RESUMEN
In treating wounds, long lasting infection is considered the major impediment. Drugs are rendered ineffective by pathogenic microorganisms via antibiotic resistance and calls for designing and development of new drugs. Herein, we report synthesis of eight different N-alkylated pyridine-based organic salts QAS 1-8 and their antibacterial, antibiofilm and wound healing activities. 3-(2-R-hydrazinecarbonyl)-1-propylpyridinium Bromide was the parent compound while R group was varying in each salt composed of different aromatic aldehyde moieties. In the antibacterial activity against S. aureus and E. coli, amoxicillin shows IC50 near to 25 µg/mL inhibiting 58 ± 0.4% S. aureus while ceftriaxone inhibited 55 ± 0.5% E. coli at a concentration of 10 µg/mL. The highest IC50 (56 ± 0.5% against S. aureus; 55 ± 0.5% against E. coli) was shown by compound QAS 7 at the concentration of 100 µg/mL; followed by the QAS 6 (55 ± 0.5% against E. coli) and QAS 2 (55 ± 0.5% against E. coli). In the antibiofilm activity, QAS 6, QAS 1 and QAS 8 inhibited 58 ± 0.4% S. aureus at a concentration of 75 µg/mL, while QAS 2 inhibited E. coli at the same concentration and amount. QAS 7, 3 and 1 inhibited almost 90% while QAS 6 inhibited 95 ± 1.1%of E. coli at a concentration of 250 µg/mL. Highest MBIC was provided by QAS 7 (52 ± 0.4%) against S. aureus at a concentration of 50 µg/mL that is very near to the standard amoxicillin. Antibacterial and antibiofilm activity results were also supported by the atomic force microscopy (AFM). In the wound healing activity, QAS 8 healed 90.8 ± 4.3% of the wound in 21 days with an average period of epithelialization (POE) of 19 ± 1.4 days; that is far better than povidone iodine ointment (81.5 ± 3.3% of the wound in the 21 days with 22.4 ± 2.9 days of POE). It is concluded from this study that the synthesized compounds QAS 2, 7 and 8 can be used for further mechanistic studies to be employed as antibacterial, antibiofilm and wound healing agents.
Asunto(s)
Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Piridinas/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Escherichia coli/fisiología , Ratones , Pruebas de Sensibilidad Microbiana , Microscopía de Fuerza Atómica , Piridinas/síntesis química , Piridinas/farmacología , Sales (Química)/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Relación Estructura-ActividadRESUMEN
Alkyl moieties-open chain or cyclic, linear, or branched-are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties.
Asunto(s)
Alquilantes/química , Preparaciones Farmacéuticas/química , Desarrollo de Medicamentos , Hidroxilación , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Redes y Vías Metabólicas , Estructura Molecular , Preparaciones Farmacéuticas/clasificación , Relación Estructura-Actividad , Compuestos de Sulfonilurea/administración & dosificación , Compuestos de Sulfonilurea/químicaRESUMEN
Supramolecular macrocycles-based drug delivery systems are receiving wider recognition due to their self-assembly into nanostructures with unique characteristics. This study reports synthesis of resorcinarene-based novel and biocompatible amphiphilic supramolecular macrocycle that self-assembles into nano-vesicular system for Amphotericin B (Am-B) delivery, a model hydrophobic drug. The macrocycle was synthesized through a two-step reaction and was characterized with 1 H NMR and mass spectrometric techniques. Its biocompatibility was assessed in cancer cell lines, blood and animals. Its critical micelle concentration (CMC) was determined using UV spectrophotometer. Am-B loaded in novel macrocycle-based vesicles were examined according to their shape, size, surface charge, drug entrapment efficiency and excepients compatibility using atomic force microscope (AFM), Zetasizer, HPLC and FT-IR spectroscopy. Drug-loaded vesicles were also investigated for their in-vitro release, stability and in-vivo oral bioavailability in rabbits. The macrocycle was found to be nontoxic against cancer cells, haemo-compatible and safe in mice and revealed lower CMC. It formed mono-dispersed spherical shape vesicles of 174.4 ± 3.78 nm in mean size. Vesicles entrapped 92.05 ± 4.39% drug and were stable upon storage with gastric-simulated fluid and increased the drug oral bioavailability in rabbits. Results confirmed novel macrocycle as biocompatible vesicular nanocarrier for enhancing the oral bioavailability of lipophilic drugs.
Asunto(s)
Anfotericina B , Portadores de Fármacos , Nanopartículas , Administración Oral , Anfotericina B/química , Anfotericina B/farmacocinética , Anfotericina B/farmacología , Animales , Línea Celular Tumoral , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Humanos , Ratones , Células 3T3 NIH , Nanopartículas/química , Nanopartículas/uso terapéutico , ConejosRESUMEN
Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development.
Asunto(s)
Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Analgésicos Opioides/química , Codeína/química , Isoenzimas/química , Isoenzimas/metabolismo , Oxidación-ReducciónRESUMEN
Neopine, a minor opium alkaloid and an isomer of codeine (also known as beta-codeine), has been detected in both the urine of opium users and pharmaceutical codeine users. The characterization of neopine was achieved by comparison of the mass spectra and GC retention times of the trimethylsilyl derivative. The presence of neopine in the urine of pharmaceutical codeine users was attributed to the metabolism of codeine through a double bond migration in ring C, from the 7-8 to the 8-14 position. The potential use of the alkaloid as a confirmation marker of opium and/or pharmaceutical codeine use and the ability to differentiate these from heroin use has been discussed.