The emergence of non-tuberculous mycobacteria (NTM) infections, in Europe and North America, is higher than that of M. tuberculosis (M. tb). NTM are ubiquitous and opportunistic in persons with immunodeficiency or chronic lung disease. Among six NTM with proven pulmonary pathogenicity, M. avium complex (MAC) and M. abscessus are the most common. Current NTM treatments are moderately efficient, as they were initially designed to cure M. tb infections. First-line treatments require the combination of at least three antibiotics with different mechanisms of action to limit cross-resistance over a long period (12 to 24 months). Consequently, it is urgent to develop new anti-NTM molecules more specific and more efficient to reduce treatment duration and overcome resistant strains. Two quinoline-based compounds, bedaquiline (BQ) and mefloquine (MQ) target the ATP synthase, a vital enzyme for mycobacteria. However, BQ is only used as a treatment of last resort due to many drug interactions and significant hepatic and cardiac side effects. MQ is safer than BQ but is moderately active against NTM (e.g., MIC = 4 µg/mL on MAC). Recently, we developed a first series of MQ analogs active against MAC and M. abscessus with a better selectivity index (SI) than MQ (SI = 2.86 vs 0.38). In continuation of this work, new MQ analogs with piperazine core were designed, prepared by short asymmetric synthesis and characterized. The first in vitro antimycobacterial evaluations on several strains and cytotoxicity study were carried out.

The paper serves two goals. Its first aim is to approach mass spectrometric measurands such as mass-to-charge and peak intensity variables of molecular isotopologues of halogenated pharmaceutics diclofenac (1) and loratadine (2) with respect to experimental conditions of measurements, involving collision energy and concentration of the presented formic acid; if any via our stochastic dynamic method and model equation . In addition, it is tested its most recently derivative formulas and , connecting among experimental measurands with respect to experimental conditions of measurements, particularly, accounting for the collision energy values and concentration of formic acid. So far, the latter two models have been tested on only two molecular models of labetalol and acetaminophen. Secondly, the first shown equation is used to determine 3D molecular and electronic structures of the analytes, mass spectrometrically. The task is carried out via its complementary application with the Arrhenius’s equation. Those two domains constitute the fundamental background of the analytical mass spectrometry consisting in quantitative and 3D structural analysis of analytes, which are approaches only employing one and the same stochastic dynamic equation. There are used ultra-high resolution electrospray ionization mass spectrometric data in addition to high accuracy quantum chemical static methods as well as molecular dynamics. Tests of chemometrics are employed, as well.

In the modern world, liver diseases are of great relevance. It is important to search and study new drugs with a hepatoprotective effect with a simultaneous positive effect on carbohydrate and lipid metabolism. The issues of synthesis of various derivatives of cyanothioacetamide are being studied on the basis of the research laboratory "KhimEx" of the Lugansk State University named after Vladimir Dahl. As a result of preliminary experiments in silico, compounds with laboratory codes AZ-383, AZ-257, AZ-020 were selected, which have biotargets for influencing carbohydrate and lipid metabolism, as well as liver function.

The aim of the study was to study the hepatoprotective activity of thieno[2,3-b]quinoline and 1,4-dihydropyridine derivatives in a model of metabolic disorders, evaluating morphological changes, biochemical and immunohistochemical parameters of the liver.

Materials and methods of research. The experiment was carried out on 72 mature Wistar rats. Animals of the control groups were modeled metabolic disorders by high-fat diet, steroid load and their sequential combined effects. Pharmacocorrection of the induced disorders was carried out for 14 days with reference drugs (metformin and vildagliptin) and experimental compounds with codes AZ-383, AZ-257, AZ-020. When the animals were hatched, blood was taken to determine the concentration of ALT, AST, total bilirubin, histomorphometric study of the liver, immunohistochemical detection for Ki-67.

Results. All studied derivatives of alpha-cyanothioacetamide showed hepatoprotective activity, which was manifested by a significant decrease in the activity of ALT, AST, the level of total bilirubin, which were increased after prolonged alimentary and steroid loading. The ability of the compounds to neutralize the phenomena of pronounced vacuolar and fatty degeneration, necrosis of hepatocytes recorded on sections of the liver is more effective than comparators. The most pronounced proliferative activity of the liver was recorded in rats, which, after a long-term alimentary and dexamethasone load, were injected for 2 weeks with a cyanothioacetamide derivative with the code AZ-383 at a dose of 1 mg/kg.

Conclusions.New derivatives of cyanothioacetamide have hepatoprotective activity under alimentary and dexamethasone loads, which was confirmed in this study. The most pronounced hepatoprotective properties have a compound with code AZ-383 (2-methyl-N-(2-methylphenyl)-4-(2-furyl)-5-cyano-6-({2-[(4-ethoxyphenyl)amino] -2-oxoethyl}thio)-1,4-dihydropyridine-3-carboxamide).

Chronic wounds (CWs) are frequently associated with bacterial infections. The development of antibiotic-resistant microorganisms makes it crucial to think of alternative solutions. Considering these issues, a drug delivery system made of coaxial wet-spun fibers loaded with essential oils (EOs) was proposed. Coaxial structures were produced using the wet-spinning technique, in which 10% w/v polycaprolactone (PCL, a synthetic polymer with excellent mechanical properties and elastic behavior) was used to produce the core and loaded with three EOs, Clove Oil (CO), Cinnamon Leaf Oil (CLO) and Tea Tree Oil (TTO) at 2×Minimum Bactericidal Concentration (MBC). The shell was made of a blend of 10% w/v cellulose acetate (CA, a natural polymer which has been reported to offer good structural integrity) and 10% w/v polyethylene glycol (PEG, a synthetic polymer often used as a plasticizer), mixed at a ratio of 90/10 v/v, respectively, so pores could be opened in the outer layer, allowing for a sustained release of the EOs loaded at the fibers’ core overtime. The formation of coaxial structures was confirmed by Brightfield Microscopy. Coaxial fibers exhibited high maximum elongations at break (≈350%). EO-loaded fibers were effective against S. aureus, S. epidermidis, E. coli and P. aeruginosa, the most common bacteria present in CWs. Results confirmed the potential of the engineered coaxial wet-spun fibers for wound healing applications. Still, further characterization on the fibers is necessary, including cytocompatibility tests to assure non-toxic profiles of the fibers when in contact with fibroblasts and keratinocytes.

Deciphering Phosphodiesterase-5 Inhibitors from Aframemum melegueta: Computational Models against Erectile dysfunction

Damilola A. Omoboyowa^1* and Damilola S. Bodun

¹Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria

^*Corresponding Author e-mail: damilola.omoboyowa@aaua.edu.ng

Abstract

Insufficient and inability to maintain erection in male for satisfactory sexual performance remains global challenge among couples. The identification of phosphodiesterase-5 (PDE-5) antagonist in the pathogenesis of erectile dysfunction has improved the search for therapeutic agents for the management of this sexual dysfunction. Here in, bioactive compounds from Aframomum melegueta were virtually screened against PDE-5 using Schrodinger suite 2017-1 as computational tool. The lead compound was further validated in comparison with Viagra by performing 100 ns molecular dynamics (MD) simulation using Desmond. Among 109 bioactive compounds screened, nine (9) molecules were predicted as potent inhibitors of PDE-5 with binding affinities comparable to the co-crystalized ligand (sildenafil). 1,7-bis(3,4-dihyroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate was observed to have the best docking score (-11.522 kcal/mol) among the hit compounds which is very close to the co-crystalized ligand (-11.872 kcal/mol). Validation using pharmacophore hypothesis and QSAR modeling further confirmed the prediction of the hit compounds with fitness score ranging from 0.754 to 2.605 and predicted pIC50 of 3.835 to 7.976 µM. All the hit compounds obeyed Lipinski’s rule of five and within the reference range of the pharmacokinetics parameters. The MD simulation result predicted the stability of 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate-PDE-5 complex comparable to the sildenafil-PDE-5 complex. The outcome of this study predicted nine molecules from A. melegueta as potent PDE-5 antagonists which required isolation and experimental validation for the management of erectile dysfunction.

Colorants, in paricular, carminic acid and indigotine are widely used in pharmaceutical industry. High concentration of these colorants affect human health that require a control of their content in pharmaceutical dosage forms. In current work, novel voltametric sensors based on glassy carbon electrodes modified with selenium dioxide nanoparticles dispersed in surfactant media have been developed for the determination of carminic acid and indigotine. Combination of selenium dioxide nanoparticles with surfactant media provides stabilization of nanoparticles dispersion by suppression of their aggregation as well as action of the surfactant as a co-modifier of the electrode surface, i.e. as a part of sensing layer of the electrode. The effect of surfactant nature (cationic, nonionic, and anionic) and concentration on the colorants' voltammetric characteristics has been investigated. The best response of colorants has been obtained in the case of selenium dioxide nanoparticles dispersed in cationic surfactants (0.10 mM cetyltriphenylphosphonium bromide for carminic acid and 1.0 mM cetylpyridinium bromide for indigotine). The sensors developed have been used under conditions of differential pulse voltammetry in acidic medium. A linear dynamic ranges of 0.010‒2.5 and 2.5‒10 μM of carminic acid and 0.025–1.0 and 1.0–10 µM of indigotine with the detection limits of 3.4 and 4.3 nM, respectively, have been achieved that are the best ones among the methods reported to date. Another advantage of the sensors developed is a simple one-step fabrication as well as easy and fast preparation of the modifier. Sensors have been successfully applied in the analysis of pharmaceutical dosage forms (vitamin tablets, capsules, and lozenges for sore throat treatment) and validated with spectrophotometry. The direct analysis of colorants in various pharmaceutical dosage forms confirms versatility of the sensors developed that can be used as an alternative method for the quality control of the pharmaceutical products.

This study aimed to evaluate the inhibitory potential of Ginkgo biloba polyphenols against colorectal cancer biomarkers through in-silico analysis. The biomarkers investigated included KRAS-G12D, BRAF-V600E, PIK3CA-E545K, NRAS-Q61K, and DCC-T315I, which are commonly associated with colorectal cancer. In-silico docking simulations were conducted using the MOE software to assess the affinity of Ginkgo biloba polyphenols for the active sites of the mutant codons. A total of 152 ligands were docked, and their interactions and docking scores were analyzed. The results revealed significant inhibitory potential of Ginkgo biloba polyphenols against the mutant codons under investigation. Ligands such as quercetin-3-O-6''-rhamnosyl-2''-(6'''-p-coumaroylglucosyl)glucoside (L15), quercetin 3-O-[2-{6'-(7''''-O-glucosyl)-trans-p-coumaroyl)}-glucosyl]-rhamnoside (L17), and isorhamnetin-3-O-alpha-L-rhamnosyl-2''-(6'''-p-coumaroyl)-beta-D-glucoside (L47) demonstrated promising therapeutic potential. These ligands exhibited multi-targeting effects by interacting with multiple mutant codons simultaneously. L15 interacted with BRAF-V600E and PIK3CA-E545K, L17 targeted BRAF-V600E and DCC-T315I, and L47 showed affinity for both KRAS-G12D and PIK3CA-E545K. The findings suggest that Ginkgo biloba polyphenols, including L15, L17, and L47, have potential as therapeutic agents against colorectal cancer mutant codons. Their multi-targeting effects offer new opportunities for therapeutic development. Further investigations are needed to fully explore the therapeutic potential of these natural compounds and their application in cancer treatment. Overall, this in-silico study provides valuable insights into the inhibitory potential of Ginkgo biloba polyphenols against colorectal cancer biomarkers. The findings contribute to the field of natural compound-based cancer therapeutics and highlight the significance of multi-targeting approaches in developing effective treatments for complex diseases.

Small molecule compounds which interact with the tubulin-microtubule system are recognized as one of the major clinical options for cancer treatment such taxol and vincristine. The stilbene Combretastatin A-4 (CA-4) demonstrates potent anticancer activity in human cancer cells together with inhibition of tubulin polymerisation and antivascular effects. We report the synthesis of a panel of nineteen conformationally restricted 1,4-diaryl-2-azetidinones containing the 3,5-dimethoxyphenyl substituent at N-1 replacing the characteristic 3,4,5-trimethoxyphenyl Ring A of CA-4, together with phenyl, chloro, hydroxyl, phenoxy substituents at C-3. X-Ray crystallographic studies determined the specific structural features of selected compounds together with the role of the novel 3,5-dimethoxyphenyl Ring A interactions with the colchicine tubulin binding site residues.

The effect of these compounds on cancer cell proliferation was determined in vitro with the 3-hydroxyl, 3-phenoxy and 3-unsubstituted compounds identified as the most potent examples, having IC50 values of 3-25 nM in MCF-7 human breast cancer and 8-25 nM in chemoresistant HT-29 colon cancer cells which compare favourably with control CA-4. Low levels of in vitro cytotoxicity was confirmed for the novel β-lactams in MCF-7 cells using the lactate dehydrogenase (LDH) assay (< 3.5% cell death observed). The interactions of the methoxy groups at C-3 and C-5 of Ring A with key hydrophobic tubulin binding site residues Valβ318, Cysβ241, Alaβ354, Alaβ316, Alaβ317, Leuβ242, Valβ238 and Ileβ378 are explored to provide binding stabilisation. The structural study of these compounds will facilitate further design of more effective and diverse β-lactams for potential development in breast and chemoresistant colon cancer applications.

Breast, cervical and colorectal cancers are the most common female cancer types world-wide. One important approach in the search for chemotherapeutic agents is the combination of different building blocks, fragments from known drugs, leading structures, or "hit" structures into a single molecule. This strategy involves creating hybrid compounds that aim to achieve a synergistic effect and enhanced efficacy compared to the individual starting compounds [1].

The main aim of this research was to synthesize new N-(4-acryloylphenyl)-2,4-dichloro-5-sulfamoylbenzamide derivatives with potential anticancer activity. The compounds were designed as molecular hybrids, incorporating fragments of chalcone and benzenesulfonamide. The structures of the compounds were confirmed using elemental analysis, spectroscopic techniques such as (IR, ¹H NMR, ¹³C NMR), and mass spectrometry.

MTT assays were performed on three cancer cell lines: MCF-7 (breast cancer), HCT-116 (colorectal cancer), and HeLa (cervical cancer). Results showed that all compounds 6-9 and 11-13 are highly active against all three cell lines and their IC₅₀ are between 3 µM to 13 µM. The highest sensitivity shows HCT-116 cell line with IC₅₀ values from 3 µM to 4 µM for all tested compounds. The highest cytotoxic activity present 8 and 11 with IC₅₀ = 3 µM. Activity of compounds 6-9 and 11-13 is also high against cell lines MCF-7 and HeLa with IC₅₀ = 4.5‒9 µM (MCF-7) and IC₅₀ = 4‒13 µM (HeLa). Compound 9 shows the best results with average IC₅₀ = 4 µM.

[1] Fortin S, et al. Expert Opin. Drug. Discov. 2013, 8, 1029–1047.

Objective: Animal welfare is a growing concern and the well-being of animals used for scientific and educational purposes is under detailed analysis. This work aimed to monitor the welfare of a rat model of mammary cancer chemically-induced fed with a western diet (WD) during resistance training.

Methods: Twenty-eight female Wistar rats were randomly divided into four groups: WD; WD+N-methyl-N-nitrosourea (MNU); WD+Exercised (EX); WD+MNU+EX. MNU groups received an intraperitoneal injection of carcinogen MNU (50mg/Kg), at seven weeks of age. Water and food (WD with 60% of total calories coming from fat) were supplied ad libitum. Exercised animals performed a resistance training by climbing a 1-meter-hight homemade ladder. For each session they made 4-8 climbs and 8-12 dynamic movements for each climb. Animals were trained 3 days/week for 18 consecutive weeks. All animals were observed every day and the following parameters was checked every week: food and water intake, body condition and weight, coat and grooming, posture, mucosal, eyes, ears and whiskers, response to external stimuli, mental status, respiratory and heart rate, hydration status, body temperature, and tumors’ location, macroscopic evaluation, and burden. A score from 0 to 3 was attributed to each parameter. Data were compared using SPSS.

Results: At the 5^th week of the experiment, we noticed a statistically non-significant change in body weight on two animals from WD+MNU group (p>0.05). No significant alterations were recorded until 10^th week of the experiment, in which animals from WD+MNU+EX group exhibited a significant lack of grooming compared with other groups (p=0.00). After this week, animals from all groups began to show lack of grooming, without statistically significant differences among groups (p>0.05).

Conclusions: It is crucial to implement humane endpoints in experimental protocols to lessen the distress, discomfort and pain experienced by animals. The initial body weight change can be due to the stress caused by the adaptation to the lab conditions. The lack of grooming in WD groups may be related to the increase of the coat oiliness due to the high fat content of WD diet.