Small Peptides Targeting BACE-1, AChE, and A-ß Reversing Scopolamine-Induced Memory Impairment: A Multitarget Approach against Alzheimer's Disease.

Based on the biochemical understanding of Alzheimer's disease, here, we report the design, synthesis, and biological screening of a series of compounds against this neuro-disorder. Adopting the multitarget approach, the catalytic processes of BACE-1 and AChE were targeted, and thereby, compounds 15, 22, 25, 26, 27, and 30 were identified with IC50 in the submicromolar range against these two enzymes. Further, compounds 15 and 25 displayed more than 50% inhibition of ß-amyloid aggregation. Implying their physiological use, the compounds exhibited appreciable biological membrane permeability as observed through the parallel artificial membrane permeability experiment. Supporting these results, treatment of the mice with the test compounds reversed their scopolamine-affected memory impairment, where the highest healing effect was seen in the case of compound 25. Overall, the combination of molecular modeling and experimental studies provided highly effective molecules against Alzheimer's disease.

Targeting aromatase to restrain oestrogen production and developing efficacious interventions against ER-positive cancer.

Being the most frequently diagnosed disease, breast cancer is mainly classified as ER+ cancers due to the detection of estrogen receptor (ER) expression. Irrespetive of the successes achieved in the treatment of ER+ cancers by the use of selective estrogen receptor modulator (SERM) drugs like tamoxifen, resistance to the drug is a major clinical obstacle. Working on alternative treatment approaches, here, on the basis of mode of action of aromatase for the conversion of androstenedione to oestrogen, a series of compounds was developed. Results of all the experiments performed with these compounds led to the identification of three highly potent compounds 5d, 5e and 7d with their IC50 61.0, 83.0 and 54.0 nM for aromatase. Indicating their effectiveness in the treatment of ER+ cancers, appreciable tumor growth inhibitory activities of these compounds were observed against breast cancer cell lines. Further, the physico-chemical experiments including plasma protein binding, HSA binding, kinetic studies, solubility, ADME properties and molecular modelling studies supported the drug like features of the compounds.

Comparative Attenuating Impact of Camel Milk and Insulin in Streptozotocin-Induced Diabetic Albino Rats.

In this study, albino Wistar rats that have developed diabetes as a result of the drug streptozotocin (STZ) were treated with camel milk and insulin. For this, 36 rats were divided into six different (n = 6) groups: control, control + camel milk, diabetic control, insulin, camel milk, and combined camel milk + insulin. A 50 mg/kg intraperitoneal injection of STZ was used to induce diabetes. Rats with blood glucose levels exceeding 250 mg/dL after the induction of diabetes were taken into consideration for the study. The diabetic rats were treated with camel milk (50 mL/rat/day), insulin (6 units kg-1 b·wt/day), or their combination daily for 30 days. Throughout the course of the study, the rats' glucose levels and body weight were checked. In the diabetic control rats, a reduction in body weight and hyperglycemic condition was seen. Improvements in glycemic levels and weight gain were seen in the camel milk, insulin, and combined treatment groups compared to the diabetic control group; however, the combined treated group did not show the same degree of improvement as the alone treated group. Hematological changes in the diabetic control group included reductions in lymphocytes, platelets, total leukocyte count (TLC), and red blood cell (RBC) indices (mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), packed cell volume (PCV), and mean cell hemoglobin concentration (MCHC)). Each group that got insulin and camel milk separately and combined showed improvement in these changes. The liver, kidney, and pancreas in the diabetic control group had worsened morphological alterations. These histopathological alternations were significantly improved in the treatment groups. Hence, this study demonstrates the antidiabetic effects of camel milk in comparison to insulin. These findings highlight the potential of camel milk as an alternative therapy for diabetes, although further research is warranted to fully understand its mechanisms of action and long-term effects.

Structure and ligand based design for identification of highly potent molecules against 5-LOX.

We report here small molecules consisting of dichlorophenyl substituted oxindole that is further tagged with pyrrole/indole moieties. These molecules were designed on the basis of the analysis of binding mode of 5-LOX with arachidonic acid and zileuton. The molecules traverse the active site pocket of the enzyme that otherwise hosts AA and zileuton. Moreover, with a provision of derivatization at pyrrole/indole-N, the physico-chemical properties of the molecules can be adjusted. Appreciable 5-LOX inhibitory activities of the compounds in sub-micromolar range were observed and their aqueous solubility, binding with human serum albumin and stability in blood plasma and liver microsomes were checked. The Michaelis-Menten constants obtained during the binding of the compounds with 5-LOX indicated competitive binding of the compounds with the enzyme. Overall, the combination of molecular modelling and experimental studies identified promising molecules against inflammatory diseases.

Systematic Toxicity of Cypermethrin and Alterations in Behavior of Albino Rats.

The present study aimed to evaluate the effect of repeatedly orally administering cypermethrin (CYP) at different doses on the behavior, hematology, and histology of adult male and female albino rats for 1 month. For this, animals have divided into four different groups and each group contained 10 animals (5 males and 5 females). Group I served as a control group and groups II, III, and IV were represented as experimental groups and treated with CYP at doses of 25, 50, and 75 mg/kg body weight/day/rat, respectively. Through the behavioral results of this study, it was observed that cypermethrin intoxication causes dose-dependent moderate to high toxicity symptoms like vomiting, decreased food consumption, thick eye discharge, rolling, tremors, loss of coordination, tilted neck, and convulsion attacks. A significant reduction in body weight of high-dose (75 mg)-treated animals, especially in females, was noticed. Similarly, hematological data also revealed that CYP exposure caused a reduction in the level of Hb, RBC, WBC, neutrophil, and other blood indices such as PCV and MCV and an increase in the lymphocyte percentage in both male and female experimental groups. Microscopic observation stated that CYP produced infiltration of cells near the central vein, hepatocyte degeneration, congestion of the central and portal veins, hemorrhage, and necrosis in liver tissue. Shrinkage of the glomerulus, necrosis in the glomerulus and renal tubules, congestion of blood cells, and hemorrhage were seen in kidney tissue. The current study suggests that hepatotoxicity and nephrotoxicity due to cypermethrin exposure were more prominent in female rats.

Proline based rationally designed peptide esters against dipeptidyl peptidase-4: Highly potent anti-diabetic agents.

With the target to develop small molecules based anti-diabetic agents, we, herein, report the design, synthesis and biological studies on Lys-Pro and Gly-Pro esters, and a Phe-Pro-Phe tripeptide inhibiting the activity of glycoprotein dipeptidyl peptidase-4 (DPP-4). Since DPP-4 cleaves the glucagon like peptide (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) hormones which are responsible for inducing insulin secretion, the results of present studies could be significant in making control over glycemia. The structural analysis of DPP-4 and its binding mode with the substrate as well as the reported inhibitors provided the background for the design of new molecules. Among the 17 compounds screened against DPP-4, 14 compounds displayed IC50 better than the known drug Sitagliptin. Collectively, a highly encouraging set of molecules was identified that may prove as the clinical candidates for the treatment of diabetes.

A review on diverse heterocyclic compounds as the privileged scaffolds in non-steroidal aromatase inhibitors.

Breast cancer, emerging malignancy is common among women due to overexpression of estrogen. Estrogens are biosynthesized from androgens by aromatase, a cytochrome P450 enzyme complex, and play a pivotal role in stimulating cell proliferation. Therefore, deprivation of estrogen by blocking aromatase is considered as the effective way for the inhibition and treatment of breast cancer. In recent years, various non-steroidal heterocyclic functionalities have been extensively developed and studied for their aromatase inhibition activity. This review provides information about the structural-activity relationship of heterocycles (Type II) towards aromatase. This aids the medicinal chemist around the significance of different heterocyclic moieties and helps to design potent aromatase inhibitors.

Synthesis of Triphenylethylene-Naphthalimide Conjugates as topoisomerase-IIα inhibitor and HSA binder.

A series of triphenylethylene-naphthalimide (TPE-naph) conjugates was synthesized by a molecular hybridization technique, and their anticancer activity was evaluated in vitro on 60 human cancer cell lines through their cytotoxicity. The ratios of E and Z isomers were determined on the basis of HPLC methodology and NMR spectroscopy. The structure-activity relationship for anticancer activity was deduced on the basis of the nature and bulkiness of the amine attached to the C-4 position of the naphthalene ring. Experimental and molecular modeling studies of the most active TPE-naph conjugate bearing a morpholinyl group showed that it was able to inhibit topoisomerase-II (TOPO-II) as a possible intracellular target. Moreover, the transportation behavior of TPE-naph conjugate towards human serum albumin (HSA) indicated efficient binding affinity. The steady-state and time-dependent fluorescent results suggested that this conjugate quenched HSA significantly through static as well as dynamic quenching. Thus, this report discloses the scope of triphenylethylene-naphthalimide (TPE-naph) conjugates as efficient anticancer agents.

Triphenylethylene analogues: Design, synthesis and evaluation of antitumor activity and topoisomerase inhibitors.

To structurally relate anticancer drug tamoxifen used in the treatment of breast cancer, a sequence of compounds is designed and synthesized as potential drug candidates. McMurry coupling reaction is used as the key synthetic step in the preparation of these analogues and the ratios of E/Z-isomers are determined on the basis of NMR and HPLC experiments. The new compounds are found to be cytotoxic in the micromolar range with 60 human tumor cell lines at one dose and five dose concentration levels. Detailed studies on the most active compounds 11-13 show these compounds are capable to inhibit the growth of cancer cells. Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerase-II is assayed. The relevance of interaction of most active compounds with topoisomerase-II is demonstrated which is also supported by docking studies.