Multidrug resistance (MDR) presents a significant challenge in modern pharmacotherapy, greatly diminishing the effectiveness of chemotherapeutic agents. A primary mechanism contributing to MDR is the overexpression of P-glycoprotein (P-gp), also known as MDR1, encoded by the ABCB1 gene, which hampers the success of cancer treatments. Plants from the Plectranthus genus (Lamiaceae) have been traditionally acknowledged for their diverse therapeutic applications. The principal diterpene from Plectranthus grandidentatus Gürke, 7α-acetoxy-6β-hydroxyroyleanone (Roy), has demonstrated anti-cancer properties against various cancer cell lines. Previously synthesized ester derivatives of Roy have shown improved binding affinity to P-gp. This study employs previously acquired in vitro data on the P-gp activity of Roy derivatives to develop a ligand-based pharmacophore model, highlighting critical features necessary for P-gp modulation. Utilizing this data, we predict the potential of five novel ester derivatives of Roy to modulate P-gp in vitro against resistant NCI-H460 cells. In silico structure-activity relationship (SAR) studies were conducted on 17 previously synthesized royleanone derivatives. A binary classification model was constructed, distinguishing inactive from active compounds, generating 11,016 Molecular Interaction Field (MIF) descriptors from structures optimized at the DFT theory level. After variable reduction and selection, 12 descriptors were chosen, resulting in a model with two latent variables (LV), using only 34.14% of the encoded information for calibration (LV1: 26.82%; LV2: 7.32%). The activity prediction of new derivatives suggested that four have a high likelihood of activity, which will be validated in future in vitro biological assays.

Alkaloids are naturally occurring metabolites with a wide variety of pharmacological activities and applications in science, particularly in medicinal chemistry as anti-inflammatory drugs. Since they could be labelled as active or inactive compounds against the inflammatory biological response, the aim of this work was the calibration of quantitative structure-activity relationships (QSARs) based on machine learning classifiers to predict anti-inflammatory activity on the basis of the molecular structures of alkaloids. The dataset of 100 alkaloids (58 active and 42 inactive) was retrieved from two systematic reviews. Molecules were properly curated and the molecular geometry of compounds was optimized by the semi-empirical method (PM3) to calculate molecular descriptors, binary fingerprints (extended-connectivity fingerprints and path fingerprints) and MACCS (Molecular ACCess System) structural keys. Then, we calibrated QSAR models based on well-known linear and non-linear machine learning classifiers, i.e., partial least squares discriminant analysis (PLSDA), random forests (RF), adaptive boosting (AdaBoost), k-nearest neighbors (kNN), N-nearest neighbors (N3) and binned nearest neighbors (BNN). For validation purposes, the dataset was randomly split into training set and test set in a proportion of 70/30. When using molecular descriptors, genetic algorithms-variable subset selection (GAs-VSS) were used for the supervised feature selection. During the calibration of the models, a five-fold venetian blinds cross-validation was used to optimize the classifier parameters and to control the presence of overfitting. The performance of the models was quantified by means of the non-error rate (NER) statistical parameter.

World is moving back towards the root of medical advancement which is Ayurveda, but the issue faced during Ayurvedic medicine development is that there is no specific guideline for formulation, development, quality assurance, defining the safety profile, and assuring the efficacy of the Ayurvedic formulation as for allopathic medicine. Due to the unavailability of data regarding particular target-based Efficacy or mechanism of action of particular ingredients. This research is based on performing standardization of Ayurvedic formulation i.e., Trikatu Churna using HPTLC Instrument and carrying out force degradation studies of the Churna extract by using Piperine and Quercetin as marker compound according to ICH guidelines Q1A (R2) and Q2R1). In-house Trikatu was compared to the marketed Trikatu for analyzing the concentration of piperine and Quercetin in the churna. The presence of these chemicals in churna was marked by comparing the Rf value with Marker compounds which was found to be 0.64 for piperine and 0.51 for Quercetin..Forced degradation data showed the loss in concentration of both pure marker compound and in house Trikatu Churna as well as marketed churna.Standardization was done and validated method for standardization and estimated the Stability profile of same. The wavelength is identified for both marker compound and degradation study showed that there was decrease in concentration of marker Compound both in house Trikatu churna and as well as marketed Churna . The use of Standardization for Ayurvedic formulation discussed and validated method is developed and the stability profile of the Trikatu churna is estimated.

Introduction

The problem of resistance to antibiotics is still persistent and requires special attention. While overuse and misuse of these medicines has been in progress for many years, numerous resistant strains have appeared. Even novel active molecules are not always able to cure the infections caused by them. Still, it is possible to design new potential antibiotics based on the known pharmacophores. Our investigation is aimed at synthesis and studies of antibacterial properties of hybridized fluoroquinolones (FQ).

Experimental part

The first stage of our investigation was related to docking studies, which revealed the promising molecules among C-7 and C-3 FQ derivatives. The initial starting molecules were ciprofloxacin and norfloxacin and their C-7 position was modified with 1,2,3-triazole moiety. A convenient synthetic procedure was developed.

Then, we studied modifications of C-3 position with arylsulfonyl moiety with hybridization of C-7 and N-1. Through these stages, methods of organic synthesis were used. The structures of the obtained compounds were determined using ¹H NMR, ¹³C NMR, LC/MS spectroscopy and X-Ray diffraction studies.

Results and discussions

Modification of starting compounds with 1,2,3-triazole moiety led to novel molecules with moderate antimicrobial and antifungal activities. As for C-3 substituted arylsulfonyl derivatives, they appeared to be less soluble and, therefore, their activity was a bit smaller than for the first group. For now, these investigations are still in progress.

Ketoprofen (Keto) is a representative of the group of non-steroidal anti-inflammatory drugs widely used in modern medical therapy. The intramolecular dynamics of Keto is of particular importance, since the mobility of its main structural fragments will be one of the key factors determining the efficiency of drug binding to the enzyme. Investigations of such processes taking into account the acid-base properties of Keto have not been carried out. Therefore, studying the intramolecular dynamics of Keto, considering its possible forms (molecular, anionic and ion-pair) is of current interest.

DFT calculations for molecular, anionic and ion-pair forms of Keto were performed at BP86/def2-TZVP level of theory using ORCA software. Experimental IR-spectra of the Keto and its sodium salt were recorded at room temperature on Nicolet iS5 FTIR spectrometer. A good agreement was obtained between the experimental and DFT-calculated vibrational frequencies of the investigated objects.

The intramolecular dynamics of the main structural fragments was investigated for the molecular, anionic and ion-pair forms of Keto. The most stable conformers were revealed for all considered forms and barriers of intramolecular rotation were estimated. It was shown that the structures of the studied forms of Keto are labile but characterized by different mobility. For all forms of Keto, the benzoyl fragment is characterized by the lowest mobility. The least labile is the anionic form of Keto. Dissociation of Keto leads to a decrease in the mobility of its structural fragments, and the formation of contact ion pairs reduces this effect.

The purpose of this work was to study the phytochemical screening, antioxidant and anti-inflammatory activity of extracts from the fruit of a Saharan plant of the Appiaceae family as well as their fractions. An extensive exploration is undertaken to investigate the phytochemical composition of extracts, with a particular focus on alkaloids, tannins, flavonoids, coumarins, and saponins. Phytochemical screening revealed the presence of alkaloids, tannins, and flavonoids within extracts, suggesting a rich reservoir of bioactive compounds. Quantification assays further confirmed the abundance of polyphenols and flavonoids, indicative of the extract's potential health-promoting properties. The result of the evaluation of the antioxidant activity revealed that the methanoic extract is endowed a very powerful antioxidant activity characterized by inhibitory concentrations of 50% of the DPPH free radical (IC50 = 0.2 mg/mL), which is better than that of BHT (IC50 = 0.5 mg/mL). While for anti-inflammatory activity, the results revealed that the methanoic extract has an activity (IC50 = 42.3 µg/mL) higher than that of diclofinac (IC50 = 83.3 µg/mL). Fractionation of the extract via column chromatography allowed for the isolation of distinct fractions, enhancing the concentration of bioactive constituents.In fact, these new findings could lead to powerful approaches for the development of new antioxidant and anti-inflammatory compounds.

Natural antioxidants found in plants, especially plant phenolics, are well-known for their ability to neutralize free radicals, acting as primary antioxidants. Daucus crinitus, a herbaceous plant from the Apiaceae family, has attracted considerable interest due to its potential medicinal properties, particularly its antioxidant and anti-inflammatory activities.

This study examined the antioxidant and anti-inflammatory activities of ethanolic extract from the aerial part of Daucus crinitus, using two specific assays: the DPPH assay and the Ferric Reducing Antioxidant Power assay.

The ethanolic extract demonstrated strong free radical scavenging activity, with an IC50 value of 0.56 mg/ml, indicating significant antioxidant potential.

The FRAP assay evaluates the reducing power of the extract by assessing its ability to convert ferric ions (Fe3+) to ferrous ions (Fe2+). The results indicated that the antioxidant power increased with higher concentrations of the extract.

The anti-inflammatory potential of the ethanolic extract was assessed using the albumin denaturation method, which evaluates the extract's ability to prevent protein denaturation. The extract exhibited a more modest anti-inflammatory effect compared to its antioxidant activity, with an IC50 value of 0.69 mg/ml, suggesting that higher doses may be necessary to achieve notable anti-inflammatory effects.

The ethanolic extract of Daucus crinitus shows impressive antioxidant properties, as highlighted by its strong performance in both the DPPH and FRAP assays. These results indicate that Daucus crinitus is a promising candidate for further research in the realm of natural antioxidants. Although its anti-inflammatory activity is relatively modest, the plant's considerable antioxidant capacity underscores its potential for medicinal applications.

Tyronamines are endogenous compounds formed from L-thyroxine or its intermediate metabolites by deiodination and decarboxylation. The biological activity of thyronamines is associated with an effect on the central nervous system, cardiovascular system, and metabolism. In the central nervous system, thyronamines exhibit properties as a neuromodulator of adrenergic and histaminergic neurons. Structural features of thyronamines and their synthetic analogues in solutions can be investigated using the possibilities of complementary experimental and computational NMR spectroscopy.

Molecular modeling of the structure and evaluation of chemical shifts of ¹H and ¹³C nuclei were performed for the 4-[4-(2-aminoethoxy)benzyl]aniline, that is a structural analogue of thyronamines. The intramolecular dynamics of the key structural fragments of 4-[4-(2-aminoethoxy)benzyl]aniline was studied by the PM6-DH2 method as well as at B3LYP/6-31G(d,p) level of theory. Nonspecific solvation with dimethyl sulfoxide was taken into account within the polarized continuum model IEFPCM. Chemical shifts of the ¹H and ¹³C nuclei were estimated for the basic conformers of 4-[4-(2-aminoethoxy)benzyl]aniline. Calculated chemical shifts of the ¹H and ¹³C nuclei are in good agreement with the experimental ones obtained for 4-[4-(2-aminoethoxy)benzyl]aniline in DMSO-d₆ solution. In general, B3LYP/6-31G(d,p) level of theory can be recommended for further DFT-studies of the structure and properties of 4-[4-(2-aminoethoxy)benzyl]aniline as well as related compounds.

Some aspects of bioactivity of the 4-[4-(2-aminoethoxy)benzyl]aniline is discussed.

β-Carboline alkaloids and its derivatives are a significant class of natural products and pharmaceutically important molecules, which display their anticancer activities via diverse mechanisms. Since last one decade, β-carboline analogs have attained interest as anti-cancer agents and have been extensively isolated, synthesized and tested against cancer cell line. β-carboline derivatives exhibit potent anti-cancer activity via diverse mechanisms such as interfering with enzymes like CDKs (cyclin-dependent kinases), IκB kinases TOPO-I and II, and intercalating DNA. Selected list anticancer β-carboline alkaloid and synthetic derivatives²⁷ are listed.

The present study designed and computationally optimized a series of novel β-carboline derivatives to investigate the interaction between designed ligands and selected proteins. Therefore, to find better intercalating agents, β-carboline was used as a basic skeleton, and a series of novel β-carboline derivatives with various aryl group groups at C-1 sites and an ethyl acetyl, benzyl group at N-9 position were designed. In silico docking, the study was performed to determine the maximum interaction between designed ligands and with protein 1pye CDK₂ inhibitor. The best binding post with a minimum energy of the designed ligand was selected for synthesis

The pyrido[3,4-β] indole β-carboline skeleton structure is broadly present in many naturally occurring alkaloids which display diverse and interesting medicinal activities. A few of the biologically important naturally occurring and synthetic β-carboline analogs are shown below:

Inflammation is a growing area of research and a target for intervention that is involved in the pathogenesis of several chronic diseases, such as rheumatoid arthritis, cardiovascular diseases and cancer. The chemical diversity of natural molecules and their derivatives has provided successful drugs for a wide range of diseases, including enzyme inhibitors and gene regulators, making natural products an excellent source of anti-inflammatory drugs. Among the biochemical mediators involved in inflammation, cyclooxygenases (COX) and lipoxygenases (LOX) stand out. COX-2, an inducible isoform of cyclooxygenase, is particularly important, as its expression associated to inflammatory processes and carcinogenesis. LOX, another key enzyme in the metabolism of arachidonic acid, contributes to the formation of leukotrienes, which are also part of the inflammatory response. Selective inhibition of these enzymes has been an effective strategy for developing anti-inflammatory agents with fewer side effects.

Benzo[a]phenoxazines, N-,O-heterocyclic compounds, have attracted attention due to their therapeutic potential, especially as anti-inflammatory and anti-cancer agents, besides promising pharmacological properties. They are known for their ability to inhibit the enzymatic activity of COX-2, which makes them favorable candidates for the treatment of inflammatory conditions.

This study investigates the anti-inflammatory properties of several benzo[a]phenoxazines, specifically assessing their potential as new inhibitors of COX-2 and LOX enzymes. Kinetic assay results revealed that these molecules significantly inhibited cyclooxygenase-2 (COX-2), highlighting their promise as potent anti-inflammatory agents.