Exploring the aroma profile and biomedical applications of Scutellaria nuristanica Rech. F.: A new insight as a natural remedy.

BACKGROUND: The Scutellaria genus has promising therapeutic capabilities as an aromatherapy. Based on that and local practices of S. nuristanica Rech. F. The essential oil was studied for the first time for its diverse biomedical applications. PURPOSE: This study aimed to evaluate and validate their therapeutic capabilities by screening the essential oil ingredients and examining their antimicrobial, antioxidant, carbonic anhydrase, and antidiabetic using further In silico assessment and In vivo anti-inflammatory and analgesic capabilities to devise novel sources as natural remedies alternative to the synthetic drugs. METHODS: Essential oil was obtained through hydrodistillation, and the constituents were profiled using GC-MS. The antimicrobial assessment was conducted using an agar well diffusion assay. Free radical scavenging capabilities were determined by employing DPPH and ABTS assay. The carbonic anhydrase-II was examined using colorimetric assay, while the antidiabetic significance was performed using α-Glucosidase assay. The anti-inflammatory significance was examined through carrageenan-induced paw edema, and the analgesic features of the essential oil were determined using an acetic acid-induced writhing assay. RESULTS: Fifty constituents were detected in S. nuristanica essential oil (SNEO), contributing 95.93 % of the total EO, with the predominant constituents being 24-norursa-3,12-diene (10.12 %), 3-oxomanoyl oxide (9.94 %), methyl 7-abieten-18-oate (8.85 %). SNEO presented significance resistance against the Gram-positive bacterial strains (GPBSs), Bacillus atrophaeus and Bacillus subtilis, as compared to the Salmonella typhi and Klebsiella pneumoniae, Gram-negative bacterial strains (GNBSs) as well as two fungal strains Aspergillus parasiticus and Aspergillus niger associated with their respective standards. Considerable free radical scavenging capacity was observed in DPPH compared to the ABTS assay when correlated with ascorbic acid. In addition, when equated with their standards, SNEO offered considerable in vitro carbonic anhydrase II and antidiabetic capabilities. Additionally, the antidiabetic behavior of the 9 dominant compounds of SNEO was tested via In silico techniques, such as molecular docking, which assisted in the assessment of the significance of binding contacts of protein with each chemical compound and pharmacokinetic evaluations to examine the drug-like characteristics. Molecular dynamic simulations at 100 ns and binding free energy evaluations such as PBSA and GBSA models explain the molecular mechanics and stability of molecular complexes. It was also observed that SNEO depicted substantial anti-inflammatory and analgesic capabilities. CONCLUSION: Hence, it was concluded that the SNEO comprises bioactive ingredients with biomedical significance, such as anti-microbial, antioxidant, CA-II, antidiabetic, anti-inflammatory, and analgesic agents. The computational validation also depicted that SNEO could be a potent source for the discovery of anti-diabetic drugs.

Disrupting protease and deubiquitinase activities of SARS-CoV-2 papain-like protease by natural and synthetic products discovered through multiple computational and biochemical approaches.

The single-stranded RNA genome of SARS-CoV-2 encodes several structural and non-structural proteins, among which the papain-like protease (PLpro) is crucial for viral replication and immune evasion and has emerged as a promising therapeutic target. The current study aims to discover new inhibitors of PLpro that can simultaneously disrupt its protease and deubiquitinase activities. Using multiple computational approaches, six compounds (CP1-CP6) were selected from our in-house compounds database, with higher docking scores (-7.97 kcal/mol to -8.14 kcal/mol) and fitted well in the active pocket of PLpro. Furthermore, utilizing microscale molecular dynamics simulations (MD), the dynamic behavior of selected compounds was studied. Those molecules strongly binds at the PLpro active site and forms stable complexes. The dynamic motions suggest that the binding of CP1-CP6 brought the protein to a closed conformational state, thereby altering its normal function. In an in vitro evaluation, CP2 showed the most significant inhibitory potential for PLpro (protease activity = 2.71 ± 0.33 µM and deubiquitinase activity = 3.11 ± 0.75 µM), followed by CP1, CP5, CP4 and CP6. Additionally, CP1-CP6 showed no cytotoxicity at a concentration of 30 µM in the human BJ cell line.

Design, synthesis, and in vitro and in silico studies of morpholine derived thiazoles as bovine carbonic anhydrase-II inhibitors.

Carbonic anhydrase CA-II enzyme is essential for maintaining homeostasis in several processes, including respiration, lipogenesis, gluconeogenesis, calcification, bone resorption, and electrolyte balance due to its vital function within cellular processes. Herein, we screened 25 newly synthesized thiazole derivatives and assessed their inhibitory potential against the zinc-containing carbonic anhydrase CA-II enzyme. Intriguingly, derivatives of thiazole exhibited varying degrees of inhibitory action against CA-II. The distinctive attribute of these compounds is that they can attach to the CA-II binding site and block its action. Morpholine based thiazoles can be strategically modified to improve bovine CA-II inhibitor binding affinity, selectivity, and pharmacokinetics. Thiazole and morpholine moieties can boost inhibitory efficacy and selectivity over other calcium-binding proteins by interacting with target bovine CA-II binding sites. The derivatives 23-26 exhibited greater affinity when compared to the standard acetazolamide. Furthermore, kinetic study of the most potent compound 24 was performed, which exhibited concentration dependent inhibition with a K i value of 9.64 ± 0.007 µM. Molecular docking, MD simulation and QSAR analysis was also carried out to elucidate the interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, pharmacokinetic assessments showed that most of the compounds possess attributes conducive to potential drug development.

Exploring the Anticancer Potential of Astragalin in Triple Negative Breast Cancer Cells by Attenuating Glycolytic Pathway through AMPK/mTOR.

BACKGROUND: Aerobic glycolysis is crucial for cancer cells to survive, grow, and progress. In the current study, the anti-cancer effects of astragalin (ASG) on breast cancer cells and in the glycolytic pathway through AMPK/mTOR have been evaluated. OBJECTIVE: The objective of this study was to examine the impact of ASG, a natural flavonoid, on glycolysis via targeting AMPK/mTOR signalling in MDA-MB-231 breast cancer cells. METHOD: The study utilized ASG, which was isolated from Haplophyllum tuberculatum. The cells were treated with different concentrations of ASG (20 and 40 µg/mL), and anti- glycolytic activities were measured through cell proliferation, expression of glycolytic enzymes (HK-2, LDH-A, GLUT-1), glucose uptake, and lactate concentration assays. The MTT assay was used to assess cellular proliferation, while the glucose uptake and lactate levels were determined by employing colorimetric assays. The mRNA expression of target glycolytic enzymes was determined by qRT-PCR. The protein levels of glycolytic targets, as well as that of AMPK and mTOR, were determined by western blot. in silico docking of ASG was done with mTOR and AMPK proteins. RESULT: Astragalin exhibited dose- and time-dependent anti-proliferative effects in MDA-MB-231 cells. In breast cancer cells, the mRNA and protein expression of GLUT-1, LDH-A, and HK-2 were all significantly downregulated after receiving ASG treatments. Furthermore, after ASG treatments, MDA-MB231 cells showed a significant decrease in lactate and glucose uptake compared to control cells. Mechanistically, ASG increased AMPK activation and suppressed mTOR activation in these cells. The inhibitory role of ASG on aerobic glycolysis was prevented by treatments with compound C (an AMPK inhibitor). However, combined treatment of compound C and ASG could nullify the ASG-induced anti-glycolysis effect and restore the level of p-AMPK and p-mTOR in MDA-MB231 cells. The results from molecular docking predicted that ASG had the potential to bind AMPK and mTOR, with free energy for binding, -8.2 kcal/mol and -8.1 kcal/mol, respectively. CONCLUSION: Taken together, the findings from this study indicated that ASG might modulate the AMPK/mTOR pathway to inhibit aerobic glycolysis and proliferation of MDAMB231 breast cancer.

Phytoconstituents with cardioprotective properties: A pharmacological overview on their efficacy against myocardial infarction.

Myocardial infarction (MI) is considered one of the most common cardiac diseases and major cause of death worldwide. The prevalence of MI and MI-associated mortality have been increasing in recent years due to poor lifestyle habits viz. residency, obesity, stress, and pollution. Synthetic drugs for the treatment of MI provide good chance of survival; however, the demand to search more safe, effective, and natural drugs is increasing. Plants provide fruitful sources for powerful antioxidant and anti-inflammatory agents for prevention and/or treatment of MI. However, many plant extracts lack exact information about their possible dosage, toxicity and drug interactions which may hinder their usefulness as potential treatment options. Phytoconstituents play cardioprotective role by either acting as a prophylactic or adjuvant therapy to the concurrently used synthetic drugs to decrease the dosage or relief the side effects of such drugs. This review highlights the role of different herbal formulations, examples of plant extracts and types of several isolated phytoconstituents (phenolic acids, flavonoids, stilbenes, alkaloids, phenyl propanoids) in the prevention of MI with reported activities. Moreover, their possible mechanisms of action are also discussed to guide future research for the development of safer substitutes to manage MI.

Synthesis and Enzymatic Evaluation of a Small Library of Substituted Phenylsulfonamido-Alkyl Sulfamates towards Carbonic Anhydrase II.

A small library of 79 substituted phenylsulfonamidoalkyl sulfamates, 1b-79b, was synthesized starting from arylsulfonyl chlorides and amino alcohols with different numbers of methylene groups between the hydroxyl and amino moieties yielding intermediates 1a-79a, followed by the reaction of the latter with sulfamoyl chloride. All compounds were screened for their inhibitory activity on bovine carbonic anhydrase II. Compounds 1a-79a showed no inhibition of the enzyme, in contrast to sulfamates 1b-79b. Thus, the inhibitory potential of compounds 1b-79b towards this enzyme depends on the substituent and the substitution pattern of the phenyl group as well as the length of the spacer. Bulkier substituents in the para position proved to be better for inhibiting CAII than compounds with the same substituent in the meta or ortho position. For many substitution patterns, compounds with shorter spacer lengths were superior to those with long chain spacers. Compounds with shorter spacer lengths performed better than those with longer chain spacers for a variety of substitution patterns. The most active compound held inhibition constant as low as Ki = 0.67 µM (for 49b) and a tert-butyl substituent in para position and acted as a competitive inhibitor of the enzyme.

Synthesis, biological evaluation, and molecular modelling of substituted thiazolyl thiourea derivatives: A new class of prolyl oligopeptidase inhibitors.

Prolyl oligopeptidase (POP) is a compelling therapeutic target associated with aging and neurodegenerative disorders due to its pivotal role in neuropeptide processing. Despite initial promise demonstrated by early-stage POP inhibitors, their progress in clinical trials has been halted at Phase I or II. This impediment has prompted the pursuit of novel inhibitors. The current study seeks to contribute to the identification of efficacious POP inhibitors through the design, synthesis, and comprehensive evaluation (both in vitro and in silico) of thiazolyl thiourea derivatives (5a-r). In vitro experimentation exhibited that the compounds displayed significant higher potency as POP inhibitors. Compound 5e demonstrated an IC50 value of 16.47 ± 0.54 µM, representing a remarkable potency. A meticulous examination of the structure-activity relationship indicated that halogen and methoxy substituents were the most efficacious. In silico investigations delved into induced fit docking, pharmacokinetics, and molecular dynamics simulations to elucidate the intricate interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, our pharmacokinetic assessments confirmed that the majority of the synthesized compounds possess attributes conducive to potential drug development.

Antimicrobial topical polymeric films loaded with Acetyl-11-keto-ß-boswellic acid (AKBA), boswellic acid and silver nanoparticles: Optimization, characterization, and biological activity.

The study examined the antimicrobial and antioxidant potential of pure Acetyl-11-keto-ß-boswellic acid (AKBA), boswellic acid (70%) and AKBA loaded nanoparticles as topical polymeric films. The optimized concentration (0.05 % w/v) of pure AKBA, boswellic acid (BA), and AKBA loaded silver nanoparticles were used to study its impact on film characteristics. Carboxymethyl cellulose (CMC), sodium alginate (SA), and gelatin (Ge) composite films were prepared in this study. The polymeric films were evaluated for their biological (antioxidant and antimicrobial activities) and mechanical characteristics such as tensile strength (TS) and elongation (%). Moreover, other parameters including water barrier properties and color attributes of the film were also evaluated. Furthermore, assessments were conducted using analytical techniques like FTIR, XRD, and SEM. Surface analysis revealed that AgNP precipitation led to a few particles in the film structure. Overall, the results indicate a relatively consistent microstructure. Moreover, due to the addition of AKBA, BA, and AgNPs, a significant decrease in TS, moisture content, water solubility, and water vapor permeation was observed. The films transparency also showed a decreasing trend, and the color analysis revealed decreasing yellowness (b*) of the films. Importantly, a significant increase in antioxidant activity against DPPH free radicals and ABTS cations was observed in the CSG films. Additionally, the AgNP-AKBA loaded films displayed significant antifungal activity against C. albicans. Moreover, the molecular docking analysis revealed the inter-molecular interactions between the AKBA, AgNPs, and composite films. The docking results indicate good binding of AKBA and silver nanoparticles with gelatin and carboxymethyl cellulosemolecules. In conclusion, these polymeric films have potential as novel materials with significant antioxidant and antifungal activities.

An efficient and practical approach for the synthesis of indoloquinolines and indolo/pyrroloquinoxalines via a Cu-catalyzed Ugi-C/Ugi-N-arylation sequence.

A Cu-catalyzed tandem transformation of Ugi adducts through CH/NH bond functionalization reactions was reported for synthesizing a broad spectrum of indolo/pyrrolo-[1,2-a]quinoxaline-6/4-carboxamide, 7H-indolo[2,3-c]quinoline-6-carboxamide, and 1-(cyclohexylamino)-14H-indolo[2,3-c][1,4]oxazino[4,3-a]quinolin-4(3H)-one derivatives in moderate to excellent yields. In this protocol the Ugi condensation of aromatic aldehydes, anilines, acids, and isocyanides leads to the formation of bis-amides in methanol at room temperature. This approach employed simple reaction conditions, including Ugi product as starting material, CuI, l-proline as a ligand, and cesium carbonate, in DMSO for 8 h. This method demonstrated efficiency in synthesizing fused-nitrogen-containing heterocycles through a convenient pathway.

Drug Release and Stability Study of Innovated Losartan Potassium and Rosuvastatin Calcium Fixed-dose Combination Tablet.

BACKGROUND: Patient adherence to therapy and compliance is always a challenge for care providers in the management of chronic disorders with multiple medications. OBJECTIVE: Our study focused on formulating concurrently prescribed ARB (Angiotensin Receptor Blocker), i.e., losartan potassium, and a cholesterol-lowering statin derivative, i.e., rosuvastatin calcium, in a fixed-dose combination tablet. METHODS: The drugs were selected based on the presence of synergism and variation in solubility characteristics. Trial batches with fixed concentrations of both active pharmaceutical ingredients (APIs) and varying quantities of different excipients were prepared by dry granulation technique and subjected to different quality control tests for tablets. Batch F5 was selected on the basis of in-process quality control data for the development of a drug release protocol. Experimental conditions were optimized. Based on the sink condition, phosphate buffer (pH 6.8) was selected as the dissolution medium. Simultaneous determination of both APIs in samples collected at predetermined time intervals was carried out using the RP-HPLC technique with acetonitrile, methanol, and water (20:25:55 v/v/v) as mobile phase. RESULTS: Complete dissolution of both APIs in the FDC tablet was achieved in 45 min in 900 mL of the selected medium. The in vitro drug release protocol was validated for accuracy and precision without interference with sample analysis. CONCLUSION: In this study, a validated, accurate, and robust dissolution testing method was developed for the newly formulated FDC tablet.

Synthesis, Characterization, and Stability Optimization of Ibuprofen Cocrystals eEploying Various Hydrophilic Polymers.

BACKGROUND: Cocrystals are an efficient way for the delivery of low soluble drugs but when dissolved they rapidly disproportionate. To formulate the cocrystals in tablets, cocrystals must be stabilized. In this study ibuprofen-nicotinamide (IBU-NIC) cocrystals were synthesized initially by slow solvent evaporation and for bulk production by fast solvent evaporation techniques. METHOD: The cocrystals were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectrophotometer (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and optical microscopy. The ibuprofen cocrystals showed greater solubility compared to the parent drug. RESULT: Intrinsic dissolution data was utilized for efficacious screening of tablet formulations. Using hydrophilic polymers at a ratio of 6:1 (polymer to IBU-NIC cocrystal ratio), hydroxypropyl methylcellulose (F1), polyvinylpyrrolidone (PVP) K-30 (F2) and PVP K-90 (F3), three tablet formulations were prepared that stabilized cocrystals during dissolution. The drug release profiles after 60 minutes from formulations F1 (92.30), F2 (98.54), F3 (99.88) were all higher compared to the marketed brand BRUFEN® F, (79.61%) in a simulated intestinal media (p<0.001). CONCLUSION: Significant increase in the dissolution rate of cocrystal was observed with no phase change in all formulations.

Genetic characterization and phylogenetic analysis of the Nigella sativa (black seed) plastome.

In this study, the complete plastome sequence of Nigella sativa (black seed), was analyzed for the first time. The plastome spans approximately 154,120 bp, comprising four sections: the Large Single-Copy (LSC) (85,538 bp), the Small Single-Copy (SSC) (17,984 bp), and two Inverted Repeat (IR) regions (25,299 bp). A comparative study of N. sativa's plastome with ten other species from various genera in the Ranunculaceae family reveals substantial structural variations. The contraction of the inverted repeat region in N. sativa influences the boundaries of single-copy regions, resulting in a shorter plastome size than other species. When comparing the plastome of N. sativa with those of its related species, significant divergence is observed, particularly except for N. damascena. Among these, the plastome of A. glaucifolium displays the highest average pairwise sequence divergence (0.2851) with N. sativa, followed by A. raddeana (0.2290) and A. coerulea (0.1222). Furthermore, the study identified 12 distinct hotspot regions characterized by elevated Pi values (> 0.1). These regions include trnH-GUG-psbA, matK-trnQ-UUG, psbK-trnR-UCU, atpF-atpI, rpoB-psbD, ycf3-ndhJ, ndhC-cemA, petA-psaJ, trnN-GUU-ndhF, trnV-GAC-rps12, ycf2-trnI-CAU, and ndhA-ycf1. Approximately, 24 tandem and 48 palindromic and forward repeats were detected in N. sativa plastome. The analysis revealed 32 microsatellites with the majority being mononucleotide repeats. In the N. sativa plastome, phenylalanine had the highest number of codons (1982 codons), while alanine was the least common amino acid with 260 codons. A phylogenetic tree, constructed using protein-coding genes, revealed a distinct monophyletic clade comprising N. sativa and N. damascene, closely aligned with the Cimicifugeae tribe and exhibiting robust support. This plastome provides valuable genetic information for precise species identification, phylogenetic resolution, and evolutionary studies of N. sativa.

Synthesis of organic solvent-free nitrogen-doped carbon quantum dots as unique green fluorimetric probes for analysis of abrocitinib in human plasma.

Atopic dermatitis (AD) is a persistent, inflammatory skin condition that impacts approximately 15 to 20% of children and 1 to 3% of adults globally. Common skin manifestations include papules, papulovesicular, and brown or red patches with swelling, crusting, and flaking. Therefore, the drug abrocitinib (ABR) was approved by the US FDA as an oral treatment for atopic dermatitis. The present study outlines the development of innovative, thermostable, and pH-stable organic solvent-free nitrogen-doped carbon dots (N@CQDs) synthesized through a one-step method for evaluating ABR with a notable quantum yield of 33.84% to minimize the use of organic solvents. Their cost-effectiveness, eco-friendly characteristics, and outstanding photocatalytic properties have established them as a promising alternative to conventional luminescent techniques like fluorescent dyes and luminous derivatization technique. The reaction of ABR with N@CQDs led to a significant decrease in the luminescent response of the produced green and stable carbon quantum dots at 513 nm. The detection range was determined to be 1.0-150.0 ng mL-1, with a lower limit of quantitation (LOQ) equal to 0.52 ng mL-1 based on the linear graph. The green method effectively used for analysis of ABR in pharmaceutical tablets and pharmacokinetic study with high sensitivity.

Identification of therapeutic drug target of Shigella Flexneri serotype X through subtractive genomic approach and in-silico screening based on drug repurposing.

Shigellosis, induced by Shigella flexneri, constitutes a significant health burden in developing nations, particularly impacting socioeconomically disadvantaged communities. Designated as the second most prevalent cause of diarrheal illness by the World Health Organization (WHO), it precipitates an estimated 212,000 fatalities annually. Within the spectrum of S. flexneri strains, serotype X is notably pervasive and resilient, yet its comprehensive characterization remains deficient. The present investigation endeavors to discern potential pharmacological targets and repurpose existing drug compounds against S. flexneri serotype X. Employing the framework of subtractive genomics, the study interrogates the reference genome of S. flexneri Serotype X (strain 2,002,017; UP000001884) to delineate its proteome into categories of non-homologous, non-paralogous, essential, virulent, and resistant constituents, thereby facilitating the identification of therapeutic targets. Subsequently, a screening of approximately 9000 compounds from the FDA library against the identified drug target aims to delineate efficacious agents for combating S. flexneri serotype X infections. The application of subtractive genomics methodology yields prognostic insights, unveiling non-paralogous proteins (n = 4122), non-homologues (n = 1803), essential (n = 1246), drug-like (n = 389), resistant (n = 167), alongside 42 virulent proteins within the reference proteome. This iterative process culminates in the identification of Serine O-acetyltransferase as a viable drug target. Subsequent virtual screening endeavors to unearth FDA-approved medicinal compounds capable of inhibiting Serine O-acetyltransferase. Noteworthy candidates such as DB12983, DB15085, DB16098, DB16185, and DB16262 emerge, exhibiting potential for mitigating S. flexneri Serotype X. Despite the auspicious findings, diligent scrutiny is imperative to ascertain the efficacy and safety profile of the proposed drug candidates vis-à-vis S. flexneri.

Effects of life-story review on quality of life, depression, and life satisfaction in older adults in Oman: a randomized controlled study.

BACKGROUND: There is a need for healthcare providers to develop life-story review interventions to enhance the mental well-being and quality of life of older adults. The primary aim of this study is to examine the effects of telling their life stories and creating a life-story book intervention on QoL, depressive symptoms, and life satisfaction in a group of older adults in Oman. METHODS: A repeated-measures randomized controlled design was conducted in Oman. A total of 75 older adults (response rate = 40.1%) were randomly assigned to the intervention (n = 38) or control (n = 37) groups. Demographic data were collected as the baseline. Depression, life satisfaction, and quality of life scores were collected from each participant at weeks 1, 2, 3, 4, and 8. RESULTS: Their average age is 67.3 ± 5.5 years (range 60-82 years). There are more women (n = 50, 66.7%) than men. Over the 8 weeks, the intervention group exhibited a notable decrease in depression (intervention: 2.5 ± 1.2 vs. control: 5.3 ± 2.1, p < .001) but an increase in life satisfaction (24.6 ± 3.1 vs. 21.9 ± 6.1, p < .001) and quality of life (physical: 76.2 ± 12.7 vs. 53.6 ± 15.5, p < .001; psychological: 76.4 ± 12.1 vs. 59.9 ± 21.5, p < .001; Social relation: 78.3 ± 11.7 vs. 61.8 ± 16.6, p < .001; environment: 70.8 ± 10.2 vs. 58.6 ± 16.1, p < .001) compared to the control group. CONCLUSION: The life-story review intervention proved effective in diminishing depression and boosting life satisfaction and quality of life among the older sample within the 8-week study. Healthcare providers can apply such interventions to improve older adults' mental health and well-being.

Verapamil-Loaded Cubosomes for Enhancing Intranasal Drug Delivery: Development, Characterization, Ex Vivo Permeation, and Brain Biodistribution Studies.

Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high Er value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.

Design, synthesis, molecular docking study, and α-glucosidase inhibitory evaluation of novel hydrazide-hydrazone derivatives of 3,4-dihydroxyphenylacetic acid.

A series of novel Schiff base derivatives (1-28) of 3,4-dihydroxyphenylacetic acid were synthesized in a multi-step reaction. All the synthesized Schiff bases were obtained in high yields and their structures were determined by 1HNMR, 13CNMR, and HR-ESI-MS spectroscopy. Except for compounds 22, 26, 27, and 28, all derivatives show excellent to moderate α-glucosidase inhibition. Compounds 5 (IC50 = 12.84 ± 0.52 µM), 4 (IC50 = 13.64 ± 0.58 µM), 12 (IC50 = 15.73 ± 0.71 µM), 13 (IC50 = 16.62 ± 0.47 µM), 15 (IC50 = 17.40 ± 0.74 µM), 3 (IC50 = 18.45 ± 1.21 µM), 7 (IC50 = 19.68 ± 0.82 µM), and 2 (IC50 = 20.35 ± 1.27 µM) shows outstanding inhibition as compared to standard acarbose (IC50 = 873.34 ± 1.67 µM). Furthermore, a docking study was performed to find out the interaction between the enzyme and the most active compounds. With this research work, 3,4-dihydroxyphenylacetic acid Schiff base derivatives have been introduced as a potential class of α-glucosidase inhibitors that have remained elusive till now.

Muscle relaxant and antipyretic effects of pentacyclic triterpenes isolated from the roots of Diospyros lotus L.

The present article describes the muscle relaxant and antipyretic effects of pentacyclic triterpenes, oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) isolated from roots of Diospyros lotus in animal models. The muscle relaxant effects of isolated pentacyclic triterpenes were determined by chimney and inclined plane tests. In the chimney test, pretreatment of pentacyclic triterpenes evoked significant dose dependent influence on muscle coordination. When administered intraperitoneally (i.p.) to mice at 10 mg/kg for 90 min, OA, UA, and BA exhibited muscle relaxant effects of 66.72 %, 60.21 %, and 50.77 %, respectively. Similarly, OA, UA, and BA (at 10 mg/kg) illustrated 65.74 %, 59.84 % and 51.40 % muscle relaxant effects in the inclined plane test. In the antipyretic test, significant amelioration was caused by pretreatment of all compounds in dose dependent manner. OA, UA, and BA (at 5 mg/kg) showed 39.32 %, 34.32 % and 29.99 % anti-hyperthermic effects, respectively 4 h post-treatment, while at 10 mg/kg, OA, UA, and BA exhibited 71.59 %, 60.99 % and 52.44 % impact, respectively. The muscle relaxant effect of benzodiazepines is well known for enhancement of GABA receptors. There may exist a similar mechanism for muscle relaxant effect of pentacyclic triterpenes. The in-silico predicted binding pattern of all the compounds reflects good affinity of compounds with GABAA receptor and COX-2. These results indicate that the muscle relaxant and antipyretic activities of these molecules can be further improved by structural optimization.

One pot synthesis of 5-hydroxyalkylated thiadiazine thiones: Implication in pain management and bactericidal properties.

The synthesis of a new series of thiadiazine thiones including 5-(2-hydroxyethyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (1-5), 5-(2-hydroxypropyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (6-8), 3,5-dipropyl-1, 3, 5-thiadiazine-2-thione (9) and (2-(5-alkyl/aryl-6-thioxo-1, 3, 5-thiadiazine-3-yl) alkyl acetate/benzoate) (10-17) was accomplished via one pot reaction. The structures of the synthesized compounds were characterized through NMR and Mass spectrometry. The anti-nociceptive activity of compounds was performed on BALB/C mice by hot plate method, where compounds 3, 5 (50 µg/kg), and 8 (50, 100 µg/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time of 15, 30, and 60 min, while compounds 6 and 16 (100 µg/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time interval of 15 and 30 min. Compounds 1, 12-13, and 15 showed moderate activity. Among the tested hits, compounds 5 (17.3 ± 2.2), 11 (16.2 ± 2.1), and 8 (16.1 ± 2.1) showed significant anti-nociceptive potential. Molecular docking studies on the most active anti-nociceptive hits indicated that the activity might be attributed to the ability of the compounds to target µ-opioid receptor (µOR) effectively. Furthermore, compounds 14 and 11 showed anti-bacterial activity against Pseudomonas aeruginosa and MSRA with MIC of 40.97 and 54.77 µg/mL, respectively. In addition, the predicted ADMET profile of 5, 9, and 11 indicates that these molecules follow the drug-likeness criteria, and their activity can be enhanced through structural optimization.

Designing and Synthesis of Novel Fexofenadine-Derived Hydrazone-Schiff bases as Potential Urease Inhibitors: In-Vitro, Molecular Docking and DFT Investigations.

Thirteen novel hydrazone-Schiff bases (3-15) of fexofenadine were succesfully synthesized, structurally deduced and finally assessed their capability to inhibit urease enzyme (in vitro). In the series, six compounds 12 (IC50=10.19±0.16 µM), 11 (IC50=15.05±1.11 µM), 10 (IC50=17.01±1.23 µM), 9 (IC50=17.22±0.81 µM), 13 (IC50=19.31±0.18 µM), and 14 (IC50=19.62±0.21 µM) displayed strong inhibitory action better than the standard thiourea (IC50=21.14±0.24 µM), while the remaining compounds displayed significant to less inhibition. LUMO and HOMO showed the transferring of charges from molecules to biological transfer and MEP map showed the chemically reactive zone appropriate for drug action are calculated using DFT. AIM charges, non-bonding orbitals, and ELF are also computed. The urease protein binding analysis benefited from the docking studies.