Structure-activity relationships based on 3D-QSAR CoMFA/CoMSIA and design of aryloxypropanol-amine agonists with selectivity for the human β3-adrenergic receptor and anti-obesity and anti-diabetic profiles

Indexación: Scopus.Acknowledgments: This work was supported by FONDECYT No. 11130701. We would also like to thank fDoTr CthLeafbr efeora vthaeil afrbeilei tayvoafiltahbeilsitoyf towfa trheer seoqfutwireadret orecqaulciureladt etothcealAcuDla(thet ttph:e/ A/dDt c(lhatbt.pw:/e/dbstc.cloabm.w/seobfst.wcoamre/-stoofotlws aarned-tools and http://teqip.jdvu.ac.in/QSAR_Tools/). SDG. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest.The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2 ncv = 0.993 and 0.984 and values of r2 test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2 m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561). © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/119

A New Kind of Quinonic-Antibiotic Useful Against Multidrug-Resistant S. aureus and E. faecium Infections

Indexación: Scopus.A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1⁻32 μg/mL against Gram-positive ATCC® strains. The structure⁻activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.https://www.mdpi.com/1420-3049/23/7/177

Gold nanoparticles stabilized with βcyclodextrin-2-amino-4-(4-chlorophenyl)thiazole complex : a novel system for drug transport

While 2-amino-4-(4-chlorophenyl)thiazole (AT) drug and thiazole derivatives have several biological applications, these compounds present some drawbacks, such as low aqueous solubility and instability. A new complex of βCD-AT has been synthesized to increase AT solubility and has been used as a substrate for the deposit of solid-state AuNPs via magnetron sputtering, thus forming the βCD-AT-AuNPs ternary system, which is stable in solution. Complex formation has been confirmed through powder X-ray diffraction and 1D and 2D nuclear magnetic resonance. Importantly, the amine and sulfide groups of AT remained exposed and can interact with the surfaces of the AuNPs. The complex association constant (970 M-1) has been determined using phase solubility analysis. AuNPs formation (32 nm average diameter) has been studied by UV-Visible spectroscopy, transmission/scanning electron microscopy and energy-dispersive X-ray analysis. The in vitro permeability assays show that effective permeability of AT increased using βCD. In contrast, the ternary system did not have the capacity to diffuse through the membrane. Nevertheless, the antibacterial assays have demonstrated that AT is transferred from βCD-AT-AuNPs, being available to exert its antibacterial activity. In conclusion, this novel βCD-AT-AuNPs ternary system is a promising alternative to improve the delivery of AT drugs in therapy

Antibacterial activity the βCD-AT-AuNPs, βCD-AT and AT.

<p>Antibacterial activity the βCD-AT-AuNPs, βCD-AT and AT.</p

ROESY spectra of the βCD-AT complex and proposed inclusion geometries.

<p>Cross peaks between: (A) the H-3, H-5 and H-6 protons of βCD with the H’-2’/3’/5’/6’ protons of the aromatic ring of AT, (B) OH-2 and OH-3 groups of βCD with the H’-2’/3’/5’/6’ protons of the aromatic ring of AT, (C) OH-2 and OH-3 groups of βCD with NH₂’-2 and H'-5 protons of the thiazole group of AT.(D) Proposed inclusion geometries of the βCD-AT complex.</p

Chemical shifts of the IC and free species.

<p>Chemical shifts of the IC and free species.</p

SEM micrographs.

<p>Shown are (A) pure AT, (B) pure βCD, (C, D), βCD-AT crystals, and (E) AuNPs deposited on the βCD-AT crystals.</p

Effective permeability measurements.

<p>Shown are the effective permeability for the AT drug, βCD-AT complex, and βCD-AT-AuNPs system, as well as the corresponding positive (+) and negative (-) controls.</p

Powder x-ray diffraction (PXRD) intensities.

<p>PXRD diffractograms of (A) βCD, (B) AT,(C) the βCD-AT complex, and (D) the physical βCD/AT mixture.</p