Markovian Chemicals “in silico” Design (MARCH-INSIDE), a Promising Approach for Computer-Aided Molecular Design III: 2.5D Indices for the Discovery of Antibacterials

The 9th International Electronic Conference on Synthetic Organic Chemistry session Computational ChemistryThe present work continues our series on the use of MARCH-INSIDE molecular descriptors [parts I and II: J. Mol. Mod. (2002) 8: 237-245 and (2003) 9: 395-407]. These descriptors encode information regarding to the distribution of electrons in the molecule based on a simple stochastic approach to the idea of electronegativity equalization (Sanderson’s principle). Here, 3D-MARCH-INSIDE molecular descriptors for 667 organic compounds are used as input for a Linear Discriminant Analysis. This 2.5D-QSAR model discriminates between antibacterial compounds and non-antibacterial ones with a 92.9 % of accuracy in training sets. On the other hand, the model classifies correctly 94.0 % of the compounds in test set. Additionally, the present QSAR performs similar-to-better than other methods reported elsewhere. Finally, the discovery of a novel compound illustrates the use of the method. This compound, 2-bromo-3-(furan-2-yl)-3-oxo-propionamide have MIC50 of 6.25 and 12.50 µg/mL against Ps. Aeruginosa ATCC 27853 and E. Coli ATCC 27853 respectively while ampicillim, amoxicillim, clindamycin, and metronidazole have, for instance, MIC50 values higher 250 µg/mL against E. Coli. Consequently, the present method may becomes a useful tool for the in silico discovery of antibacterialsWe thank the Spanish Ministry of Science and Technology (SAF2003-02222), for partial financial support. Molina RR, Castañedo C, and Almeida SM, acknowledges support from the Universität Rostock, German

Validación de un método espectrofotométrico para la determinación del contenido de aldehídos en el aceite de girasol ozonizado (OLEOZON®)

El aceite de girasol ozonizado OLEOZON® presenta excelentes propiedades germicidas (bactericida, fungicida virucida y antiparasitario) que permiten su utilización en el tratamiento de enfermedades de origen infeccioso. En este trabajo se presenta la validación del método espectrofotométrico de determinación de los aldehídos presentes en el aceite de girasol ozonizado OLEOZON®, a través de la formación de sus derivados 2,4-dinitrofenilhidrazonas y la posterior medición de la absorbancia a 338 nm. La evaluación del método establecido se realizó mediante la determinación de los parámetros de linealidad, precisión, exactitud, especificidad y sensibilidad. En la evaluación de este método analítico se obtuvieron pruebas suficientes para demostrar que dicho método resulta lineal (r = 0,999 y r2 = 0,998), preciso (repetibilidad CV = 0,38 %, precisión intermedia CV = 0,81 %) exacto (recobrado³ 97,8 %) y sensible (límite de detección = 1,04 · 10-9 mol/L y límite de cuantificación = 1,28 · 10-9 mol/L) en el intervalo de concentraciones de aldehídos estudiado. Los diferentes compuestos presentes en el OLEOZON®, tales como: peróxidos, ácidos carboxílicos, ozónidos, y compuestos poliméricos no interfieren en la determinación del contenido de aldehídos por este método, por lo que es específico. Se realizó la determinación de la concentración de aldehídos referida al nonanal, en una muestra representativa de OLEOZON® que resultó de (1,21 ± 0,04) mmol/g

Nanostructured thin films obtained from Fischer aminocarbene complexes

The synthesis of four amphiphilic organometallic complexes with the general formula RC = M(CO)5NH(CH2)15CH3, where R is a ferrocenyl 2(a-b) or a phenyl 4(a-b) group as a donor moiety and a Fischer carbene of chromium (0) or tungsten (0) as an acceptor group, are reported. These four push-pull systems formed Langmuir (L) monolayers at the air-water interface, which were characterized by isotherms of surface pressure versus molecular area and compression/expansion cycles (hysteresis curves); Brewster angle microscopic images were also obtained. By using the Langmuir-Blodgett (LB) method, molecular monolayers were transferred onto glass substrates forming Z-type multilayers. LB films were characterized through ultraviolet-visible spectroscopy, atomic force microscopy and X-ray diffraction techniques. Results indicated that films obtained from 2b complex [(Ferrocenyl)(hexadecylamine)methylidene] pentacarbonyl tungsten (0) are the most stable and homogeneous; due to their properties, these materials may be incorporated into organic electronic devices

Optimize the parameters for the synthesis by the ionic gelation technique, purification, and freeze-drying of chitosan-sodium tripolyphosphate nanoparticles for biomedical purposes

Abstract Background Polymeric nanoparticles can be used for wound closure and therapeutic compound delivery, among other biomedical applications. Although there are several nanoparticle obtention methods, it is crucial to know the adequate parameters to achieve better results. Therefore, the objective of this study was to optimize the parameters for the synthesis, purification, and freeze-drying of chitosan nanoparticles. We evaluated the conditions of agitation speed, anion addition time, solution pH, and chitosan and sodium tripolyphosphate concentration. Results Chitosan nanoparticles presented an average particle size of 172.8 ± 3.937 nm, PDI of 0.166 ± 0.008, and zeta potential of 25.00 ± 0.79 mV, at the concentration of 0.1% sodium tripolyphosphate and chitosan (pH 5.5), with a dripping time of 2 min at 500 rpm. The most representative factor during nanoparticle fabrication was the pH of the chitosan solution, generating significant changes in particle size and polydispersity index. The observed behavior is attributed to the possible excess of sodium tripolyphosphate during synthesis. We added the surfactants poloxamer 188 and polysorbate 80 to evaluate the stability improvement during purification (centrifugation or dialysis). These surfactants decreased coalescence between nanoparticles, especially during purification. The centrifugation increased the zeta potential to 40.8–56.2 mV values, while the dialyzed samples led to smaller particle sizes (152–184 nm). Finally, freeze-drying of the chitosan nanoparticles proceeded using two cryoprotectants, trehalose and sucrose. Both adequately protected the system during the process, and the sugar concentration depended on the purification process. Conclusions In Conclusion, we must consider each surfactant's benefits in formulations for selecting the most suitable. Also, it is necessary to do more studies with the molecule to load. At the same time, the use of sucrose and trehalose generates adequate protection against the freeze-drying process, even at a 5% w/v concentration. However, adjusting the percentage concentration by weight must be made to work with the CS-TPP NPs purified by dialysis

Alteration of the blood-brain barrier by COVID-19 and its implication in the permeation of drugs into the brain

Diverse neurological symptoms have been reported in patients with SARS-CoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms “COVID-19” or “SARS-CoV-2” and “blood-brain barrier injury” or “brain injury” from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1β, IL-6, TNF-α, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs’ beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters

TOPS-MODE based QSARs derived from heterogeneous series of compounds. Applications to the design of new anti-inflammatory compounds

A new application of TOPological Sub-structural MOlecular DEsign (TOPS-MODE) was carried out in anti-inflammatory compounds using computer-aided molecular design. Two series of compounds, one containing anti-inflammatory and the other containing nonanti-inflammatory compounds were processed by a k-means cluster analysis in order to design the training and prediction sets. A linear classification function to discriminate the anti-inflammatory from the inactive compounds was developed. The model correctly and clearly classified 88% of active and 91% of inactive compounds in the training set. More specifically, the model showed a good global classification of 90%, that is, (399 cases out of 441). While in the prediction set, they showed an overall predictability of 88% and 84% for active and inactive compounds, being the global percentage of good classification of 85%. Furthermore this paper describes a fragment analysis in order to determine the contribution of several fragments towards anti-inflammatory property, also the present of halogens in the selected fragments were analyzed. It seems that the present TOPS-MODE based QSAR is the first alternate general `in silico' technique to experimentation in anti-inflammatory discovery. The TOPological Sub-Structural Molecular Design (TOPS-MODE) approach has been applied to the study of the anti-inflammatory compounds. The model correctly and clearly classified 88% of active and 91% of inactive compounds in the training set. More specifically, the model showed a good global classification of 90%, that is, (399 cases out of 441)

Nanostructured Thin Films Obtained from Fischer Aminocarbene Complexes

The synthesis of four amphiphilic organometallic complexes with the general formula RC = M(CO)5NH(CH2)15CH3, where R is a ferrocenyl 2(a-b) or a phenyl 4(a-b) group as a donor moiety and a Fischer carbene of chromium (0) or tungsten (0) as an acceptor group, are reported. These four push-pull systems formed Langmuir (L) monolayers at the air-water interface, which were characterized by isotherms of surface pressure versus molecular area and compression/expansion cycles (hysteresis curves); Brewster angle microscopic images were also obtained. By using the Langmuir–Blodgett (LB) method, molecular monolayers were transferred onto glass substrates forming Z-type multilayers. LB films were characterized through ultraviolet-visible spectroscopy, atomic force microscopy and X-ray diffraction techniques. Results indicated that films obtained from 2b complex [(Ferrocenyl)(hexadecylamine)methylidene] pentacarbonyl tungsten (0) are the most stable and homogeneous; due to their properties, these materials may be incorporated into organic electronic devices

Modifications in Vaginal Microbiota and Their Influence on Drug Release: Challenges and Opportunities

Vaginal drug delivery represents an attractive alternative to achieve local and systemic effects due to the high contact surface exposed, the mucoadhesion of the epithelium, and the high innervation that facilitates the absorption of drugs into the bloodstream. However, despite the confinement of the vaginal cavity, it is an organ with a highly variable microenvironment. Mechanical alterations such as coitus, or chemical changes such as pH and viscosity, modify the release of drugs. In addition, changes in vaginal microbiota can influence the entire vaginal microenvironment, thus determining the disposition of drugs in the vaginal cavity and decreasing their therapeutic efficacy. Therefore, the influence of microorganisms on vaginal homeostasis can change the pre-established scenario for the application of drugs. This review aims to provide an explanation of normal vaginal microbiota, the factors that modify it, its involvement in the administration of drugs, and new proposals for the design of novel pharmaceutical dosage forms. Finally, challenges and opportunities directed toward the conception of new effective formulations are discussed

Formulations of Curcumin Nanoparticles for Brain Diseases

Curcumin is a polyphenol that is obtained from Curcuma longa and used in various areas, such as food and textiles. Curcumin has important anti-inflammatory and antioxidant properties that allow it to be applied as treatment for several emerging pathologies. Remarkably, there are an elevated number of publications deriving from the terms “curcumin„ and “curcumin brain diseases„, which highlights the increasing impact of this polyphenol and the high number of study groups investigating their therapeutic actions. However, its lack of solubility in aqueous media, as well as its poor bioavailability in biological systems, represent limiting factors for its successful application. In this review article, the analysis of its chemical composition and the pivotal mechanisms for brain applications are addressed in a global manner. Furthermore, we emphasize the use of nanoparticles with curcumin and the benefits that have been reached as an example of the extensive advances in this area of health