COX-1, COX-2 inhibitors and antifungal agents from Croton hutchinsonianus

Two new compounds, 3'-(4'-hydroxy-3',5'-dimethoxyphenyl)-propyl benzoate (1) and 3'-(4'-hydroxyphenyl)-propyl benzoate (3) together with known compounds, 3'-(4'-hydroxy-3'-methoxyphenyl)-propyl benzoate (2), poilaneic acid (4), farnesyl acetone (5) and 4-hydroxybenzaldehyde (6) were isolated and identified from the branches of Croton hutchinsonianus. Their structures were determined by spectroscopic methods. The three phenylpropyl benzoates (1-3) were found to exhibit antifungal activity against Candida albicans (IC(50) 5.36-11.41 microg/ml). Compounds 1-2 (IC(50) 2.11-4.95 microg/ml) exhibited potent but non-selective activity against the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) whereas 3 (IC(50) 1.88 microg/ml) preferentially inhibited the enzyme COX-2.     

Preparation of 3-arylmethylindoles as selective COX-2 inhibitors

The 3-arylmethylation of indoles using TMSOTf/Et₃SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO₂ and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO₂ and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, an unprecedented Pd(0) mediated arylorganozinc coupling with the requisite substituted 3-methylcarbonatomethylindole proved successful in affording the desired 2-cyano-6-MeSO₂-3-arylmethylindoles effective as selective COX-2 inhibitors.     

2, 3-Diaryl-5-ethylsulfanylmethyltetrahydrofurans as a new class of COX-2 inhibitors and cytotoxic agents

2,3-Diaryl-5-ethylsulfanylmethyltetrahydrofuran-3-ols were designed and synthesized by the allylations of benzoins followed by iodocyclization and nucleophilic replacement reactions with ethanthiol. These molecules exhibit IC(50) for COX-2 at <10 nM concentration and exhibit average GI(50) over all the 59 human tumor cell lines at microM concentration.     

Photoelectron spectra and structures of three cyclic dipeptides: PhePhe, TyrPro, and HisGly

We have investigated the electronic structure of three cyclic dipeptides: cyclo(Histidyl-Glycyl) (cHisGly), cyclo(Tyrosyl-Prolyl) (cTyrPro), and cyclo(Phenylalanyl-Phenylalanyl) (cPhePhe) in the vapor phase, by means of photoemission spectroscopy and theoretical modeling. The last compound was evaporated from the solid linear dipeptide, but cyclised, losing water to form cPhePhe in the gas phase. The results are compared with our previous studies of three other cyclopeptides. Experimental valence and core level spectra have been interpreted in the light of calculations to identify the basic chemical properties associated with the central diketopiperazine ring, and with the additional functional groups. The valence spectra are generally characterized by a restricted set of outer valence orbitals separated by a gap from most other valence orbitals. The theoretically simulated core and valence spectra of all three cyclic dipeptides agree reasonably well with the experimental spectra. The central ring and the side chains act as independent chromophores whose spectra do not influence one another, except for prolyl dipeptides, where the pyrrole ring is fused with the central ring. In this case, significant changes in the valence and core level spectra were observed, and explained by stronger hybridization of the valence orbitals.     

QSAR models of cytochrome P450 enzyme 1A2 inhibitors using CoMFA,CoMSIA and HQSAR

Quantitative structure–activity relationship (QSAR) studies were conducted on an in-house database of cytochrome P450 enzyme 1A2 inhibitors using the comparative molecular field analysis (CoMFA), comparative molecular similarity analysis (CoMSIA) and hologram QSAR (HQSAR) approaches. The database consisted of 36 active molecules featuring varied core structures. The model based on the naphthalene substructure alignment incorporating 19 molecules yielded the best model with a CoMFA cross validation value q² of 0.667 and a Pearson correlation coefficient r² of 0.976; a CoMSIA q² value of 0.616 and r² value of 0.985; and a HQSAR q² value of 0.652 and r² value of 0.917. A second model incorporating 34 molecules aligned using the benzene substructure yielded an acceptable CoMFA model with q² value of 0.5 and r² value of 0.991. Depending on the core structure of the molecule under consideration, new CYP1A2 inhibitors will be designed based on the results from these models.     

Syntheses and comparison of three reagents for allyldimethylsilylation of prostaglandins and steroids: a gas chromatographic method

Three reagents used for allyldimethylsilylation of prostaglandins and steroids have been prepared: N,O-bis(allyldimethylsilyl)trifluoroacetamide, N-methylallyl-dimethylsilyltrifluoroacetamide and allyldimethylsilyl-N,N-diphenylamine. The reaction kinetics of the reagents have been studied at room temperature in several solvents, and the optimal conditions for the derivatization of prostaglandins and steroids are discussed.     

Monte Carlo method based QSAR modelling of natural lipase inhibitors using hybrid optimal descriptors

Obesity is one of the most provoking health burdens in the developed countries. One of the strategies to prevent obesity is the inhibition of pancreatic lipase enzyme. The aim of this study was to build QSAR models for natural lipase inhibitors by using the Monte Carlo method. The molecular structures were represented by the simplified molecular input line entry system (SMILES) notation and molecular graphs. Three sets – training, calibration and test set of three splits – were examined and validated. Statistical quality of all the described models was very good. The best QSAR model showed the following statistical parameters: r² = 0.864 and Q² = 0.836 for the test set and r² = 0.824 and Q² = 0.819 for the validation set. Structural attributes for increasing and decreasing the activity (expressed as pIC₅₀) were also defined. Using defined structural attributes, the design of new potential lipase inhibitors is also presented. Additionally, a molecular docking study was performed for the determination of binding modes of designed molecules.     

Molecular docking,linear and nonlinear QSAR studies on factor Xa inhibitors

Structural Chemistry - Factor Xa (FXa) enzyme has an important role in the blood coagulation system. Disruption in the enzyme function results in the production of blood clots. Therefore,...