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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 ± 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.

Three novel series of dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1–64 µg/mL. Compounds 4b and 4c presented the most potent inhibitory activity against Gram-positive bacteria (S. aureus 4220, MRSA 3167, QRSA 3519) and Gram-negative bacteria (E. coli 1924), with minimum inhibitory concentration values of 1 or 2 µg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. The cytotoxic activity of the compounds 4a, 4b, 4c and 11n were assessed in L02 cells. In vitro enzyme study implied that compound 4c exerted its antibacterial activity through DHFR inhibition.

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains, with minimum inhibitory concentrations (MICs) in the range of 2.1–181.2 μmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Gram-positive bacteria ( e.g. , Staphylococcus aureus 4220), Gram-negative bacteria ( e.g. , Escherichia coli 1924), and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 μmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 μmol/L against four multidrug-resistant, Gram-positive bacterial strains. The cytotoxic activity of the compound 7a , 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.67 ± 0.09 µM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

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.

Three series of 1,3-diaryl pyrazole derivatives bearing aminoguanidine or furan-2-carbohydrazide moieties have been synthesized, characterized and evaluated for antibacterial and anti-inflammatory activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1-64 μg/mL. Compounds 6g, 6l and 7l presented the most potent inhibitory activity against Gram-positive bacteria (e.g. Staphylococcus aureus 4220), Gram-negative bacteria (e.g. Escherichia coli 1924) and the fungus, Candida albicans 7535, with minimum inhibitory concentration values of 1 or 2 μg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. Furthermore, compound 7l showed the greatest anti-inflammatory activity (93.59% inhibition, 30 min after intraperitoneal administration), which was more potent than the reference drugs ibuprofen and indomethacin.

Five series of dihydrotriazine derivatives containing chalcone (13a–i), phenoxy acetophenone (14a–b), benzyl benzene (15a–c), naphthoxyl acetophenone (16a–b) and benzyl naphthalene (17a–h) moieties were designed and synthesized. The antibacterial and antifungal activities of these compounds were evaluated against several strains of Gram-positive and Gram-negative bacteria, as well as a single fungus. Compound 17h was found to be the most potent of all of the compounds tested, with an MIC value of 0.5 μg/mL against several Gram-positive (Staphylococcus aureus 4220 and QRSA CCARM 3505) and Gram-negative (Escherichia coli 1924) strains of bacteria. However, this compound was inactive against Pseudomonas aeruginosa 2742 and Salmonella typhimurium 2421, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. The cytotoxic activity of the compound 13i, 16b and 17h was assessed in Human normal liver cells.

Three series of rhodanine derivatives bearing a quinoline moiety (6a-h, 7a-g, and 8a-e) have been synthesized, characterized, and evaluated as antibacterial agents. The majority of these compounds showed potent antibacterial activities against several different strains of Gram-positive bacteria, including multidrug-resistant clinical isolates. Of the compounds tested, 6g and 8c were identified as the most effective with minimum inhibitory concentration (MIC) values of 1 μg/mL against multidrug-resistant Gram-positive organisms, including methicillin-resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA, respectively). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. The cytotoxic activity assay showed that compounds 6g, 7g and 8e exhibited in vitro antibacterial activity at non-cytotoxic concentrations. Thus, these studies suggest that rhodanine derivatives bearing a quinoline moiety are interesting scaffolds for the development of novel Gram-positive antibacterial agents.

Two series of furan derivatives bearing a rhodanine moiety (4a–l and 5a–l) have been synthesized, characterized, and evaluated for their antibacterial activity. The majority of these compounds showed potent levels of inhibitory activity against a variety of different Gram-positive bacteria, including multidrug-resistant clinical isolates, with minimum inhibitory concentration (MIC) values in the range of 2–16 μg/mL. In particular, compound 4l was found to be the most potent of the synthesized compounds against the multidrug-resistant strains, with a MIC value of 2 or 4 μg/mL. None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. An examination of the cytotoxicities of these agents revealed that they displayed low levels of toxicity toward HeLa cells. All of the compounds synthesized in the current paper were characterized by 1H and 13C NMR, infrared, and mass spectroscopy. Two novel series of furan derivatives bearing a rhodanine moiety were synthesized, and evaluated for their antibacterial activity. Compounds 4l and 5a presented high potency against several multidrug-resistant clinical isolates.

A series of rhodanine-3-acetic acid derivatives were synthesized and investigated for their antibacterial activity against gram-positive bacteria including multidrug-resistant clinical isolates. Among these compounds, 6k with a MIC of 2 μg/mL was as active as the standard drug (norfloxacin) but less active than oxacillin against S. aureus. The compounds 6b, 6e, 6h, 6k, 6n, and 6u presented better activities against multidrug-resistant Staphylococcus aureus than the standard drugs (norfloxacin and oxacillin), especially 6k with a MIC of 1 μg/mL. However, none of the compounds were active against gram-negative bacteria at 64 μg/mL. This study presents a synthesis of novel rhodanine-3-acetic acid derivatives and their antibacterial activity.

Three novel series of chalcone derivatives containing an aminoguanidine or acylhydrazone moiety were designed, synthesized and evaluated in terms of their antibacterial, antifungal and anti-inflammatory activities. Most of the synthesized compounds showed potent inhibitory activity towards various bacteria and one fungus with minimum inhibitory concentrations (MICs) ranging from 1 to 8 μg/mL. Compared with our previously reported chalcone derivatives (MICs >64 μg/mL), these compounds exhibited improved antibacterial activities (MICs = 2 μg/mL) against Gram-negative bacterial strains (Escherichia coli 1924 and 1356). Compounds 4f and 4h were found to be the most potent with an MIC value of 1 μg/mL against the Gram-negative bacterial strains Salmonella typhimurium 1926 and the fungus Candida albicans 7535. In addition, compound 4f displayed the most potent anti-inflammatory activity of all of the compounds prepared in the current study with 92.45% inhibition after intraperitoneal administration, making it more potent than the reference drugs indomethacin and ibuprofen. The cytotoxic activity of the compound 4f was assessed in HeLa, Hep3B and L02 cells.

We describe the synthesis and positive inotropic evaluation of a series of 2-(4-substitutedbenzylpiperazin-1-yl)-N-(2-oxo-2,3-dihydrobenzooxazol-6-yl)acetamides by measuring left atrial stroke volume in preparations of isolated rabbit hearts. Several compounds were developed from and showed favorable activities compared with the standard drug milrinone. Compound 4l was the most potent with an increased stroke volume of 11.78 ± 0.18% (milrinone 6.36 ± 0.13%) at 1 × 10(-4) M in our in-vitro study. The chronotropic effects of compounds having inotropic effects were also evaluated.

A series of 2,4,6-trihydroxychalcone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC50 values in the micromolar range. Compound 4a had the greatest in vitro inhibition activity against PTP1B (IC50 = 0.27 ± 0.01 μm) and the best selectivity (6.9-fold) for PTP1B relative to T-cell protein tyrosine phosphatases. The compounds identified herein provide a foundation on which to design specific inhibitors of PTP1B and other PTPs.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor in negative regulation of the insulin pathway, and is a promising target for the treatment of type-II diabetes, obesity and cancer. Herein, compound () was first observed to have moderate inhibitory activity against PTP1B with an value of . To obtain more potent PTP1B inhibitors, we synthesized a series of chalcone derivatives using compound () as the lead compound. Compound () was 4.4-fold more potent than the lead compound (), and more potent than the positive control, ursolic acid (). These results may help to provide suitable drug-like lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

A series of novel nonphosphonate-based pTyr mimetics comprised (±)-3-(2-(2-fluorobenzyloxy)naphthalen-6-yl)-2-aminopropanoic acid derivatives were identified as reversible and competitive PTP1B inhibitors via a structure-based design approach. Among the compounds studied, 12h was found to have the best in vitro inhibition activity against PTP1B (IC(50) = 1.25 ± 0.24 μM) and the best selectivity (3-fold) between PTP1B and TCPTP. These results should provide suitable druglike lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

A series of chalcone derivatives bearing the 2,4-thiazolidinedione and benzoic acid moieties ( 8a – s ) were synthesized, characterized, and evaluated for their anti-bacterial activity. Among the tested compounds, the most effective were 8a , 8h , 8k , 8n and 8q with MIC value in the range of 0.5–4 μg/mL against six Gram-positive bacteria (including multidrug-resistant clinical isolates). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 and E. coli 1682 at 64 μg/mL.

With an intention to synergize the anti-bacterial activity of chalcones and rhodanine-3-acetic acid, several hybrid compounds possessing chalcone and rhodanine-3-acetic acid moieties were synthesized and tested for their anti-bacterial activity. Some compounds presented great anti-microbial activities against Gram-positive bacteria (including the multidrug-resistant clinical isolates). This class of compounds presented high potency against Staphylococcus aureus, among which the derivatives 5k with a MIC of 2 μg/mL was as active as the standard drug (norfloxacin) and less active than oxacillin. Compounds 5a-s did not inhibit the growth of Gram-negative bacteria Escherichia coli CCARM 1924 or E. coli CCARM 1356 at 64 μg/mL.

In an effort to develop potent antiinflammatory agents, a series of substituted chalcone derivatives was synthesized and evaluated for antiinflammatory activity through monitoring of their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and compounds 3f [(E)-1-(2,4-dihydroxyphenyl)-3-(4-dimethylamino)phenyl)prop-2-en-1-one] and 3h [(E)-3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one] showed the highest antiinflammatory activity (62 and 68% inhibition, respectively, 2 h before administration), comparable with or even slightly more potent than the reference drug ibuprofen (53%). Furthermore, the structure–activity relationship of these substituted chalcone derivatives was demonstrated.

A series of new triazole acetamides (III) is synthesized and screened for their positive inotropic activity.

A series of new triazole acetamides 5a–w were synthesized and evaluated for their positive inotropic activity of left atrium stroke volume on isolated rabbit-heart preparations. The majority of the derivatives presented favorable in vitro activity compared with the reference drug, milrinone. Among them triazole acetamide 5a was identified as the most potent with 20.29 ± 0.18% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10 –5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.

A series of 5,7-dihydroxyflavanone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC50 values in the micromolar range. Compound 4k had the most potent in vitro inhibition activity against PTP1B (IC50 = 2.37 ± 0.37 μM) and the greatest selectivity (3.7-fold) for PTP1B relative to T-cell protein tyrosine phosphatase. Cell-based studies revealed that 4k was membrane-permeable and enhanced insulin receptor tyrosine phosphorylation in CHO/hIR cells.

Two series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted benzylpiperazine moieties have been synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. The majority of the derivatives exhibited better in vitro activity than the existing drug, milrinone, and 6-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)tetrazolo[5,1-a]phthalazine. 8 m in particular was identified as the most potent with an increased stroke volume of 12.02 ± 0.20% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5) m. The chronotropic effects of the compounds that exhibited good potency were also evaluated.

With an intention to synergize the anti-bacterial activity of 5-aryloxy pyrazole and rhodanine derivatives, eight series of hybrid compounds have been synthesized and evaluated for their antibacterial activity. The majority of the synthesized compounds showed good inhibitory activity against selected methicillin resistant and quinolone-resistant Staphylococcus aureus (MRSA, QRSA) with minimum inhibitory concentration (MIC) values in the range of 1-32 μg/mL. The cytotoxicity test suggests that these compounds exhibited in vitro antibacterial activity at non-cytotoxic concentrations. These studies therefore suggest that rhodanine-based 5-aryloxy pyrazoles are interesting scaffolds for the development of novel Gram-positive antibacterial agents.

Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds III b, III g and III m showed the most potent levels of activity (MIC = 1 μg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents.

A series of 2,4,6-trihydroxychalcone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC₅₀ values in the micromolar range. Compound 4a had the greatest in vitro inhibition activity against PTP1B (IC₅₀= 0.27 ± 0.01 μM) and the best selectivity (6.9-fold) for PTP1B relative to T-cell protein tyrosine phosphatases. The compounds identified herein provide a foundation on which to design specific inhibitors of PTP1B and other PTPs.

Four novel series of compounds, including the l -phenylalanine-derived C5-substituted rhodanine (6a–q, 7a–j) and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone (9a–e, 11a–e) have been designed, synthesized, characterized, and evaluated for their antibacterial activity. Some of these compounds showed significant antibacterial activity against Gram-positive bacterias, especially against the strains of multidrug-resistant clinical isolates, among which compounds 6c–e, 6g, 6i, 6j and 6q exhibiting high levels of antimicrobial activity against Staphylococcus aureus RN4220 with minimum inhibitory concentration (MIC) values of 2 μg/mL. Compound 6q showed the most potent activity of all of the compounds against all of the test multidrug-resistant clinical isolates tested. Unfortunately, however, none of the compounds were active against Gram-negative bacteria at 64 μg/mL.

In the present study, a series of novel 1,3-diphenyl-1 H -pyrazoles functionalized with phenylalanine-derived rhodanine derivatives were synthesized and evaluated for their antibacterial activity. Compounds 4 , 6 , 9 , 10 , 12 and 15 exhibited stronger activity than the standard drugs, norfloxacin and oxacillin, with MIC values of 1 μg/mL against methicillin-resistant Staphylococcus aureus and quinolone-resistant S. aureus . None of the compounds showed any activity against Gram-negative bacteria.

In the present study, a series of 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid moieties were synthesized and their antimicrobial activities were tested against various Gram-positive and Gram-negative bacteria. 1,3-diaryl-4-formylpyrazoles were synthesized as key intermediates following a Vilsmeier–Haack strategy. Several compounds with an MIC of 2 μg/mL, exhibited stronger antibacterial activity against the methicillin-resistant Staphylococcus aureus (MRSA) than the controls. None of the compounds showed any activity against Gram-negative bacteria.

Herein we describe the discovery of compound 3g, a potent positive inotropic agent compared with the standard drug, milrinone. Compound 3g was developed from a series of 2-(4-substitutedbenzyl-1,4-diazepan-1-yl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl) acetamides found in an evaluation of inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. Several compounds showed favorable activities, but 3g was the most potent, with 7.68+/-0.14% increased stroke volume (milrinone 2.38+/-0.05%) at 1 x 10(-5)M in our in vitro study. The chronotropic effects of compounds having significant inotropic effects were also evaluated.

In an attempt to search for more potent positive inotropic agents, a series of 2-(4-substitutedmethylpiperazin-1-yl)- N -(3,4-dihydro-3-oxo-2 H -benzo[ b ][1,4]oxazin-7-yl)acetamides were synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit heart preparations. Several compounds showed favorable activities compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)piperazin-1-yl)- N -(3,4-dihydro-3-oxo-2 H -benzo[ b ][1,4]oxazin-7-yl)acetamide 4e showed the most potent activity with the 5.09 ± 0.00% increased stroke volume (milrinone 1.67 ± 0.64%) at a concentration of 1 × 10 −5 M in our in vitro study. The chronotropic effects of those compounds having significant inotropic effects were also evaluated in this work.

In an effort to develop potent antiplatelet agents, a series of trihydroxychalcones was synthesized and screened in vitro for their inhibitory effects on washed rabbit platelet aggregation induced by arachidonic acid (100 μM) and collagen (10 μg/ml). Of five compounds with potent inhibitory effects on arachidonic acid- and collagen-induced platelet aggregation, compound 4e was found to be the most potent. The structure–activity relationships suggested that antiplatelet activity was governed to a greater extent by the substituent on B ring of the chalcone template, and most of the active compounds had methoxy or dimethoxy groups on B ring.

Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, China. *E-mail: piaohuri@yahoo.com.cn Yanbian University Hospital, Yanji, 133002, China National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai 201203, China. *E-mail: jli@mail.shcnc.ac.cn Received October 4, 2012, Accepted January 7, 2013