Feruloyl Sucrose Esters: Potent and Selective Inhibitors of α-glucosidase and α-amylase.

INTRODUCTION: Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic patients but causes severe gastrointestinal side effects. METHODS: Systematic structure-activity relationship (SAR) studies using in silico, in vitro and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α- amylase followed by in silico docking studies to identify the binding modes. A lead candidate, FSE 12 was investigated in an STZ mouse model. RESULTS: All active FSEs showed desired higher % inhibition of α-glucosidase and desired lower inhibition of α -amylase in comparison to AGI gold standard acarbose. This suggests a greater selectivity of the FSEs towards α -glucosidase than α -amylase, which is proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position and number of the feruloyl substituents on the sucrose core, the aromatic 'OH' group, and the diisopropylidene bridges were key determinants of the % inhibition of α - glucosidase and α -amylase. In particular, the diisopropylidene bridges are critical for achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in vitro results. The molecular docking studies further reveal that the presence of free aromatic 'OH' groups and the substitution at position 3 on the sucrose core are critical for the inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12 was selected as a lead candidate for validation in vivo. The oral co-administration of FSE 12 with starch abrogated the increase in post-prandial glucose and significantly reduced blood glucose excursion in STZ-treated mice compared to control (starch only) mice. CONCLUSION: Our studies reveal the potential of FSEs as selective AGIs for the treatment of diabetes, with a hypothetical reduction of side effects associated with commercial AGIs.

Cinnamoyl Sucrose Esters as Alpha Glucosidase Inhibitors for the Treatment of Diabetes.

Cinnamoyl sucrose esters (CSEs) were evaluated as AGIs and their enzyme inhibition activity and potency were compared with gold standard acarbose. The inhibition activity of the CSEs against α-glucosidase and α-amylase depended on their structure including the number of the cinnamoyl moieties, their position, and the presence or absence of the acetyl moieties. The inhibitory values of the CSEs 2-9 generally increases in the order of mono-cinnamoyl moieties < di-cinnamoyl ≤ tri-cinnamoyl < tetra-cinnamoyl. This trend was supported from both in vitro and in silico results. Both tetra-cinnamoyl CSEs 5 and 9 showed the highest α-glucosidase inhibitory activities of 77 ± 5%, 74 ± 9%, respectively, against acarbose at 27 ± 4%, and highest α-amylase inhibitory activities of 98 ± 2%, 99 ± 1%, respectively, against acarbose at 93 ± 2%. CSEs 3, 4, 6, 7, 8 showed desired higher inhibition of α-glucosidase than α-amylase suggesting potential for further development as AGIs with reduced side effects. Molecular docking studies on CSEs 5 and 9 attributed the high inhibition of these compounds to multiple π-π interactions and favorable projection of the cinnamoyl moieties (especially O-3 cinnamoyl) in the enzyme pockets. This work proposes CSEs as new AGIs with potentially reduced side effects.

Continuous, high-throughput production of artemisinin-loaded supramolecular cochleates using simple off-the-shelf flow focusing device.

Lipid cochleates are gaining increasing interest as drug-carriers. However, their preparation relies on conventional batch processes that are complex, time consuming and lack batch-to-batch reproducibility; presenting a bottleneck for clinical translation. We report an efficient continuous preparation process for artemisinin-loaded cochleates (ART-cochleates) using inexpensive off-the-shelf flow focusing device. By carefully controlling the flow focusing parameters, we showed along with the mechanism that, ART-cochleates of uniform and tuneable size (~180 nm in width and ~1030 nm in length) were obtained with low dispersity (0.18 in width and 0.27 in length), narrow size distribution and high reproducibility compared to the batch process. The device achieved high throughput of 11.5 g/day with ART encapsulation of 64.24 ±â€¯2.5% and loading of 83.37 ±â€¯3.68 mg ART/g of cochleates. Art-cochleates were non-toxic and showed sustained in-vitro release of ART with effective transepithelial permeability across intestinal Caco-2 monolayer (~60% and ~25% transport for pure ART and ART-cochleates, respectively) resulting in better in-vitro bioavailability. The off-the-shelf device is envisioned to be highly promising platform for continuous and high-throughput manufacturing of drug-loaded cochleates in a controlled and reproducible manner. It has potential to enable clinical translation of drug-loaded cochleates with predicable drug release, absorption and bioavailability.