Synthesis of calix (4) resorcinarene based amphiphilic macrocycle as an efficient nanocarrier for Amphotericin-B to enhance its oral bioavailability.

The supramolecular-based macrocyclic amphiphiles have fascinating attention and find extensive utilization in the pharmaceutical industry for efficient drug delivery. In this study, we designed and synthesized a new supramolecular amphiphilic macrocycle to serve as an efficient nanocarrier, achieved by treating 4-hydroxybenzaldehyde with 1-bromotetradecane. The derivatized product was subsequently treated with resorcinol to cyclize, resulting in the formation of a calix(4)-resorcinarene-based supramolecular amphiphilic macrocycle. The synthesized macrocycle and intermediate products were characterized using mass spectrometry, IR, and 1H NMR spectroscopic techniques. The amphotericin-B (Amph-B)-loaded and unloaded amphiphiles were screened for biocompatibility studies, vesicle formation, particle shape, size, surface charge, drug entrapment, in-vitro release profile, and stability through atomic force microscopy (AFM), Zetasizer, HPLC, and FT-IR. Amph-B -loaded macrocycle-based niosomal vesicles were investigated for in-vivo bioavailability in rabbits. The synthesized macrocycle exhibited no cytotoxicity against normal mouse fibroblast cells and was found to be hemocompatible and safe in mice following an acute toxicity study. The drug-loaded macrocycle-based vesicles appeared spherical, nano-sized, and homogeneous in size, with a notable negative surface charge. The vesicles remained stable after 30 days of storage. The results of Amph-B oral bioavailability and pharmacokinetics revealed that the newly tailored niosomal formulation enhanced drug solubility, protected drug degradation at gastric pH, facilitated sustained drug release at the specific target site, and delayed plasma drug clearance. Incorporating such advanced niosomal formulations in the field of drug delivery systems has the potential to revolutionize therapeutic outcomes and improve the quality of patient well-being.

Nanocarrier-based localized and effective treatment of renal disorders: currently employed targeting strategies.

Renal disorders pose a global health threat, with targeted drug-delivery systems emerging as a promising strategy to enhance therapy safety and efficacy. Recent efforts have harnessed targeted nanomaterials for kidney disease treatment. While some systems remain in the early stages, they show immense potential in delivering cargo to specific sites. Through animal model experimentations, it has been demonstrated to reduce systemic side effects and enhance treatment effectiveness. This review presents current strategies for kidney disorder treatment, emphasizing site-specific targeting critical to renal disease pathophysiology. Recent advancements in nano-drug delivery systems for kidney targeting are explored. Finally, toxicological aspects and prospects of the most promising kidney-targeting delivery systems are discussed in this review article.

Pharmacokinetics and drug-likeness of anti-cancer traditional Chinese medicine: molecular docking and molecular dynamics simulation study.

MCM7 (Minichromosome Maintenance Complex Component 7) is a component of the DNA replication licensing factor, which controls DNA replication. The MCM7 protein is linked to tumor cell proliferation and has a function in the development of several human cancers. Several types of cancer may be treated by inhibiting the protein, as it is strongly produced throughout this process. Significantly, Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant use against cancer, is rapidly gaining traction as a valuable medical resource for the development of novel cancer therapies, including immunotherapy. Therefore, the goal of the research was to find small molecular therapeutic candidates against the MCM7 protein that may be used to treat human cancers. A computational-based virtual screening of 36,000 natural TCM libraries is carried out for this goal using a molecular docking and dynamic simulation technique. Thereby, ∼8 novel potent compounds i.e., ZINC85542762, ZINC95911541, ZINC85542617, ZINC85542646, ZINC85592446, ZINC85568676, ZINC85531303, and ZINC95914464 were successfully shortlisted, each having the capacity to penetrate the cell as potent inhibitors for MCM7 to curb this disorder. These selected compounds were found to have high binding affinities compared to the reference (AGS compound) i.e. < -11.0 kcal/mol. ADMET and pharmacological properties showed that none of these 8 compounds poses any toxic property (carcinogenicity) and have anti-metastatic, and anticancer activity. Additionally, MD simulations were run to assess the compounds' stability and dynamic behavior with the MCM7 complex for about 100 ns. Finally, ZINC95914464, ZINC95911541, ZINC85568676, ZINC85592446, ZINC85531303, and ZINC85542646 are identified as highly stable within the complex throughout the 100 ns simulations. Moreover, the results of binding free energy suggested that the selected virtual hits significantly bind to the MCM7 which implied these compounds may act as a potential MCM7 inhibitor. However, in vitro testing protocols are required to further support these results. Further, assessment through various lab-based trial methods can assist with deciding the action of the compound that will give options in contrast to human cancer immunotherapy.Communicated by Ramaswamy H. Sarma.

A therapeutic epitopes-based vaccine engineering against Salmonella enterica XDR strains for typhoid fever: a Pan-vaccinomics approach.

A prevalent food-borne pathogen, Salmonella enterica serotypes Typhi, is responsible for gastrointestinal and systemic infections globally. Salmonella vaccines are the most effective, however, producing a broad-spectrum vaccine remains challenging due to Salmonella's many serotypes. Efforts are urgently required to develop a novel vaccine candidate that can tackle all S. Typhi strains because of their high resistance to multiple kinds of antibiotics (particularly the XDR H58 strain). In this work, we used a computational pangenome-based vaccine design technique on all available (n = 119) S. Typhi reference genomes and identified one TonB-dependent siderophore receptor (WP_001034967.1) as highly conserved and prospective vaccine candidates from the predicted core genome (n = 3,351). The applied pan-proteomics and Immunoinformatic approaches help in the identification of four epitopes that may trigger adequate host body immune responses. Furthermore, the proposed vaccine ensemble demonstrates a stable binding conformation with the examined immunological receptor (HLAs and TRL2/4) and has large interaction energy determined via molecular docking and molecular dynamics simulation techniques. Eventually, an expression vector for the Escherichia. coli K12 strain was constructed from the vaccine sequence. Additional analysis revealed that the vaccine may help to elicit strong immune responses for typhoid infections, however, experimental analysis is required to verify the vaccine's effectiveness based on these results. Moreover, the applied computer-assisted vaccine design may considerably decrease vaccine development costs and speed up the process. The study's findings are intriguing, but they must be evaluated in the experimental labs to confirm the developed vaccine's biological efficiency against XDR S. Typhi.Communicated by Ramaswamy H. Sarma.

Synthetic star shaped tetra-tailed biocompatible supramolecular amphiphile as an efficient nanocarrier for Amphotericin B.

Macrocycle-based amphiphiles are capable of self-assembling into multidimensional nano-architecture with defined dimensions for various applications. Herein we report the synthesis, physio-chemical characterizations and oral drug delivery profiling of resorcinarene-based amphiphilic supramolecular macrocycle. The macrocycle was synthesized in two-step reaction and characterized using 1H NMR, Mass spectrometry and IR spectroscopic techniques. The synthesized macrocycle was assessed for vesicles formation, checked for biocompatibility and then Amphotericin B (Amp-B) was entrapped in macrocycle-based vesicles. The drug loaded vesicles were characterized for shape, size, homogeneity, drug entrapment, surface charge, in-vitro release profile and stability. Amp-B loaded macrocycle based vesicles were examined in rabbits for in-vivo bioavailability and compared with plan drug suspension. The synthesized macrocycle was non-toxic in normal mouse fibroblast cells, compatible with blood and safe in mice. The drug loaded macrocycle based vesicles appeared spherical with 279.4 nm size and - 12.2 mV zeta potential loading 85.45 % drug. The drug loaded vesicles storage stability for 30 days and gastric fluid stability for 1 h were it retained nearly 90 % drug at 30th day and 83.79 % drug at 1 h in gastric fluid. Oral bioavailability of Amp-B in rabbits was markedly enhanced when delivered in synthesized macrocycle based vesicles in comparison with plan drug suspension. Results of this study indicate that the synthesized star shaped tetra-tailed supramolecular amphiphile could be used as an efficient nanocarrier for enhancing oral bioavailability of drugs with solubility and bioavailability issues like Amp-B.

Screening of phytochemical constituents and potential antioxidant, antibacterial and anticancerous activities of Carpesium nepalense seeds oil.

The pharmacological importance and ecofriendly nature of medicinal plants holding a unique edge in the arena of pharmaceutical industries. Therefore, the current research was aimed to evaluate the phytochemical constituents and potential antioxidant, in vitro anticancer and antibacterial activity of Carpesium nepalense seeds essential oil. The analysis performed through Gas chromatography/Mass spectroscopy confirmed the presence of different types of biologically active compounds. At the concentration of 500µg/mL, n-hexane fraction of C. nepalense showed highly significant (P<0.001) antioxidant activity in 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid and superoxide assays with the percentage inhibitions of 86.60±1.6%, 82.55±1.0% and 80.50±1.0% respectively. The extract also produced highly significant anticancerous activity against different cell lines at 500µg/mL. The significant antibacterial activity of extract was observed against bacterial strains with the zone of inhibitions of 24.3±0.8, 28.20±0.10, 22.33±0.11 and 33.22±0.10 mm respectively. The significant damage in bacterial cell membranes was also observed in atomic force microscopic analysis. In the light of obtained findings, it is concluded that C. nepalence proved to be a potential candidate as an alternative medicinal agent.

Phytochemical, acute toxicity and renal protective appraisal of Ajuga parviflora hydromethanolic leaf extract against CCl4 induced renal injury in rats.

BACKGROUND: Degenerative kidney diseases are mostly associated with oxidative stress. Natural products are considered as the antioxidants enrich food that can restrict the progress of oxidative stress induced disorders. Therefore, the present study was aimed to evaluate the renal protective effect of Ajuga parviflora leaf extract in carbon tetrachloride intoxicated rats. METHODS: The hydromethanolic extract of A. parviflora leaves was obtained by extracting twice in 60% methanol. The principal bioactive constituents were detected by LC/MS analysis. Toxicity of plant extract was assessed using brine shrimp lethal toxicity test and acute toxicity model on healthy Sprague-Dawley male rats. Nephroprotective effects of plant extract were also evaluated on rats by inducing CCl4 renal toxicity in comparison with positive control and naïve groups. The dose of A. parviflora administered to animal was 100, 200 and 300 mg/kg. All administrations were given orally on an alternate day basis for 30 days. Urine and serum biomarkers were analyzed, along with antioxidant enzymes. Finally, the DNA damages, lipid peroxides, hydrogen peroxides and nitrites were assessed in rat's renal tissue. The histopathology alterations in renal tissues were further studied for kidney damages. RESULTS: The LC/MS analysis confirmed the presence of different important pharmacological compounds in A. parviflora methanolic leaf extract. The key bioactive compounds include pyocyanin, zonisamide, D Saccharic acid, altretamine, carbocyclic thromboxane A2, Sinapyl alcohol, and vitamin C. The important polypeptides identified include Lys-Tyr-Lys, His-His-Lys, Met-Asp-Arg, Phe-Val-Arg, and PyroGlu-Val-Arg. The LD50 of A. parviflora was found to be > 1000 µg/mL. A. parviflora administration significantly subsides CCl4 toxicity in rats, reduced the elevated level of RBCs, pus and epithelial cells. The abnormal elevated level of specific gravity, creatinine, urobilinogen, urea and albumin were also reduced to normal physiological level. The reduced urinary protein and pH were also normalized. The serum urobilinogen, urea and total bilirubin levels were also reversed to normal levels while the diminished albumin and total protein levels also came to normal. The important phase I and II enzyme levels were also reversed in A. parviflora administered rats. The H2O2, thiobarbituric acid reactive substance (TBARS) and nitrite levels were significantly decreased. Furthermore, the damaged DNA and histopathological changes in CCl4 exposed rats were also highly significantly reversed after the administration of A. parviflora. All effects were significant (P < 0.05) and highly significant (P < 0.005) at 100 and 300 mg/kg respectively. CONCLUSION: The restored urine and serum profile of various parameters to normal physiological levels suggests that the A. parviflora has potential antioxidant and repairing potential in renal disorders.

Synthesis and characterization of pyridine-based organic salts: Their antibacterial, antibiofilm and wound healing activities.

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.

Synthesis and characterization of Schiff base of nicotinic hydrazide as antibacterial agent along with in vivo wound healing activities and atomic force microscopic study of bacterial cell wall affected by synthesized compound.

The present work reports the synthesis of Schiff base series of nicotinic hydrazide (C-1-C-5) and it's antibacterial and wound healing evaluation. The synthetic molecules were characterized with different spectroscopic techniques and explored for their antibacterial potential. The objective of this work was to explore antimicrobial agent using two types of microorganisms, one Gram-positive (S. aureus ATCC 9144) and one Gram-negative (E. coli ATCC 10536). C-2, C-4 and C-5 potentially inhibit bacterial growth (p<0.001). Atomic force microscopy (AFM) imaging was obtained to get high-resolution images of the effect of treated drugs on the bacterial morphology. The images obtained also revealed the antibacterial effects of potent molecule. The magnified pictures captured under AFM suggest significantly damaged cell surface and disturbed morphology. The compounds were further analyzed for in vivo wound healing potential on mice. The compound C-2, C-4 and C-5 heal the wounds comparatively in less time duration as compared to control group (p<0.001). Compound C-1 and C-3 took more time to heal the wound as compare to compound C-2, C-4 and C-5. The re-epithelialization process of wound in animals group treated with potent compound was highly significant (p<0.001) and faster than control. Results of this study suggest that the compounds C-2, C-4 andC-5 possess pronounced antibacterial and wound healing potential and need to be further evaluated for mechanism of action.

GC/MS assisted phytochemical analysis of Ajuga parviflora leaves extract along with anti-hepatotoxic effect against anti-tubercular drug induced liver toxicity in rat.

Owing to its traditional applications, the current study focuses on Ajuga parviflora (A. parviflora) leaves extract for phytochemical and pharmacological analysis. The principle constituents were identified through gas chromatography (GC), and gas chromatography/mass spectroscopy (GC/MS), these includes phthalic acid, squalene, α-tocopherol, vitamin E, phytol, 2-methylenecholestan-3-ol, stigmasterol, cholest-22-ene-21-ol and 3,5-dehydro-6-methoxy. Hepatoprotective effect of A. parviflora was evaluated through isoniazid and rifampicin (INH and RFP) induced hepatotoxicity in rat. Animals in group A were treated with INH and RFP 50 mg/kg. Animals in group B, C, and D were pre-treated with A. parviflora extract at 100, 200 and 300 mg/kg dose prior drug administration. A. parviflora extract at 200 and 300 mg/kg in group C and D significantly reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and bilirubin (p<0.001) as compare to group B (100mg/kg). Total protein (TP) was also significantly (p<0.01) reduced in group C and D at dose of 200 and 300 mg/kg, respectively. The extract pre-treated animals with (A. parviflora, 200, and 300 mg/kg) showed that the epithelium of the central portal vein is intact with replete glucagon. The pre-treatment with A. parviflora protected the liver from INH and RFP induced hepatotoxicity. The results of pre-treated animals with A. parviflora 200, and 300 mg/kg dose prettily revert the severely disturb parameters like, cytolysis, lymphocytic infiltration, and lymphoid aggregate in portal vein and hydropic degeneration. The decrease peroxisome proliferator-receptor activator-δ (PPAR-δ) gene expression by INH, and RFP was significantly up regulated by A. parviflora extract in pre-treated animals at 200 and 300 mg/kg dose. These findings provide baseline pharmacological uses of A. parviflora in liver disorders. Further investigations are required for identification and isolation of biologically active components responsible for pharmacological activity.

Comparative study of antibacterial activity between Schiff base nicotinic hydrazide derivative and its silver architected nanoparticles with atomic force microscopic study of bacterial cell wall.

The threat of multi-drug resistant bacterial pathogens evokes researchers to synthesized safe and effective chemotherapeutic agents for nano-drug delivery system. In current study, Schiff base of nicotinic hydrazide(NHD) and its silver nanoparticles(NHD-AgNPs) were synthesized and characterized. These compounds were investigated for cytotoxicity, antibacterial and AFM activity. The NHD showed LD50 at >1000µg/mL while NHD-AgNPs didn't exhibit toxicity at 1000µg/mL against 3T3 cell line. The NHD showed zone of inhibition against two strains of salmonella enteric (ATCC 14028 and 700408) 45.29±1.66 and 48.01±1.43mm respectively at 160µg/mL (p<0.01) while NHD-AgNPs exhibited 55.87±2.08 and 52.88±1.42 mm respectively at 130µg/mL (p<0.001) in disc diffusion method. NHD showed more than 70% growth inhibition for both strains at 85 and 125µg/ml (p<0.01) respectively, while NHD-AgNPs inhibit 80% and 75% respectively at 75 and 125 µg/ml (p<0.01, p<0.001) against Alamar blue antibacterial assay. For morphological changes in bacterial cell wall NHD and NHD-AgNPs treated bacterial cells were observed under atomic force microscope(AFM) and treated bacterial cells were severely damaged with leaked cytoplasmic contents as compare to untreated bacterial cell. These results validate that NHD-AgNPs were highly active as compared to NHD against both strains at their MIC concentrations. In future, comparative wound healing potential will be emphasized.

GC-MS profiling, FTIR, metal analysis, antibacterial and anticancer potential of Monotheca buxifolia (Falc.) leaves.

Monotheca buxifolia has traditionally been employed in folk medicines to cure of infectious diseases. Current study was aimed to standardize the M. buxifolia leaves extract and evaluate its antibacterial and anticancer activity. Phytochemical analysis was carried through GC, GC/MS, FTIR, and ICP-OES analytical techniques. Antibacterial assay of the crude extract was performed by using tetrazolium micro plates. The extract treated bacteria were observed under (AFM) atomic force microscope and PCR was used for DNA amplification. The anti-proliferative activity of M. buxifolia leaves extract was examined through MTT cytotoxicity assay. The bacterial strains employed in this study were S. epidermidis ATCC (13518), S. aureus ATCC (25923), P. aeruginosa ATCC (10145), and E. coli ATCC (10536). Minimum inhibitory concentration (MIC50) against gram positive bacteria was significantly (p<0.01) achieved at 50 and 75µg/mL. MIC50 against E. coli and P. aeruginosa was also significant at 100µg/mL (p<0.01). M. buxifolia leaves extract damaged the cell walls gram-positive and gram-negative bacteria, while biofilm around gram positive bacteria was significantly damaged. The DNA decantation was also inhibited of S. aureus and S. epidermidis, however, no any impact was observed on E. coli and P. aeruginosa DNA decantation. The cytotoxicity findings suggested that the crude extract of M. buxifolia leaves at 1000µg/mL gives significant inhibition 73.96±2.0%, 83.76±1.2%, 77.66±1.2% and 72.67±1.6% against MDA-MB-231, MCF-7, HeLa and H460 cell lines respectively at (p<0.001). It may be concluded that M. buxifolia leaves extract have significant and promising antibacterial and anti-cancer activities which could be helpful to establish new antimicrobial and anticancer agents.

Phytochemical screening, antioxidant, and in vivo neuropharmacological effect of Monotheca buxifolia (Falc.) barks extract.

Owing to its pharmacological versatility, the current study focuses the evaluation of Monotheca buxifolia (M. buxifolia) bark crude extract and its fractions for phytochemical and pharmacological analysis. Phytochemical investigation of bark extract was carried out through GC-MS, LC-MS and FT-IR. ICP-OES was used for analyzing essential metals in bark extract. Plant samples were further investigated for their in vitro antioxidant and in vivo neuropharmacological activities in mice. Phytochemical analysis of bark extract revealed the presence of various active constituents such as serotonin, α-tocopherol, 3-deoxyestradiol, ascorbyl palmitate and cirsimaritin. Metal analysis showed presence of various metals in diverse concentration. M. buxifolia bark extract and its chloroform fraction showed significant antioxidant activity against DPPH (89.55 ±1.29; 84.80±1.66%), superoxide (82.10 ±1.86; 80.0±1.0%), H2O2 (80.55±2.0; 78.10±2.26%) at 500µg/mL concentration. Similarly, bark extract and its chloroform fraction demonstrated antidepressant activity in mice and improve generalized locomotive behavior. The effective use of M. buxifolia in treatment and management of depression and free radicals based disorders can be safely concluded from the results of present study.