Nomogram to predict severe retinopathy of prematurity in Southeast China.

AIM: To define the predictive factors of severe retinopathy of prematurity (ROP) and develop a nomogram for predicting severe ROP in southeast China. METHODS: Totally 554 infants diagnosed with ROP hospitalized in the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University and hospitalized in Taizhou Women and Children's Hospital were included. Clinical data and 43 candidate predictive factors of ROP infants were collected retrospectively. Logistic regression model was used to identify predictive factors of severe ROP and to propose a nomogram for individual risk prediction, which was compared with WINROP model and Digirop-Birth model. RESULTS: Infants from the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (n=478) were randomly allocated into training (n=402) and internal validation group (n=76). Infants from Taizhou Women and Children's Hospital were set as external validation group (n=76). Severe ROP were found in 52 of 402 infants, 12 of 76 infants, and 7 of 76 infants in training group, internal validation group, and external validation group, respectively. Birth weight [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.996-0.999; P<0.001], multiple births (OR, 1.885; 95%CI, 1.013-3.506; P=0.045), and non-invasive ventilation (OR, 0.288; 95%CI, 0.146-0.570; P<0.001) were identified as predictive factors for the prediction of severe ROP, by univariate analysis and multivariate analysis. For predicting severe ROP based on the internal validation group, the areas under receiver operating characteristic curve (AUC) was 78.1 (95%CI, 64.2-92.0) for the nomogram, 32.9 (95%CI, 15.3-50.5) for WINROP model, 70.2 (95%CI, 55.8-84.6) for Digirop-Birth model. In external validation group, AUC of the nomogram was also higher than that of WINROP model and Digirop-Birth model (80.2 versus 51.1 and 63.4). The decision curve analysis of the nomogram demonstrated better clinical efficacy than that of WINROP model and Digirop-Birth model. The calibration curves demonstrated a good consistency between the actual severe ROP incidence and the predicted probability. CONCLUSION: Birth weight, multiple births, and non-invasive ventilation are independent predictors of severe ROP. The nomogram has a good ability to predict severe ROP and performed well on internal validation and external validation in southeast China.

Synthesis and Herbicidal Activity of α-(Substituted Phenoxybutyryloxy or Valeryloxy)alkylphosphonates and 2-(Substituted Phenoxybutyryloxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one.

On the basis of our work on the modification of alkylphosphonates 1, a series of α-(substituted phenoxybutyryloxy or valeryloxy)alkylphosphonates (4-5) and 2-(substituted phenoxybutyryloxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one (6) were designed and synthesized. The bioassay results indicated that 14 of title compounds 4 exhibited significant postemergence herbicidal activity against velvetleaf, common amaranth, and false daisy at 150 g ai/ha. Compounds 5 were inactive against all tested weeds. Compounds 6 exhibited moderate to good inhibitory effect against the tested dicotyledonous weeds. Structure-activity relationship (SAR) analyses showed that the length of the carbon chain as linking bridge had a great effect on the herbicidal activity. Broad-spectrum tests of compounds 4-1, 4-2, 4-9, 4-30, and 4-36 were carried out at 75 g ai/ha. Especially, 4-1 exhibited 100% inhibition activity against the tested dicotyledonous weeds, which was higher than that of glyphosate.

Synthesis and antifungal activity of 5-iodo-1,4-disubstituted-1,2,3-triazole derivatives as pyruvate dehydrogenase complex E1 inhibitors.

To identify new antifungal lead compound based on inhibitors of pyruvate dehydrogenase complex E1, a series of 5-iodo-1,4-disubstituted-1,2,3-triazole derivatives 3 were prepared and evaluated for their Escherichia coli PDHc-E1 inhibitory activity and antifungal activity. The in vitro bioassay for the PDHc-E1 inhibition indicated all the compounds exhibited significant inhibition against E. coli PDHc-E1 (IC50<21µM), special compound 3g showed the most potent inhibitory activity (IC50=4.21±0.11µM) and was demonstrated to act as a competitive inhibitor of PDHc-E1. Meanwhile, inhibitor 3g exhibited very good enzyme-selective inhibition of PDHc-E1 between pig heart and E. coli. The assay of antifungal activity showed compounds 3e, 3g, and 3n exhibited fair to good activity against Rhizoctonia solani and Botrytis cinerea even at 12.5µg/mL. Especially compound 3n (EC50=5.4µg/mL; EC90=21.1µg/mL) exhibited almost 5.50 times inhibitory potency against B. cinerea than that of pyrimethanil (EC50=29.6µg/mL; EC90=113.4µg/mL). Therefore, in this study, compound 3n was found to be a novel lead compound for further optimization to find more potent antifungal compounds as microbial PDHc-E1 inhibitors.

Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors.

By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.

Design, synthesis and molecular modeling of novel N-acylhydrazone derivatives as pyruvate dehydrogenase complex E1 inhibitors.

As potential inhibitors of pyruvate dehydrogenase complex E1 (PDHc-E1), a series of 19 1-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-methyl-N'-(substituent)benzylidene-1H-1,2,3-triazole-4-carbohydrazide 4 has been synthesized and tested for their PDHc-E1 inhibitory activity in vitro. Some of these compounds such as 4a, 4g, 4l, 4o, 4p, and 4q were demonstrated to be effective inhibitors by the bioassay of Escherichia coli PDHc-E1. SAR analysis indicated that the PDHc-E1 inhibitory activity could be further enhanced by optimizing the substituted groups in the parent compound. Molecular modeling study with compound 4o as a model was performed to evaluate docking. The results of modeling study suggested a probable inhibition mechanism.

α-(Substituted-phenoxyacetoxy)-α-heterocyclylmethylphosphonates: synthesis, herbicidal activity, inhibition on pyruvate dehydrogenase complex (PDHc), and application as postemergent herbicide against broadleaf weeds.

Pyruvate dehydrogenase complex (PDHc) is the site of action of a new class of herbicides. On the basis of the previous work for O,O'-dimethyl α-(substituted-phenoxyacetoxy)alkylphosphonates (I), further synthetic modifications were made by introducing a fural and a thienyl group to structure I. A series of α-(substituted-phenoxyacetoxy)-α-heterocyclylmethylphosphonate derivatives (II) were synthesized as potential inhibitors of PDHc. The postemergent activity of the title compounds II was evaluated in greenhouse experiments. The in vitro efficacy of II against PDHc was also examined. Compounds II with fural as R(3) and 2,4-dichloro as X and Y showed significant herbicidal activity and effective inhibition against PDHc from plants. O,O'-Dimethyl α-(2,4-dichlorophenoxyacetoxy)-α-(furan-2-yl)methylphosphonate II-17 had higher inhibitory potency against PDHc from Pisum sativum than against PDHc from Oryza sativa in vitro and was most effective against broadleaf weeds at 50 and 300 ai g/ha. II-17 was safe for maize and rice even at the dose of 900-1200 ai g/ha. Field trials at different regions in China showed that II-17 (HWS) could control a broad spectrum of broad-leaved and sedge weeds at the rate of 225-375 ai g/ha for postemergent applications in maize fields. II-17 (HWS) displayed potential utility as a selective herbicide.

Synthesis and herbicidal activity of 2-(substituted phenoxyacetoxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one.

A series of 2-(substituted phenoxyacetoxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-ones IIa-s were designed and synthesized on the basis of the previous work for the modification of alkylphosphonates I, and their structures were confirmed by (1)H NMR, (31)P NMR, (13)C NMR, IR, MS, and elemental analysis. Their herbicidal activities against seven species of weeds were evaluated in a greenhouse. A part of the title compounds such as IIa-g, IIk, IIo, and IIr exhibited significant postemergence herbicidal activity against Abutilon theophrasti, Brassica juncea, Amaranthus retroflexus, and Eclipta prostrate at a dosage of 150 g ai/ha. Structure-activity relationship analyses indicated that the introduction of a phosphorus-containing heterocyclic ring had a favorable effect on herbicidal activity, and their herbicidal activity could be further increased by a reasonable combination of X, Y, and R in parent structure II. It could be found that the title compounds IIa 2-[(2,4-dichlorophenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one and IIr 2-[(4-chloro-2-methyl-phenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one possess high activity and a broad spectrum against all of the test broadleaf weeds with 70-100% inhibition effect at a dosage of 75 g ai/ha, and the title compounds IIa and IIr are safe for corn and wheat at a dosage of 150 g ai/ha. Furthermore, the title compound IIa possesses low rat toxicity. These results suggest that the title compounds IIa and IIr could be potential and selective postemergence herbicides for further development.

Ethyl 4-[({[(6-chloro-pyridin-3-yl)meth-yl](meth-yl)amino}(4-fluoro-anilino)-methyl-idene)amino]-3-phenyl-2-sulfanyl-idene-2,3-dihydro-1,3-thia-zole-5-carboxyl-ate.

In the title compound, C(26)H(23)ClFN(5)O(2)S(2), the mean plane of the guanidine fragment makes dihedral angles of 58.94 (13), 78.37 (17) and 50.76 (15)°, respectively, with the attached thia-zole, pyridine and phenyl rings. The crystal structure features N-H⋯S and C-H⋯O hydrogen bonds and weak π-π stacking inter-actions [centroid-centroid separation = 3.7702 (17) Å]. The terminal methyl group of the eth-oxy-carbonyl group is disordered over two orientations in a 0.836 (10):0.164 (10) ratio.

Synthesis and in vitro antiproliferative evaluation of pyrimido[5,4-c]quinoline-4-(3H)-one derivatives.

A series of pyrimido[5,4-c]quinoline-4-(3H)-one derivatives variously substituted at positions 2 and 3 were synthesized and evaluated for their in vitro antiproliferative activities against a panel of six human cancer cell lines. Biological evaluation revealed that the vast majority of derivatives exhibited moderate tumor growth inhibitory activities. In particular, compound 7e showed effective anti-tumor activity with broad-spectrum toward numerous cell lines and the most active member in this study. This derivative displaying significant activity against KB (IC(50): 4.9 µM), CNE2 (IC(50): 13.8 µM), MGC-803 (IC(50): 4.8 µM), GLC-82 (IC(50): 7.88 µM), MDA-MB-453 (IC(50): 18.2 µM) and MCF-7 (IC(50): 10.1 µM) cell lines could be considered as the most promising and useful template for future development to obtain more potent anti-tumor agent(s).

Synthesis and cytotoxicity of 8-cyano-3-substitutedalkyl-5-methyl-4-methylene-7-methoxy-3,4-dihydropyrido[4,3-d]pyrimidines.

Synthesis and cytotoxicity of 11 4-methylene pyrido[4,3-d]pyrimidines 5a-k were described. Cytotoxicity assay results showed that some compounds had much stronger antitumor activity than Fluorouracil against KB cell lines. The most active compound 5i exhibited high potency against KB, CNE2, MGC-803 cell lines with IC(50) values of 0.48, 0.15, 0.59 µM, respectively. The preliminary structure-activity relationships indicated that the introduction of benzyl groups bearing electron-donating function groups is favorable for the activity.

Studies of O,O-dimethyl α-(2,4-dichlorophenoxyacetoxy)ethylphosphonate (HW02) as a new herbicide. 1. Synthesis and herbicidal activity of HW02 and analogues as novel inhibitors of pyruvate dehydrogenase complex.

On the basis of the previous work for optimization of O,O-diethyl α-(substituted phenoxyacetoxy)alkylphosphonates, further extensive synthetic modifications were made to the substituents in alkylphosphonate and phenoxy moieties of the title compounds. New O,O-dimethyl α-(substituted phenoxyacetoxy)alkylphosphonates were synthesized as potential inhibitors of pyruvate dehydorogenase complex (PDHc). Their herbicidal activity and efficacy in vitro against PDHc were examined. Some of these compounds exhibited significant herbicidal activity and were demonstrated to be effective inhibitors of PDHc from three different plants. The structure-activity relationships of these compounds including previously reported analogous compounds were studied by examining their herbicidal activities. Both inhibitory potency against PDHc and herbicidal activity of title compounds could be increased greatly by optimizing substituent groups of the title compounds. O,O-Dimethyl α-(2,4-dichlorophenoxyacetoxy)ethylphosphonate (I-5), which acted as a competitive inhibitor of PDHc with much higher inhibitory potency against PDHc from Pisum sativum and Phaseolus radiatus than from Oryza sativa , was found to be the most effective compound against broadleaf weeds and showed potential utility as herbicide.

Prenylated xanthones from the bark of Garcinia xanthochymus and their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities.

Garcinia xanthochymus has been widely used in traditional Chinese medicine for expelling worms and removing food toxins. Bioassay-guided fractionation of an EtOAc-soluble extract of G. xanthochymus stem bark led to the isolation of six new xanthones. Their structures were elucidated by spectroscopic methods, especially 2D-NMR techniques. Free-radical-scavenging activities of the isolated compounds were elucidated through DPPH method. Most of the isolated compounds showed considerable free radical scavenging activity on DPPH assay. Compound 1 exhibited effective antioxidant scavenging activity against DPPH radical with an IC50 value of 19.64 µM, and compound 6 showed the lowest activity among all the tested molecules, with an IC50 value of 66.88 µM. These findings support the notion that the plant genus Garcinia is a good source of bioactive compounds.

Efficient synthesis and biological evaluation of 1,2,9-trisubstituted 1,9-dihydro-6H-purin-6-ones.

The carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aromatic isocyanates, reacted with amines in the presence of a catalytic amount of RO(-)Na(+) to give the 1,2,9-trisubstituted 1,9-dihydro-6H-purin-6-ones 6 in good yields. Compound 6 exhibited cytotoxicity against various cancer cells. For example, compounds 6b showed the best inhibition activities against KB, HepG2 and OVCAR3 with IC(50) 9.5, 20.4 and 10.0 microM.

6-(4-Fluoro-pheneth-yl)-7-imino-3-phenyl-2,3,6,7-tetra-hydro-1,3-thia-zolo[4,5-d]pyrimidine-2-thione.

In the title compound, C(19)H(15)FN(4)S(2), the mean plane of the thia-zolopyrimidine makes a dihedral angle of 77.6 (1)° with the attached phenyl ring. The crystal packing is stabilized by inter-molecular C-H⋯N hydrogen bonds and weak C-H-π stacking inter-actions.

[2-(Phenyl-diazen-yl)pyrrolato]bis(2-pyridylphen-yl)iridium(III).

In the title compound, [Ir(C(10)H(8)N(3))(C(11)H(8)N)(2)], the Ir center is octa-hedrally coordinated by the three chelating ligands, with two cyclo-metalated 2-pyridylphenyl ligands [Ir-N = 2.049 (5) and 2.030 (5) Å; Ir-C = 2.016 (6) and 2.012 (6) Å] and a bidentate 2-(phenyl-diazen-yl)pyrrolate ligand [Ir-N = 2.204 (5) and 2.079 (5) Å]. The Ir-N(diazen-yl) bond is longer than the Ir-N(pyrrolate) bond. The structure is stabilized by aromatic π-π stacking, the shortest parallel distance between ring centroids being 3.426 (8) Å..

2-[3-(Trifluoro-meth-yl)phen-oxy]ethyl 1-oxo-2,6,7-trioxa-1λ-phosphabicyclo-[2.2.2]octane-4-carboxyl-ate.

In the crystal structure of the title compound, C(14)H(14)F(3)O(7)P, the central chain, which connects the phosphate bicyclic system and the benzene ring, is made up of an approximately planar C-C(O)-O-C(H(2)) fragment and a C(H(2))-O-C(Ph) link; the mean planes make a dihedral angle of 75.9 (2)°. The F atoms are disordered over two positions; the site occupancy factors are ca 0.6 and 0.4.

Molecular docking and three-dimensional quantitative structure-activity relationship studies on the binding modes of herbicidal 1-(substituted phenoxyacetoxy)alkylphosphonates to the E1 component of pyruvate dehydrogenase.

Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies on the title compounds were performed to explore the possible inhibitory mechanism. To determine the probable binding conformations of the title phosphonate derivatives, the most potent compound 12 was chosen as a standard template and docked into the active site of PDHc E1. On the basis of the binding conformations, highly predictive 3D-QSAR models were developed with q2 values of 0.872 and 0.873 for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), respectively. The predictive abilities of these models were validated by using a set of compounds that were not included in the training set. Both the CoMFA and the CoMSIA field distributions are in good agreement with the spatial and electronic structural characteristics of the binding groove of PDHc E1 selected in this work. Mapping the 3D-QSAR models to the active site of PDHc E1 provides new insight into the protein-inhibitor interaction mechanism, which is most likely valuable and applicable for designing highly active compounds in the future.

(E)-Ethyl 4-[4-(diethyl-amino)styr-yl]benzoate.

In the title mol-ecule, C(21)H(25)NO(2), the dihedral angle between the two benzene rings is 4.8 (2)°. Both the ethyl group of the ester group and one of the ethyl groups attached to the N atom are disordered over two sites, the approximate occupancies being 66:34 and 81:19, respectively. In the cystal structure, there are no direction-specific inter-actions.

(E)-Methyl 3-{3-[(4-bromo-phen-oxy)-methyl]phen-yl}acrylate.

In the mol-ecule of the title compound, C(17)H(15)BrO(3), the rings make a dihedral angle of 75.54 (17)°. In the crystal structure, inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers, and the π-stacked dimers inter-act with neighbouring dimers via C-H⋯π stacking inter-actions.