Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches.

Diabetes mellitus (DM) is counted among one of the leading challenges in the recent era, and it is a life-threatening disorder. Compound 4-hydroxy 3-methoxy phenylacetone (compound 1) was previously isolated from Polygonum aviculare. This compound was reacted with N-benzylmaleimide to synthesize the targeted compound 3. The purpose of this research is to exhibit our developed compound 3's ability to concurrently inhibit many targets that are responsible for hyperglycemia. Compound 3 was capable of inhibiting α-amylase, α-glucosidase, and protein tyrosine phosphatase 1 B. Even so, outstanding in vitro inhibition was shown by the compound against dipeptidyl peptidase-4 (DPP-4) with an IC50 value of 0.07 µM. Additionally, by using DPPH in the antioxidant activity, it exhibited good antioxidant potential. Similarly, in the in vivo activity, the experimental mice proved to be safe by treatment with compound 3. After 21 days of examination, the compound 3 activity pattern was found to be effective in experimental mice. Compound 3 decreased the excess peak of total triglycerides, total cholesterol, AST, ALT, ALP, LDL, BUN, and creatinine in the STZ-induced diabetic mice. Likewise, the histopathology of the kidneys, liver, and pancreas of the treated animals was also evaluated. Overall, the succinimde moiety, such as compound 3, can affect several targets simultaneously, and, finally, we were successful in synthesizing a multi-targeted preclinical therapy.

New Succinimide-Thiazolidinedione Hybrids as Multitarget Antidiabetic Agents: Design, Synthesis, Bioevaluation, and Molecular Modelling Studies.

Diabetes mellitus (DM) is a metabolic disorder majorly arising from the pathophysiology of the pancreas manifested as a decline in the insulin production or the tissue's resistance to the insulin. In this research, we have rationally designed and synthesized new succinimide-thiazolidinedione hybrids for the management of DM. In a multistep reaction, we were able to synthesize five new derivatives (10a-e). All the compounds were new containing a different substitution pattern on the N-atom of the succinimide ring. Initially, all the compounds were tested against the in vitro α-glucosidase, α-amylase, PTP1B, and DPP4 targets. In all of these targets, the compound 10d was observed to be the most potential antidiabetic agent. Based on this, the antidiabetic activity of the compound 10d was further investigated in experimental animals, which overall gave us encouraging results. The molecular docking studies of the compound 10d was also performed against the target enzymes α-glucosidase, α-amylase, PTP1B, and DPP4 using MOE. Overall, we observed that we have explored a new class of compounds as potential antidiabetic agents.

3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent.

The chiral drug candidates have more effective binding affinities for their specific protein or receptor site for the onset of pharmacological action. Achieving all carbon stereopure compounds is not trivial in chemical synthesis. However, with the development of asymmetric organocatalysis, the synthesis of certain vital chiral drug candidates is now possible. In this research, we have synthesized 3-(((1S,3S)-3-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione (S,S,R-5) and have evaluated it potential as multi-target antidiabetic agent. The stereopure compound S,S,R-5 was synthesized with a 99:1 enantiomeric ratio. The synthesized compound gave encouraging results against all in vitro antidiabetic targets, exhibiting IC50 values of 6.28, 4.58, 0.91, and 2.36 in α-glucosidase, α-amylase, PTP1B, and DPPH targets, respectively. The molecular docking shows the binding of the compound in homology models of the respective enzymes. In conclusion, we have synthesized a new chiral molecule (S,S,R-5). The compound proved to be a potential inhibitor of the tested antidiabetic targets. With the observed results and molecular docking, it is evident that S,S,R-5 is a potential multitarget antidiabetic agent. Our study laid the baseline for the animal-based studies of this compound in antidiabetic confirmation.

α-Glucosidase, α-Amylase and Antioxidant Evaluations of Isolated Bioactives from Wild Strawberry.

Diabetes mellitus is a metabolic disorder and is a global challenge to the current medicinal chemists and pharmacologists. This research has been designed to isolate and evaluate antidiabetic bioactives from Fragaria indica. The crude extracts, semi-purified and pure bioactives have been used in all in vitro assays. The in vitro α-glucosidase, α-amylase and DPPH free radical activities have been performed on all plant samples. The initial activities showed that ethyl acetate (Fi.EtAc) was the potent fraction in all the assays. This fraction was initially semi-purified to obtain Fi.EtAc 1-3. Among the semi-purified fractions, Fi.EtAc 2 was dominant, exhibiting potent IC50 values in all the in vitro assays. Based on the potency and availability of materials, Fi.EtAc 2 was subjected to further purification to obtain compounds 1 (2,4-dichloro-6-hydroxy-3,5-dimethoxytoluene) and 2 (2-methyl-6-(4-methylphenyl)-2-hepten-4-one). The two isolated compounds were characterized by mass and NMR analyses. The compounds 1 and 2 showed excellent inhibitions against α-glucosidase (21.45 for 1 and 15.03 for 2 µg/mL), α-amylase (17.65 and 16.56 µg/mL) and DPPH free radicals (7.62 and 14.30 µg/mL). Our study provides baseline research for the antidiabetic bioactives exploration from Fragaria indica. The bioactive compounds can be evaluated in animals-based antidiabetic activity in future.

In Silico Molecular Docking and Simulation Studies of Protein HBx Involved in the Pathogenesis of Hepatitis B Virus-HBV.

Current drug discovery involves finding leading drug candidates for further development. New scientific approaches include molecular docking, ADMET studies, and molecular dynamic simulation to determine targets and lead compounds. Hepatitis B is a disease of concern that is a life-threatening liver infection. The protein considered for the study was HBx. The hepatitis B X-interacting protein crystal structure was obtained from the PDB database (PDB ID-3MSH). Twenty ligands were chosen from the PubChem database for further in silico studies. The present study focused on in silico molecular docking studies using iGEMDOCK. The triethylene glycol monoethyl ether derivative showed an optimum binding affinity with the molecular target HBx, with a high negative affinity binding energy of -59.02 kcal/mol. Lipinski's rule of five, Veber, and Ghose were followed in subsequent ADMET studies. Molecular dynamic simulation was performed to confirm the docking studies and to analyze the stability of the structure. In these respects, the triethylene glycol monoethyl ether derivative may be a promising molecule to prepare future hepatitis B drug candidates. Substantial research effort to find a promising drug for hepatitis B is warranted in the future.

Insights Into MRI Neuroimaging Patterns of COVID-19 in Children: A Retrospective Comprehensive Analysis.

RATIONALE AND OBJECTIVES: Neurological complications associated with coronavirus disease (COVID-19) have been reported in children; however, data on neuroimaging findings remain limited. This study aimed to comprehensively examine neuroimaging patterns of COVID-19 in children and their relationship with clinical outcomes. MATERIALS AND METHODS: This retrospective cross-sectional study involved reviewing the medical records and MRI scans of 95 children who developed new neurological symptoms within 2-4 weeks of clinical and laboratory confirmation of COVID-19. Patients were categorized into four groups based on guidelines approved by the Centers for Disease Control and Prevention (CDC). Initial brain/spinal MRI was performed. Images were reviewed by three blinded radiologists, and the findings were analyzed and categorized based on the observed patterns in the brain and spinal cord. Follow-up MRI was performed and analyzed to track lesion progression. RESULTS: Encephalopathy was the most common neurological symptom (50.5%). The most common initial MRI involvement patterns were non-confluent multifocal hyperintense white matter (WM) lesions (36.8%) and ischemia (18.9%). Most patients who underwent follow-up MRI (n = 56) showed complete resolution (69.9%); however, some patients developed encephalomalacia and myelomalacia (23.2% and 7.1%, respectively). Non-confluent hyperintense WM lesions were associated with good outcomes (45.9%, P = 0.014), whereas ischemia and hemorrhage were associated with poor outcomes (44.1%, P < 0.001). CONCLUSION: This study revealed diverse neuroimaging patterns in pediatric COVID-19 patients. Non-confluent WM lesions were associated with good outcomes, whereas ischemia and hemorrhage were associated with poorer prognoses. Understanding these patterns is crucial for their early detection, accurate diagnosis, and appropriate management.

A Glimpse into Milestones of Insulin Resistance and an Updated Review of Its Management.

Insulin is the main metabolic regulator of fuel molecules in the diet, such as carbohydrates, lipids, and proteins. It does so by facilitating glucose influx from the circulation into the liver, adipose tissue, and skeletal myocytes. The outcome of which is subjected to glycogenesis in skeletal muscle and lipogenesis in adipose tissue, as well as in the liver. Therefore, insulin has an anabolic action while, on the contrary, hypoinsulinemia promotes the reverse process. Protein breakdown in myocytes is also encountered during the late stages of diabetes mellitus. The balance of the blood glucose level in physiological conditions is maintained by virtue of the interactive functions of insulin and glucagon. In insulin resistance (IR), the balance is disturbed because glucose transporters (GLUTs) of cell membranes fail to respond to this peptide hormone, meaning that glucose molecules cannot be internalized into the cells, the consequence of which is hyperglycemia. To develop the full state of diabetes mellitus, IR should be associated with the impairment of insulin release from beta-cells of the pancreas. Periodic screening of individuals of high risk, such as those with obesity, hypercholesterolemia, and pregnant nulliparous women in antenatal control, is vital, as these are important checkpoints to detect cases of insulin resistance. This is pivotal as IR can be reversed, provided it is detected in its early stages, through healthy dietary habits, regular exercise, and the use of hypoglycemic agents. In this review, we discuss the pathophysiology, etiology, diagnosis, preventive methods, and management of IR in brief.

Design, synthesis and bioevaluation of new vanillin hybrid as multitarget inhibitor of α-glucosidase, α-amylase, PTP-1B and DPP4 for the treatment of type-II diabetes.

Diabetes mellitus (DM) is a real challenge to the recent era and is one of the major diseases for initiating life-threatening disorders. In current research, a compound was designed by combining vanillin, thiazolidinedione and morpholine. The goal of our designed work is to demonstrate the ability of our design compound (9) to modulate more than one target responsible for hyperglycemia at the same time. The synthesized compound was able to show good to moderate inhibition potential against α-glucosidase, α-amylase and protein tyrosine phosphatase 1B. However, it exhibited excellent in-vitro inhibition of Dipeptidyl peptidase-4 (DPP-4) with IC50 value of 0.09 µM. Antioxidant activity by using DPPH assay also showed its good antioxidant potential. In in-vivo experiments, the compound 9 was proved to be safe in experimental mice. The activity profile of the compound was observed for 21 days which showed that the compound was also effective in experimental mice. Binding orientations and Interactions with key amino acid residues of the selected targets were also studied by using docking studies. Overall, we were successful in synthesizing multitarget preclinical therapeutic by combining three pharmacophoric moieties into a single chemical entity that can modulate more than one target at the same time.

Preparation of Spice Extracts: Evaluation of Their Phytochemical, Antioxidant, Antityrosinase, and Anti-α-Glucosidase Properties Exploring Their Mechanism of Enzyme Inhibition with Antibrowning and Antidiabetic Studies In Vivo.

Tyrosinase and α-glucosidase enzymes are known as promising target candidates for inhibitors to control unwanted pigmentation and type II diabetics mellitus. Therefore, twenty extracts as enzyme inhibitors were prepared from edible spices: nutmeg, mace, star anise, fenugreek, and coriander aiming to explore their antioxidant, antibrowning, and antidiabetic potential. Results confirmed that all extracts showed potent antioxidant activity ranging from IC50 = 0.14 ± 0.03 to 3.69 ± 0.37 µg/mL. In addition, all extracts exhibited excellent antityrosinase (IC50 = 1.16 ± 0.06 to 71.32 ± 4.63 µg/mL) and anti-α-glucosidase (IC504.76 ± 0.71 to 42.57 ± 2.13 µg/mL) activities outperforming the corresponding standards, hydroquinone, and acarbose, respectively. Among all extracts, star anise ethyl acetate (Star anise ETAC) was found most potent inhibitor for both tyrosinase and α-glucosidase enzymes and was further studied to explore the mechanism of enzyme inhibition. Kinetic analysis revealed its irreversible but mixed-type tyrosinase inhibition with preferentially competitive mode of action. However, it binds reversibly with α-glucosidase through competitive mode of action. Further, star anise ETAC extract showed concentration dependent and posttreatment time-dependent antibrowning effect on potato slices and antidiabetic effect on diabetic rabbits in vivo proposing it promising candidate for tyrosinase-rooted antibrowning and α-glucosidase-associated diabetes management for future studies.