Novel Penicillin Derivatives Against Selected Multiple-Drug Resistant Bacterial Strains: Design, Synthesis, Structural Analysis, in silico and in Vitro Studies.

INTRODUCTION: The rising numbers of multiple drug-resistant (MDR) pathogens and the consequent antibacterial therapy failure that resulted in severe medical conditions push to illustrate new molecules with extended activity against the resistant strains. In this manner, chemical derivatization of known antibiotics is proposed to save efforts in drug discovery, and penicillins serve as an ideal in this regard. METHOD: Seven synthesized 6-aminopenicillanic acid-imine derivatives (2a-g) were structure elucidated using FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. In silico molecular docking and ADMET studies were made. The analyzed compounds obeyed Lipinski's rule of five and showed promising in vitro bactericidal potential when assayed against E. coli, E. cloacae, P. aeruginosa, S. aureus, and A. baumannii. MDR strains using disc diffusion and microplate dilution techniques. RESULT: The MIC values were 8 to 32 µg/mL with more potency than ampicillin, explained by better membrane penetration and more ligand-protein binding capacity. The 2g entity was active against E. coli. This study was designed to find new active penicillin derivatives against MDR pathogens. CONCLUSION: The products showed antibacterial activity against selected MDR species and good PHK, PHD properties, and low predicted toxicity, offering them as future candidates that require further preclinical assays.

Determination of Kα,ß excitation factors in thin target for selected elements from Y to Te at 59.54 keV excitation energy.

The paper presents the first measurements of the Kα and Kß excitation factors for some selected elements from Y to Te. To determine the Kα and Kß excitation factors, the experimental values of K shell X-ray production cross sections and total absorption photoelectric cross sections were used. The measurements were performed using a Si(Li) detector coupled with 2048 multichannel analyzer and an Am-241 annular radioisotope source which is emitted 59.54 keV γ-photons. It is observed that the Kα excitation factors are 5-6 times larger than the Kß excitation factors. The measured excitation factors were compared only with theoretical calculated ones since there are no other experimental reports for the present elements in the literature. The present experimental values of Kα and Kß excitation factors are in satisfactory agreement with the theoretical results.

Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate.

In vivo study was performed to determine the tolerability and pharmacokinetics of ISIS 104838, a phosphorothioate antisense oligonucleotide targetting human tumour necrosis factor alpha (TNF-alpha) mRNA, following multi-dose administration via intravenous and oral routes. Oral tablet formulations of ISIS 104838 were pre-formulated with the permeation enhancer, sodium caprate, in an enteric-coated solid dosage form. The average plasma bioavailability of ISIS 104838 was 1.4% relative to IV. The tissue distribution profile was similar following both routes of administration, with highest concentrations observed in the kidney followed by the liver, lymph nodes and spleen. Plasma bioavailability underestimated the tissue accumulation of ISIS 104838 observed 1 day after the last dose. Mean systemic tissue bioavailability ranged from 2.0 to 4.3%, relative to IV tissues, and was dependent on tissue type. No marked differences were noted in the pharmacokinetic parameters following multi-dosing either via intravenous or oral routes. All formulations administered were well tolerated. This paper reports the first evaluation of solid oral dosage forms comprising sodium caprate and an antisense oligonucleotide. Furthermore, this study demonstrates the oral delivery of ISIS 104838 from solid oral dose formulations, with the achievement of comparable tissue concentrations of the oligonucleotide to that of the intravenous treatment.

Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs.

Sodium caprate, a medium chain fatty acid, is known to enhance the transport of drugs across the intestinal mucosa in cell culture systems and small animal species. The aim of the present study was to evaluate the effect of this enhancer on the oral absorption of two chemically modified antisense oligonucleotides ISIS 2503 (phosphorothioate) and ISIS 104838 (methoxyethyl modified phosphorothioate) using an intra-intestinal catheterised pig model. Sodium caprate at doses 25, 50 and 100 mg/kg was effective in enhancing systemic delivery of both antisense chemistries. At all enhancer doses, the absorption of both chemistries was rapid (T(max) 10 min) and short lived (plasma levels fell below detection by 2 h following administration). The pharmacokinetic parameters (AUC, C(max), T(max)) of both chemistries were unchanged with the increase in the permeation enhancer dose. The oral bioavailability with methoxyethyl modified phosphorothioate (ISIS 104838) was higher relative to unmodified phosphorothioate. Sodium caprate was rapidly absorbed following intra-intestinal administration (T(max) approximately 7 min regardless of the dose) and its pharmacokinetics were linear with dose. All tested formulations were well tolerated by the animals and no abnormal histopathological findings were observed following histological evaluation of intestinal tissues from pigs exposed to multi-dose administration of sodium caprate. It is concluded that sodium caprate can improve the oral delivery of antisense oligonucleotides in pigs and that its membrane-permeation effect is rapid, short-lived and dose independent.