity indexes (SI = 3504, 30488 and 22846, respectively), which were higher than for nevirapine and comparable to the values for etravirine. The RT inhibition activity, preliminary structure-activity relationship and molecular docking study showed that the side chain at the C-6 position of the DAPYs occupied the entrance channel and significantly influenced anti-HIV activity and selectivity. Additionally, the physicochemical properties were investigated to evaluate the drug-like features, which indicated that introducing various substituents on the pyrimidine ring can improve solubility.

The novel ginsenoside AD2 prevents angiotensin II-induced connexin 40 and connexin 43 dysregulation by activating AMP kinase signaling in perfused beating rat atria.

Connexin-40 (Cx40) and Cx43 are the principal components of gap junctions. Dysregulation of connexin expression is clinically related to cardiac pathologies. 25-Hydroxy protopanaxadiol [25-OH-PPD, 20 (R)-dammarane-3ß, 12ß, 20, 25-tetrol], known as AD2, is a novel protopanaxadiol extracted from Panax ginseng that exhibits many pharmacological activities, but its effects on cardiac gap junctions are poorly understood. The aim of this study was to evaluate the effects of AD2 on angiotensin II (Ang II)-induced Cx40 and Cx43 dysregulation. In this study, isolated beating rat atria were perfused with Ang II (5 µM) for 1 h to induce Cx40 and Cx43 dysregulation. The effects of AD2 (1.6, 16, and 160 µg/100 g body weight) on Ang II-induced hemodynamics in rats were analyzed by biological recorder, and changes in proteins levels were analyzed by western blotting. The results showed that AD2 ameliorated Ang II-induced hyper hemodynamics and abnormal P-waves, and prevented fibrotic collagen deposition (3.77% ± 1.64%-26.31% ± 1.64% with Ang II, 5.76% ± 0.94% with AD2). Ang II upregulated expression of nuclear factor kappa B, activator protein 1, and transforming growth factor ß1, and downregulated of Cx40 and Cx43 expression, which were inhibited by AD2 concomitantly with increased of AMP-activated protein kinase (AMPK) expression via liver kinase B1 activation. The present findings suggest that AD2 inhibited Ang II-induced dysregulation of Cx40 and Cx43 via activation of AMPK signaling, thus highlighting the promise and utility of AD2 for treatment of connexin dysregulation-related heart disease.

Synthesis and evaluation of the epithelial-to- mesenchymal inhibitory activity of indazole-derived imidazoles as dual ALK5/p38α MAP inhibitors.

Drugs of targeting both activin receptor-like kinase 5 (ALK5) and p38α have therapeutic advantages, making them attractive treatment options for tumors. Two series of 4-(1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 13a-g and 4-(1-methyl-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 20a-g were synthesized and evaluated for ALK5 and p38α mitogen-activated protein kinase inhibitory activity. The most potent compound, 13c (J-1090), inhibited ALK5- and p38α-mediated phosphorylation with half-maximal inhibitor concentrations of 0.004 µM and 0.004 µM, respectively, in the enzymatic assay. In this study, the effectiveness of 13c in transforming growth factor (TGF-ß)-exposed U87MG cells was investigated using western blotting, immunofluorescence assays, cell migration assay, invasion assay, and RT-PCR analysis. 13c inhibited the protein expression of Slug and the protein and RNA expression of the mesenchymal-related proteins N-cadherin and vimentin. Furthermore, 13c markedly suppressed TGF-ß-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion in U87MG cells. These results suggest that 13c is a novel inhibitor of ALK5 with potential utility in the treatment of human glioma.

Synthesis and Antimicrobial Activity Evaluation of Imidazole-Fused Imidazo[2,1-b][1,3,4]thiadiazole Analogues.

Three series of new imidazole-fused imidazo[2,1-b][1,3,4]thiadiazole analogues (compounds 20 a-g, 21 a-g, and 22 a-g) have been synthesized, and their antibacterial and antifungal activities have been evaluated. All the target compounds showed strong antifungal activity and high selectivity for the test fungus Candida albicans over Gram-positive and -negative bacteria. N-((4-(2-Cyclopropyl-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl)methyl)aniline (21 a) showed the highest activity against C. albicans (MIC50 =0.16 µg/mL), 13 and three times that of the positive control compounds gatifloxacin and fluconazole, respectively. Compounds 21 a and 20 e did not show cytotoxicity against human foreskin fibroblast-1 cells, and compound 21 a was as safe as the positive control compounds in hemolysis tests. These results strongly suggest that some of the compounds produced in this work have value for development as antifungal agents.

Design, synthesis and evaluation of carbazole derivatives as potential antimicrobial agents.

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5-2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure-activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.

5-Aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety as potential PTP1B inhibitors.

Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best PTP1B inhibitory potency (IC50 = 2.66 ± 0.16 µM) and the best cell division cycle 25 homolog B (CDC25B) inhibitory potency (IC50 = 0.25 ± 0.02 µM). Enzymatic data together with molecular modeling results demonstrated that the introduction of a sec-butyl group at the 2-position of the carboxyl group remarkably improved the PTP1B inhibitory activity.

Synthesis and evaluation of HIF-1α inhibitory activities of novel panaxadiol derivatives.

Hypoxia-inducible factor 1α (HIF-1α) is a known regulator of tumor cell proliferation, migration, and angiogenesis. The presence of a high concentration of HIF-1α is positively correlated with the severity of cancer. Therefore, the inhibition of this pathway represents an important therapeutic target for the treatment of various types of cancer. Here, we designed and synthesized 30 panaxadiol (PD) derivatives and evaluated their inhibitory activities against HIF-1α transcription. Of these, compound 3l exhibited the most promising inhibitory activity (IC50 = 3.7 µM) and showed significantly decreased cytotoxicity compared with PD. Compound 9e exhibited the strongest cytotoxic effect and may be considered for further preclinical development.

Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways.

BACKGROUND AND PURPOSE: Arctigenin, a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies. EXPERIMENTAL APPROACH: The effects of chronic unpredictable mild stress (CUMS) on wild-type (WT) and TLR4-/- mice were examined. Antidepressant-like effects of arctigenin were tested using the CUMS-induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-α-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-α and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co-immunoprecipitation assays. KEY RESULTS: The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4-/- mice, compared with WT mice. Arctigenin exhibited antidepressant-like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF-α and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. CONCLUSIONS AND IMPLICATIONS: Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression.

Synthesis and evaluation of the HIF-1α inhibitory activity of 3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles as inhibitors of ALK5.

The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in apoptosis, metastasis, and proliferation and is recognized as an important potential therapeutic target for cancer. Six series of 3(5)-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)pyrazoles (11a-d, 12a-d, and 18a-d) and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridin-4-yl)pyrazoles (19a-d, 20a-d, and 21a-d) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) and HIF-1α inhibitory activity at the enzyme and cell levels. The effect of the lead compound 20d (J-1012) on HIF-1α activation in HCT116 cells was investigated. J-1012 markedly decreased the hypoxia-induced or TNF-induced accumulation of HIF-1α protein dose-dependently. Analysis revealed that J-1012 inhibited HIF-1α protein synthesis, without affecting the degradation of HIF-1α protein. Furthermore, by inhibiting the activation of HIF-1α, J-1012 suppressed the metastasis and proliferation and promoted apoptosis of HCT116 cells. These results suggest that J-1012 may be a potential therapeutic agent against human colon cancer.

Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl- pyridin-2-yl)pyrazole and 3(5)-(6-methylpyridin- 2-yl)-4-(thieno-[3,2,-c]pyridin-2-yl)pyrazole derivatives.

Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a-d, 19a-d, 22a-d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a-d, 21a-d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC50 value of 0.030 µM in the enzymatic assay. Compound 22c showed four-fold more potent activity against ALK5 kinase than the clinical candidate, compound LY-2157299. The selectivity index of 22c against p38α MAP kinase is 235, which is much higher than that of LY-2157299 (4) and equally selective to that of EW-7197 (218). Compound 22c effectively suppressed protein and mRNA expression of collagen I and α-SMA in TGF-ß-induced LX-2 human hepatic stellate cell (HSC), this result shows that compound 22c has the ability to inhibit the activation of HSC. Compound 22c is expected to be a preclinical candidate for the treatment of hepatic fibrosis.

Acylation of 25-hydroxyprotopanaxatriol with aromatic acids increases cytotoxicity.

20(R)-25-hydroxyprotopanaxadiol (25-OH-PPD) is a natural compound showing a variety of anti-tumor effects. In an attempt to search for a new anti-cancer compound with higher antitumor activities, we designed and synthesized a series of 25-OH-PPD derivatives. Cytotoxicity assay of these derivatives towards MCF-7, A549, U87, HO-8901, Hela cancer cell lines and normal IOSE144 cell lines were tested by MTT assay. Results showed that compared with compound 25-OH-PPD, Compounds 4, 5, 6, 10, 11 showed strong anticancer activity, and all compounds showed low toxicity or no toxicity for normal cells. In particular, compound 6 exhibited the best anti-tumor activity in all cancer cell lines (MCF-7, A549, U87, HO-8901, and Hela) with IC50 values of 5.04 µM, 1.36 µM, 3.24 µM, 3.47 µM, 4.57 µM, respectively. Among the five cell lines, all the compounds showed strong inhibition on A549 cells. Further studies showed that Compound 6 significantly inhibited the proliferation of A549 cells by inducing apoptosis. Our results indicate that Compound 6 is a potential anticancer inhibitor and provides a theoretical basis for further research.

Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors.

Transforming growth factor (TGF-ß), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a-g) and thieno[3,2-c]-pyridin-2-yl imidazoles (20a-g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC50 = 0.008 µM) against ALK5 kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157299 (IC50 = 0.129 µM) and EW-7197 (IC50 = 0.014 µM), respectively. Compound 14g (350) showed the highest selectivity index of ALK5 against p38α MAP kinase, which was significantly higher than that of positive control compounds LY-2157299 (4) and EW-7197 (211). The inhibitory effects of compound 14c on TGF-ß-induced Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors.

Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents.

Several series of novel tryptophan-derived rhodanine derivatives were synthesized and identified as potential competitive PTP1B inhibitors and antibacterial agents. Among the compounds studied, 10b was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.36 ±â€¯0.02 µM). In addition, the compounds also showed potent inhibition against other PTPs, especially CDC25B. Molecular docking analysis demonstrated that compounds 7c and 10b could occupy both the catalytic site and the adjacent pTyr binding site simultaneously. The compounds also showed higher levels of activity against gram-positive strains, the gram-negative strain Escherichia coli 1924, and multidrug-resistant gram-positive bacterial strains. Compounds 7c, 8c, 9e, 10a, and 10c had comparable or more potent antibacterial activity than the positive controls.