Synthesis of N-substituted acetamide derivatives of azinane-bearing 1,3,4-oxadiazole nucleus and screening for antibacterial activity

Purpose: To synthesize some acetamide derivatives bearing azinane and 1,3,4-oxadiazole heterocyclic cores and to evaluate their antibacterial potentials.Methods: Ethyl piperidin-4-carboxylate (2) was converted to ethyl 1-[(4-chlorophenyl)sulfonyl]piperidin- 4-carboxylate (3), 1-[(4-chlorophenyl)sulfonyl]piperidin-4-carbohydrazide (4) and 5-[1-(4-chlorophenylsulfonyl)-4-piperidinyl]-1,3,4-oxadiazol-2-thiol (5) using three consecutive steps. The target molecules, 5-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-2-{[N-(substituted)-2-acetamoyl]thio]}-1,3,4- oxadiazole (8a-n) were synthesized by stirring 5 and N-aryl-2-bromoacetamides (7a-n) in an aprotic polar solvent. The structures were corroborated by infrared (IR), electron impact mass spectrometry (EIMS) and proton/carbon nuclear magnetic resonance (1H/13C-NMR) spectroscopic techniques. The evaluation of antibacterial activity was based on the effect on the increase in absorbance of the broth medium due to log phase microbial growth.Results: Compound 8g bearing a 2-methylphenyl group was the most the active growth inhibitor of Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis bacterial strains with minimum  inhibitory concentrations (MIC) of 10.63±0.97, 10.31±1.00, 10.45 ± 0.94 and 11.77±5.00 μM, respectively. Ciprofloxacin was used as reference standard.Conclusion: All the synthesized compounds are moderate inhibitors but relatively more active against Gram-negative bacterial strains. 5-{1-[(4- Chlorophenyl)sulfonyl]piperidin-4-yl}-2-{[N-(2-methylphenyl)-2- acetamoyl]thio]}-1,3,4-oxadiazole (8g) is the most active growth inhibitor of all the strains except Staphylococcus aureus.Keywords: 1,3,4-Oxadiazole, Acetamides, Antibacterial activity, Piperidin

Novel Hydrolytic Degradable Crosslinked Interpenetrating Polymeric Networks (IPNs): An Efficient Hybrid System to Manage the Controlled Release and Degradation of Misoprostol

Purpose: The goal of this study was to make pH-sensitive HPMC/Neocel C19-based interpenetrating polymeric networks (IPNs) that could be used to treat different diseases. An assembled novel carrier system was demonstrated in this study to achieve multiple functions such as drug protection and self-regulated release. Methods: Misoprostol (MPT) was incorporated as a model drug in hydroxyl-propyl-methylcellulose (HPMC)- and Neocel C19-based IPNs for controlled release. HPMC- and Neocel C19-based IPNs were fabricated through an aqueous polymerization method by utilizing the polymers HPMC and Neocel C19, the initiator ammonium peroxodisulfate (APS), the crosslinker methylenebisacrylamide (MBA), and the monomer methacrylic acid (MAA). An IPN based on these materials was created using an aqueous polymerization technique. Samples of IPN were analyzed using scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), thermal analysis (TGA), and powder X-ray diffraction (PXRD). The effects of the pH levels 1.2 and 7.4 on these polymeric networks were also studied in vitro and through swelling experiments. We also performed in vivo studies on rabbits using commercial tablets and hydrogels. Results: The thermal stability measured using TGA and DSC for the revised formulation was higher than that of the individual components. Crystallinity was low and amorphousness was high in the polymeric networks, as revealed using powder X-ray diffraction (PXRD). The results from the SEM analysis demonstrated that the surface of the polymeric networks is uneven and porous. Better swelling and in vitro results were achieved at a high pH (7.4), which endorses the pH-responsive characteristics of IPN. Drug release was also increased in 7.4 pH (80% in hours). The pharmacokinetic properties of the drugs showed improvement in our work with hydrogel. The tablet MRT was 13.17 h, which was decreased in the hydrogels, and its AUC was increased from 314.41 ng h/mL to 400.50 ng h/mL in hydrogels. The blood compatibility of the IPN hydrogel was measured using different weights (100 mg, 200 mg, 400 mg, and 600 mg; 5.34%, 12.51%, 20.23%, and 29.37%, respectively). Conclusions: As a result, IPN composed of HPMC and Neocel C19 was successfully synthesized, and it is now possible to use it for the controlled release of MPT

Biocompatible hydrogels for the controlled delivery of anti-hypertensive agent: development, characterization and in vitro evaluation

The aim of the present exploration was to develop novel pH-sensitive cross-linked Gelatin/Polyvinyl pyrrolidone hydrogels using different ratios of both the polymers and to investigate the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and invitro release pattern of the model drug (captopril). Grafting polymerization technique was used for the preparation of these hydrogels using glutaraldehyde as crosslinking agent. These polymeric materials were then used as model systems to envisage various important characterizations like FTIR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction) and scanning electron microscopy (SEM). Phosphate buffers of pH 1.2, 6.5 and 7.5 were used for swelling and invitro drug release profile investigation. Different parameters like swelling analysis, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), solvent interaction parameter (χ), volume fraction of polymer (V2,s) and diffusion coefficient that affects the drug release behavior were also determined. Higher swelling and release was observed at lower pH values. FTIR spectra showed interaction between gelatin and polyvinyl pyrrolidone and successful formation of cross-linked structure. Pulsatile drug release study showed the controlled delivery of model drug. The release of drug occurred through non-fickian diffusion or anomalous mechanism. Aforementioned characterizations reveal successful formation of copolymer. pH sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable which also predicts their possible use for site specific captopril delivery

Phytochemical Characterization and Heavy Metal and Thermal Analyses of <i>Saussurea hypoleuca</i> Root and Evaluation of Its Anthelmintic and Antioxidant Activity In Vitro and In Silico

Phytochemical characterization of the ethyl acetate fraction of Saussurea hypoleuca root extract resulted in the isolation of oleic acid (1) and luteolin (2), which were isolated for the first time from Saussurea hypoleuca root. A heavy metal analysis of the root powder performed using atomic absorption spectroscopy showed that the contents of iron, cadmium, lead, zinc, nickel, and copper were within the certified limits according to the WHO guidelines. Differential scanning calorimetry (DSC) revealed its crystalline and amorphous nature; meanwhile, standardization of the root with UHPLC revealed the presence of 14.79 ± 0.015 µg/mL of luteolin. Both the total methanol extract and the ethyl acetate fraction of the plant root held significant anthelmintic activity. Oleic acid and luteolin exhibited potent antioxidant activity, evidenced by their IC50 values, which were equal to 47.0 and 119.8 µg/mL, respectively, in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. In silico studies showed that luteolin exerted the highest fitting within the binding sites of NADPH oxidase (Nox). For myeloperoxidase (MP), oleic acid revealed the best fitting in its active sites. The results of ADMET (absorption, distribution, metabolism, excretion, and toxicity) and TOPKAT (toxicity prediction) protocols revealed acceptable pharmacodynamic and pharmacokinetic characteristics, in addition to reasonable toxicity characteristics for both compounds. Thus, they can be incorporated into pharmaceutical dosage forms to combat oxidative stress

Evaluation of the Antihyperglycemic and Antihyperlipidemic Activity of <i>Saussurea hypoleuca</i> Root in Alloxan-Induced Diabetes in Rat Model and Correlation to Its Major Secondary Metabolites

Saussurea hypoleuca belongs to the family Asteraceae, which has previously shown hepatoprotective, anticancer, and antioxidant activity. This study aimed to evaluate the antihyperglycemic and antihyperlipidemic activity of its root methanol extract and various fractions for the first time. This was performed using alloxan-induced diabetes in the rat model for both short, and long-term periods using different administration doses. Different biochemical parameters were studied and further consolidated by histopathological examination and in silico molecular modeling. The results showed that in the long-term study, at a dose of 400 mg/kg b.wt, the ethyl acetate fraction caused a pronounced reduction in fasting blood glucose level (FBG) and glycated hemoglobin (HbA1c) by 77.2% and 36.8%, respectively, compared to the diabetic group. This was confirmed by the histopathological examination of the animals’ pancreatic sections. The ethyl acetate fraction also showed a reduction in total cholesterol (TC), total glycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels. It improved kidney and liver functions, causing a reduction in aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine transaminase (ALT), urea, and creatinine levels. This is mainly attributed to its richness in secondary metabolites. Molecular docking showed that all the tested compounds showed certain inhibitory potential towards human α-glucosidase (HAG) and ATP citrate lyase (ACL). Thus, Saussurea hypoleuca roots can help in the management of hyperglycemia, hyperlipidemia, and hepatic and kidney dysfunction