A novel series of Schiff bases 5b-g was synthesized by the reaction of N-substitutedbenzylisatin 3b-g with nalidixic acid hydrazide 4 in order to optimize the antimycobacterial activity of our lead Schiff base 5a. Antimycobacterial (anti-mtb) activity of the synthesized hydrazones was investigated against four Mycobacterium strains: M. intercellulari, M. xenopi, M. cheleneo and M. smegmatis. It was found that para-substitution, with electron withdrawing group, of benzyl moiety in N-benzylisatins resulted in 7 fold enhancement of the anti-mtb activity as shown with compounds 5b, 5d and 5f (MIC 0.09 μg/ml) with p-chloro, fluoro and nitro substituents respectively. In silico docking study of these hydrazones with mtb-DNA gyrase revealed that there is parallelism between the antimycobacterial activity of these hydrazones and docking with the active site of the mtb-DNA gyrase B subunit.

A novel series of Schiff bases 5b-g was synthesized by the reaction of N-substitutedbenzylisatin 3b-g with nalidixic acid hydrazide 4 in order to optimize the antimycobacterial activity of our lead Schiff base 5a. Antimycobacterial (anti-mtb) activity of the synthesized hydrazones was investigated against four Mycobacterium strains: M. intercellulari, M. xenopi, M. cheleneo and M. smegmatis. It was found that para-substitution, with electron withdrawing group, of benzyl moiety in N-benzylisatins resulted in 7 fold enhancement of the anti-mtb activity as shown with compounds 5b, 5d and 5f (MIC 0.09 μg/ml) with p-chloro, fluoro and nitro substituents respectively. In silico docking study of these hydrazones with mtb-DNA gyrase revealed that there is parallelism between the antimycobacterial activity of these hydrazones and docking with the active site of the mtb-DNA gyrase B subunit.

BACKGROUND: Cancer is one of the most dreaded diseases and it is a leading cause of mankind death worldwide. Recent reports documented a remarkable antiproliferative activity of isatin nucleus against various cancer cell lines. The current work describes the antiproliferative activity of Schiff bases of combinatorial mixtures of the isatin derivatives M1-M22 as well as the individual compounds 1-11(A-K) of these combinatorial mixtures. RESULTS: The designed combinatorial library composed from eleven hydrazides A-K and eleven isatin derivatives 1-11 has been synthesized to formally generate 22 mixtures, M1-M22 of 121 Schiff bases, and their antiproliferative activity against K562 chronic myelogenous leukemia cells was evaluated. The indexed method of analysis of the prepared library was applied to elucidate the active components in the tested mixtures M1-M22. The predictions from the crossing procedure was validated through evaluation of the antiproliferative activity of individual compounds 1-11(A-K) of the library. Individual compounds 1-11(A-K) were also evaluated against the non-tumorigenic MCF-12A cell line to investigate their selectivity. A pharmacophore model was developed to further optimize the antiproliferative activity among this series of compounds. CONCLUSIONS: Variable antiproliferative activity was revealed with the investigated mixtures M1-M22 and the individual compounds 1-11(A-K). Most of the tested mixtures and several individual Schiff bases displayed high potency with IC50 values in the low micromolar range. A considerable selectivity of some individual compounds to the tumorigenic K562 cell line compared with the non-tumorigenic MCF-12A cell line was observed as indicated by their selectivity index (SI).

BACKGROUND: Cancer is one of the most dreaded diseases and it is a leading cause of mankind death worldwide. Recent reports documented a remarkable antiproliferative activity of isatin nucleus against various cancer cell lines. The current work describes the antiproliferative activity of Schiff bases of combinatorial mixtures of the isatin derivatives M1-M22 as well as the individual compounds 1-11(A-K) of these combinatorial mixtures. RESULTS: The designed combinatorial library composed from eleven hydrazides A-K and eleven isatin derivatives 1-11 has been synthesized to formally generate 22 mixtures, M1-M22 of 121 Schiff bases, and their antiproliferative activity against K562 chronic myelogenous leukemia cells was evaluated. The indexed method of analysis of the prepared library was applied to elucidate the active components in the tested mixtures M1-M22. The predictions from the crossing procedure was validated through evaluation of the antiproliferative activity of individual compounds 1-11(A-K) of the library. Individual compounds 1-11(A-K) were also evaluated against the non-tumorigenic MCF-12A cell line to investigate their selectivity. A pharmacophore model was developed to further optimize the antiproliferative activity among this series of compounds. CONCLUSIONS: Variable antiproliferative activity was revealed with the investigated mixtures M1-M22 and the individual compounds 1-11(A-K). Most of the tested mixtures and several individual Schiff bases displayed high potency with IC50 values in the low micromolar range. A considerable selectivity of some individual compounds to the tumorigenic K562 cell line compared with the non-tumorigenic MCF-12A cell line was observed as indicated by their selectivity index (SI).

Double hydrophilic block copolymers (DHBC) were prepared by end-to-end coupling of two biocompatible water-soluble homopolymers: the polysaccharide dextran (Mw 8300 or 14,700 g mol1) and -amino poly(ethylene glycol) (PEG-NH2, Mw 3000 or 7000 g mol1). The synthesis involved, first, specific oxidation of the dextran terminal aldehyde group and, second, covalent linkage of PEG-NH2 via a lactone aminolysis reaction. The diblock copolymers dextran-PEG (DEX-PEG) were converted in high yield into the corresponding carboxymethyldextran-PEG (CMD-PEG) derivatives with control over the degree of substitution, from 30 to 85 mol% CH2COOH groups per glucopyranosyl unit. Further modifications of a CMD-PEG block copolymer led to N-(2-aminoethyl)carbamidomethyldextran-PEG yielding a pair of oppositely-charged DHBC of identical charge density, chain length, and neutral block/charged block content. The properties of CMD-PEG in aqueous solutions were studied by static and dynamic light scattering as a function of solution pH, providing evidence of the pH-sensitive assembly of the copolymers driven by inter- and intra-chain hydrogen-bond formation.

The micellization of a model cationic drug, diminazene diaceturate (DIM) and a series of new diblock copolymers, carboxymethyldextranpoly(ethylene glycols) (CMD-PEG), were evaluated as a function of the ionic charge density or degree of substitution (DS) of the carboxymethyldextran block and the molar ratio, [+]/[−], of positive charges provided by the drug to negative charges provided by CMD-PEG. Micelles ([+]/[−] = 2) incorporated up to 64% (w/w) DIM and ranged in hydrodynamic radius (RH) from 36 to 50 nm, depending on the molecular weight and DS of CMD-PEG. The critical association concentration (CAC) was on the order of 15-50 mg/L for CMD-PEG of DS > 60%, and ca. 100 mg/L for CMD-PEG of DS~30%. The micelles were stable upon storage in solution for up to 2 months and after freeze-drying in the presence of trehalose. They remained intact within the 4 pH 11 range and for solutions of pH 5.3, they resisted increases in salinity up to ~0.4 M NaCl in the case of CMD-PEG of high DS. However, micelles of DIM and a CMD-PEG of low DS (30%) disintegrated in solutions containing more than 0.1 M NaCl, setting a minimum value to the DS of copolymers useful in in-vivo applications. Sustained in-vitro DIM release was observed for micelles of CMD-PEG of high DS ([+]/[−] = 2).

Omeprazole (OME) is a proto type anti-secretary agent. This compound is very unstable, especially in acidic aqueous solutions. A stability indicating HPLC assay has been developed in order to investigate the effect of different factors on the stability of omeprazole. These factors included the pH with the tested values ranging from 6-10 and the temperature by monitoring the drug stability at 25, 37 and 40ºC. The study was then extended to investigate the effect of cyclodextrins, namely beta-cyclodextrin (β-CD), dimethyl-beta-cyclodextrin (DMβ-CD), hydroxypropyl-beta-cyclodextrin (HPβ-CD) and maltosyl-beta-cyclodextrin (Mβ-CD) on the stability of omeprazole. The results showed the dependence of drug stability on the pH and temperature with the degradation being significant below pH 7 and at higher temperature. The degradation kinetics follows the first-order kinetics. The addition of different cyclodextrins accelerates the degradation of drug, and this effect was in the following manner: β-CD> DMβ-CD> Mβ-CD> HPβ-CD. The effect of different concentrations of HPβ-CD on the degradation of drug was also studied. It was noted that the degradation of drug depends on the concentration of HPβ-CD up to 1.0 mM; above this concentration the degradation was constant.

The basic objectives of this study were to prepare and characterize solid dispersions of poorly soluble drug spironolactone (SP) using gelucire carriers by spray-drying technique. The properties of the microparticles produced were studied by differential scanning calorimetry (DSC), scanning electron microscopy, saturation solubility, encapsulation efficiency, and dissolution studies. The absence of SP peaks in DSC profiles of microparticles suggests the transformation of crystalline SP into an amorphous form. The in-vitro dissolution test showed a significant increase in the dissolution rate of microparticles as compared with pure SP and physical mixtures (PMs) of drug with gelucire carriers. Therefore, the dissolution rate of poorly water-soluble drug SP can be significantly enhanced by the preparation of solid dispersion using spray-drying technique.

Chitosan (CH), partially N-deacetylated chitin, is a biodegradable and biocompatible polymer that has shown great potential in drug delivery and tissue engineering applications. Although bioadhesive, CH has limited mucoadhesion in wet conditions due to weak interactions with biological surfaces. DOPA (3,4-dihydroxy-L-phenylalanine), a catechol-containing molecule naturally present in marine mussel foot proteins, has been shown to increase the mucoadhesion of several polymers. We report here a simple and bioinspired approach to enhance CH mucoadhesion in wet conditions by preparing mixed hydrogels including CH and different catechol-containing compounds, namely DOPA, hydrocaffeic acid (HCA), and dopamine (DA). We characterized the hydrogels for their swelling, release kinetics of the catechol compounds, and mucoadhesive strength to rabbit small intestine. The swelling of the hydrogels was pH dependent with maximum swelling at pH 1. The hydrogel swelling was higher in the presence of the DOPA and DA but lower in the presence of HCA. HCA/CH hydrogel also showed the slowest catechol release, most likely due to electrostatic interactions between CH and HCA. Lower hydrogel swelling and slower HCA release resulted in increased mucoadhesion: HCA/CH showed more than 2-fold enhancement of mucoadhesion to rabbit small intestine compared to CH alone. Since it is known that catechol compounds can be oxidized, we analyzed the oxidation of DOPA, HCA, and DA at different pH values and its effect on mucoadhesion. We found that oxidation occurring before contact with the intestinal mucosa did not improve mucoadhesion, while oxidation occurring during the contact further increased the mucoadhesion of HCA/CH hydrogels. These results show that mucoadhesion of CH hydrogels can be increased with a simple bioinspired approach, which has the potential to be applied to other polymers since it does not require any chemical modification.

Omeprazole microparticles were prepared by different drying techniques using Kollicoat IR® and hydroxypropyl-β-cyclodextrin hydrophilic polymers. Physico-chemical properties were investigated using differential scanning calorimetry and powder X-ray diffractometry. Dissolution rate was determined and compared to the physical mixtures and the morphology was studied using a scanning electron microscope. Omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Omeprazole dissolution rate was enhanced significantly from its spray- and freeze-dried microparticles as compared to the corresponding physical mixtures and drug alone (P 0.05). F3 and F5 formula possessed superior release rate over other formulations. In acidic medium, the release of drug from enteric-coated capsules was not detectable, while it is completely released within 40 min after changing dissolution medium to phosphate buffer (pH 7.4). The transformation of OME from crystalline to amorphous state by using either Kollicoat IR® or hydroxylpropyl-β-cyclodextrin is considered a promising way to improvement of drug dissolution.