Design, synthesis, molecular docking and in vitro anticancer activities of 1-(4-(benzamido)phenyl)-3-arylurea derivatives.

In both premenopausal and postmenopausal women, oestrogens play a critical role in the development of breast cancer. Aromatase is an enzyme that catalyses the final step in the biosynthesis of estrogen and has emerged as a promising target for therapeutic intervention. This study aimed to design and evaluate novel 1-(4-(benzamido)phenyl)-3-arylurea derivatives as potential aromatase inhibitors. Through molecular docking, promising leads were identified and synthesized. Spectroscopic techniques confirmed their structural integrity. Cytotoxicity against various cancer cell lines was assessed using MTT assay. Docking investigations against the aromatase enzyme (3s7s) elucidated binding interactions and energies. Compound 6g, exhibiting a binding energy of -8.6 kcal mol-1 and interacting with ALA306 and THR310 residues, showed the most promising activity. It demonstrated GI50 values ranging from 14.46 µM, 13.97 µM, 11.35 µM, 11.58 µM, and 15.77 µM against A-498, NCI-H23, MDAMB-231, MCF-7, and A-549 respectively. Lastly, the physicochemical, and ADMET properties of the compound were predicted. These findings highlight the potential of 1-(4-(benzamido)phenyl)-3-arylureas as a new class of antitumor agents targeting aromatase. Their versatility and superior activity compared to standard chemotherapeutic agents, like doxorubicin, warrant further investigation for the development of broader-spectrum anticancer drugs.

Development and Optimization of Proniosomal Formulation of Irbesartan Using a Box-Behnken Design to Enhance Oral Bioavailability: Physicochemical Characterization and In Vivo Assessment.

This research work aimed to develop and evaluate proniosomes for the oral delivery of the lipophilic drug Irbesartan (IRB) to improve its solubility and bioavailability. Proniosomes of Irbesartan were formulated using a lipid, surfactant, and carrier by a slurry method. Based on the prepared preliminary trial batches and their evaluation, the formulation was optimized by employing a Box-Behnken design (BBD) in which concentrations of span 60 (X1), cholesterol (X2), and mannitol (X3) were used as three independent variables and the vesicular size (VS) (Y1), % entrapment efficiency (% EE) (Y2), and % cumulative drug release (% CDR) (Y3) were used as dependent variables. The optimized batch B1 was obtained from the BBD experiment after validation of checkpoint analysis, and their characterization was done for VS, % EE, % CDR, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analysis. The optimized batch showed a VS of 199 ± 5.4 nm, a % EE of 99.25 ± 2.24%, and a % CDR of 97.36 ± 1.13% at 24 h. Scanning electron microscopy (SEM) study showed a smooth surface of batch B1. DSC and XRD studies indicated the amorphous nature of the proniosomal formulation. The proniosomal formulation showed increased solubility (2.65 ± 0.2 mg/mL) in phosphate buffer, pH 6.8, as compared to water (0.059 ± 0.02 mg/mL). The pharmacokinetic study in rats confirmed the increased bioavailability of the drug in optimized proniosomal formulation compared with its pure drug suspension. Cmax, Tmax, and AUC0-t of the drug also increased by 2-fold compared to those of drug suspension. Thus, in conclusion, the proniosomal formulation proved to be an efficient carrier for improved oral delivery of Irbesartan by improving the solubility and bioavailability of the drug.

Solid Lipid Nanoparticles as an Innovative Lipidic Drug Delivery System.

In order to overcome some of the drawbacks of traditional formulations, increasing emphasis has recently been paid to lipid-based drug delivery systems. Solid lipid nanoparticles (SLNs) are among these delivery methods, and they hold promise because of their simplicity in production, capacity to scale up, biocompatibility, and biodegradability of formulation components. Other benefits could be connected to a particular route of administration or the makeup of the ingredients being placed into these delivery systems. This article aims to review the significance of solid lipid nanocarriers, their benefits and drawbacks, as well as their types, compositions, methods of preparation, mechanisms of drug release, characterization, routes of administration, and applications in a variety of delivery systems with a focus on their efficacy.

Nanostructured Lipid Carrier-loaded In situ Gel for Ophthalmic Drug Delivery: Preparation and In vitro Characterization Studies.

BACKGROUND: Nanostructured lipid carriers (NLCs) are explored as vehicles for ophthalmic drug delivery owing to their better drug loading, good permeation, and satisfactory safety profile. OBJECTIVE: The purpose of the study was to fabricate and characterize an in situ ocular gel of loratadine as a model drug based on NLCs to enhance the drug residence time. METHODS: NLCs were fabricated using the microemulsion method in which solid lipid as Compritol 888 ATO, lipid as oleic acid, surfactant as Tween 80, and isopropyl co-surfactant as alcohol, were used. Based on the evaluation of formulation batches of NLCs, the optimized batch was selected and further utilized for the formulation of in situ gel containing Carbopol 934 and HPMC K15M as gelling agents, and characterized. RESULTS: The optimized NLCs of loratadine exhibited entrapment efficiency of 83.13 ± 0.13 % and an average particle size of 18.98 ± 1.22 nm. Drug content and drug release were found to be 98.67 and 92.48 %, respectively. Excellent rheology and mucoadhesion were demonstrated by the loratadine NLC-loaded in situ gel to enhance its attachment to the mucosa. NLC-based in situ ocular gel showed the desired results for topical administration. The prepared gel was observed to be non-irritating to the eye. CONCLUSION: The optimized NLC-based in situ gel formulation presented better corneal retention and it was found to be stable, offering sustained release of the drug. Thus, the joined system of sol-gel was found promising for ophthalmic drug delivery.

Development of lamivudine liposomes by three-level factorial design approach for optimum entrapment and enhancing tissue targeting.

Aim: This work aimed to encapsulate lamivudine in liposomes for targeted delivery to HIV reservoirs and thereby reduce its side effects.Methods: The lamivudine liposomes were prepared by thin film hydration method using 32 factorial design and characterised for vesicle size, % drug entrapment efficiency, polydispersity index etc. Optimisation by graphical and numerical methods was carried out by fixing minimum and maximum limits for each response. In vivo plasma and tissue distribution of plain lamivudine and lamivudine encapsulated optimised liposomes were compared in rats.Results: The optimised liposomes displayed vesicle size 276.20 ± 13.36 nm, percent entrapment 60.20 ± 2.86% and PDI 0.291 ± 0.053. Compared to plain lamivudine, the liposomes were rapidly cleared from the plasma and displayed 10.97 ± 0.72 and 1.38 ± 0.52 fold accumulation in liver and spleen tissues respectively.Conclusions: Lamivudine encapsulated in liposomes remains in the body for a longer period of time with well distribution in tissues.

Characterization of natural polymers from jackfruit pulp, calendula flowers and tara seeds as mucoadhesive and controlled release components in buccal tablets.

Identification and physiochemical parameters such as solubility, loss on drying, viscosity, pH, swelling index, starch and gum constituents were determined in natural polymers and showed satisfactory results. Spectral studies established the compatibility of natural polymers. The drug release kinetics in preliminary trial batches showed that tablets containing natural mucilages and gum showed a prolonged drug release comparable to Carbopol 974P and Methocel K4M. Also, all tablets showed a satisfactory drug permeability flux. Acute toxicity studies confirmed the safety of natural polymers. Using response surface method supported by 23 factorial design, the optimized buccoadhesive tablets (C1) with drug release at 8h (R8h, %) of 53.48±0.048% showed controlled release over ≥8h and followed the Korsmeyer-Peppas model with anomalous (non-Fickian) diffusion mechanism. Mucoadhesive strength was found to be 42.71±0.49g. Comparative dissolution study between prepared and marketed formulation showed that there was no significant difference in drug release profile having similarity factor 82.97. In vivo study for optimized formulation of the buccoadhesive tablets showed the better absolute bioavailability (71.26%) against the oral solution (51.22%). Histological study confirmed non-irritant nature and stability study indicated stability of the formulation.

Steroidal carbonitriles as potential aromatase inhibitors.

Estrogens, responsible for the growth of hormone-dependant breast cancer are biosynthesized from androgens involving aromatase enzyme in the last rate limiting step. Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. Novel 4-phenylthia derivatives (2, 3 and 7) have been synthesized as aromatase inhibitors. The synthesized compounds (2, 3 and 7) exhibited noticeable enzyme inhibiting activity. Kinetics study of these compounds (2, 3, and 7) showed negligible inhibition of the enzyme under conditions conducive for irreversible inhibition of the enzyme. Introduction of unsaturation at C-4, C-1 & 4 or C-4 & 6 (compounds 5, 9 and 11) was observed to not be an effective strategy for entrancing aromatase inhibiting activity in 17-oxo-16ß-carbonitrile derivatives. The D-seco derivatives (13-15 and 17) having unsaturation at C-4, C-1 & 4 or C-4 & 6 along with carbonitrile function in ring-D showed complete loss of aromatase inhibiting activity.

Formulation and in vitro evaluation of the topical antiageing preparation of the fruit of Benincasa hispida.

Ageing is the phase of gradual decline of body efficiency and metabolic activities after reaching a maturity stage. Free radicals cause oxidative alterations in collagen, elastin material and changes in membrane characteristics and induce polymerization reactions. Use of topical antioxidants can overcome some of these effects and retard actinic ageing. Herbal products are popular due to their minimum risk of side-effects with maximum efficacy. The present study was undertaken to evaluate the antiageing potential of Benincasa hispida fruit extract as not many scientific studies have been carried out to explore its utility as skin renewal enhancer and as an antioxidant. After removing the outer layer and the seeds, the fruit pulp was dried. The dried fruit pulp was extracted successively with petroleum ether, chloroform, ethyl acetate and methanol by Soxhlation for 2 days. Methanol was recovered under vacuum and a dry extract was obtained (yield 4.2% w/w), which was stored in a desiccator. Suitable topical cream base for effective carriage of fruit extract was developed and its in vitro evaluation for skin renewal activity was tested by application to the stratum corneum of human cadaver skin and by dansyl chloride fluorescence method. The results show that the cream prepared from Benincasa fruit extract may prove as an antiageing preparation and can be used for retarding the symptoms of ageing.

Synthesis of some novel androstanes as potential aromatase inhibitors.

Novel pyrazole and isoxazole derivatives (6-9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity for compound (6) having pyrazole ring at 2,3 position showed highest activity followed by nitrile derivative (9). Isomeric forms of isoxazole (7 and 8) showed very poor activity compared to fadrozole and aminoglutethimide. Preliminary kinetic studies have shown that both of the active compounds (6 and 9) are reversible inhibitors of the enzyme.