Design, Synthesis, Characterization and in vivo Antidiabetic Activity Evaluation of Some Chalcone Derivatives.

BACKGROUND: Diabetes is one of the growing health problems worldwide, and scientists have been striving to find effective treatment methods. In this regard, chalcones have frequently been targeted by many researchers owing to their diverse biological activities. METHODS: Here, the Claisen-Schmidt condensation reaction was applied to synthesize five chalcone derivatives. The chalcone derivatives were evaluated for their relative antidiabetic activities in vivo using streptozotocin (STZ)-induced diabetic mice. Besides, the compounds were assessed for their reduction in postprandial hyperglycemia at 50 and 100 mg/kg dose levels against a standard drug, glibenclamide. In addition, the structure-activity relationship (SAR) was analyzed to determine the effect of structural modification in chalcones activity. RESULTS: A dose-dependent reduction in postprandial hyperglycemia was observed. The highest reduction in blood glucose level (BGL) was achieved by compound 3 at a dose of 100 mg/kg (39%). This was found to be even higher than glibenclamide (34.5%). In the STZ-induced diabetic animal model, all test compounds showed comparable efficacy with glibenclamide. The SAR analysis revealed that the incorporation of electron-donating groups at position 5 of the benzaldehyde ring and position 2 of the acetophenone ring is promising to increase the antihyperglycemic activities of chalcones. CONCLUSION: The chalcone derivatives considered in this study could be used as potential lead compounds in the discovery of effective drugs to treat diabetes mellitus.

Antihyperglycemic Activity of TLC Isolates from the Leaves of Aloe megalacantha Baker in Streptozotocin-Induced Diabetic Mice.

BACKGROUND: Diabetes mellitus (DM) is a group of metabolic disorders that are characterized by hyperglycemia which results from defects in insulin release or its efficient use by the human body. Although significant progress has been made to manage DM and related complications, it remains a major global health problem. To this end, the search for new antidiabetic drugs from traditionally claimed medicinal plants is important. Aloe megalacantha Baker is an endemic plant used traditionally to treat diabetes in Ethiopia. This study aimed to investigate antidiabetic activity of isolates from the leaf of A. megalacantha Baker in streptozotocin-induced diabetic mice. METHODS: The exudate of A. megalacantha was collected by cutting the leaves and scraping the yellow sap and then dried at room temperature. The dried exudate was subjected to repeated thin layer chromatographic (TLC) separations using a mixture of solvent system to isolate the major compounds identified on the TLC plate. A single dose of streptozotocin (50 mg/kg) was injected intraperitoneally to overnight fasted mice to induce diabetes. Antidiabetic activity of TLC isolates was assessed by in vivo methods including oral glucose tolerance test, antihyperglycemic and hypoglycemic activity tests. RESULTS: Three major isolates were obtained from the TLC analysis of the exudate of A. megalacantha. Exudate and TLC isolates were found to be non-toxic up to a dose of 2000 mg/kg. The TLC isolates (Ia and Ib) significantly (p<0.05) reduced blood glucose levels and also increased body weight change of the diabetic mice compared with control groups. CONCLUSION: The present study demonstrated the ability of the exudate of A. megalacantha and its TLC isolates to significantly decrease blood glucose levels and increase body weights in mice, thus strengthening the claim of its traditional use in DM-related disorders.

In Vivo Antimalarial Evaluation of Crude Extract, Solvent Fractions, and TLC-Isolated Compounds from Olea europaea Linn subsp. cuspidata (Oleaceae).

Malaria is a major global public health problem caused by Plasmodium parasites. Drug resistance is becoming a great challenge. New drugs with novel mechanism of action are urgently required. In malarious countries, medicinal plants are commonly used for malaria treatment. Olea europaea is traditionally used against malaria in Ethiopia. The aim of this study was to isolate and evaluate antimalarial activity of chemical constituents extracted from Olea europaea against chloroquine-sensitive Plasmodium berghei-infected mice. Stem bark of Olea europaea was extracted with 80% methanol and fractionated with three solvents. The butanol fraction was subjected to isolation with preparative thin-layer chromatography (PTLC). Acute oral toxicity studies were conducted in mice as per the Organization for Economic Co-operation and Development (OECD) guideline 425. Antimalarial activities of the test substances were evaluated using Peter's 4-day suppressive test. The crude extract showed significant (p < 0.01) antiplasmodial activity at all doses with a chemosuppression value of 52.40% at a dose of 600 mg/kg. All fractions also suppressed parasitaemia significantly (p < 0.05), the highest suppression (45.42%) being with butanol fraction. In the phytochemical analysis, two compounds were isolated. Both compounds showed significant (p < 0.05) antimalarial activities. Compound C inhibited parasitaemia up to 38.19% at a dose of 200 mg/kg. The crude extract, butanol fraction, and isolated compounds also prolonged survival time of mice. No sign of toxicity and mortality was seen in the test substances at up to a single dose of 2 g/kg. Findings of the current study may confirm the traditional antimalarial claim of Olea europaea and its relative safety as well as the potentiality of compound C for further investigations.

Antimicrobial Evaluation of Latex and TLC Fractions from the Leaves of Aloe adigratana Reynolds.

BACKGROUND: The highest prevalence and emergence of microbial infections coupled with the threat of antimicrobial resistance constitute a global concern, which entails searching for novel antimicrobial agents. Medicinal plants are among the major sources of medicines for novel drug discovery. Aloe adigratana is one of the endemic Aloe species in Ethiopia where the leaf latex of the plant is traditionally used for the treatment of various pathogenic conditions such as wound, dandruff, malaria, and diabetes. In spite of such claims, there was no scientific study done so far. The aim of the current study was, therefore, to evaluate the antimicrobial effect of leaf latex of A. adigratana and its thin layer chromatography (TLC) fractions. METHODS: Thin layer chromatography (TLC) separation was employed for isolation of bioactive compounds. Agar well diffusion and microdilution assay method were used to evaluate the antimicrobial actions of the leaf latex and TLC fractions against six bacterial strains and four Candida species of reference and clinical isolate microbial strains. RESULTS: Three major fractions, AA01, AA02, and AA03, were identified by TLC. Among the tested microbial strains, the reference strain of Staphylococcus aureus ATCC 29213 (MIC = 0.06 mg/mL) and clinical Candida krusei 242/18 (MIC = 0.14 mg/mL) exhibited higher susceptibility towards AA02, while reference strains of Klebsiella pneumoniae ATCC 700603 (MIC = 0.19 mg/mL) revealed the highest susceptibility towards AA01. The leaf latex displayed the highest activity against Staphylococcus aureus ATCC 29213 and clinical Candida krusei 242/18 with a MIC value of 0.19 mg/mL. CONCLUSION: The leaf latex and TLC fractions were found to be active against the tested bacterial and Candida species. Therefore, this finding supports the traditional claim of Aloe adigratana and the need for characterization of the TLC fractions to provide as lead compounds for further comprehensive antibacterial and antifungal activities.

The relevance of Ki calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor.

Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the Ki values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC50 value. This shows that kinetic characterization of inhibitors and calculation of Ki values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors.

Sirtuin functions and modulation: from chemistry to the clinic.

Sirtuins are NAD(+)-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.