Current Enzyme Inhibition - Volume 14, Issue 1, 2018

Chalcones and aurones are natural products which belong to the flavonoid family and possess a variety of pharmacological and biological activities. Chalcones and, in a lesser extent, aurones, are especially versatile chemical scaffolds, therefore a large number of synthetic analogues have been prepared and studied for their tyrosinase inhibitory activity. This report aims to briefly present all the studies about the tyrosinase inhibitory activity of chalcones and aurones, which are dated from 2009 until now. The type of inhibition mechanism as well as the key structural features that enhance activity are discussed. The review reveals the importance of tyrosinase inhibitors of the structural type as whitening agents in cosmetology, as antibrowning agents in food chemistry, and as therapeutics.

Introduction: Modified quinolines have been used as metal chelators, and they have drawn the attention of researchers due to the possible biological approaches with a broad scope of application. This study aims to evaluate the in vitro biological effects of seven quinolinic compounds in RAW macrophage culture, blood cells and in Candida albicans fungus. Methods: Cell viability and proliferation of macrophages were evaluated using trypan blue and MTT staining assays. Gene expression was analyzed through RT-qPCR. Hematological analysis was carried out using flow cytometry and coagulogram tests. The analysis of Candida albicans strains was performed through the Minimum Inhibitory Concentration test (MIC). Results: The compounds did not significantly interfere with cell viability and proliferation of macrophages; however, compounds 6 and 7 increased the expression of both TNF-α and TGF-β1. Compound 3, in turn, only increased the expression of TNF-α and compound 4 increased TGF-β1 expression. Conclusion: There were significant alterations in blood cellularity and in human coagulation cascade. Nevertheless, no fungicidal or fungistatic effect could be observed regarding Candida albicans.

Background: A range of biological activities including anti-inflammatory, antiangiogenic, antitubercular and kinase inhibitory activity have been reported for pyrazole derivatives. Serious medicinal chemistry approaches for the development of effective antibacterial agents have resulted in only few new compounds with the lack of activity against a wide range of microbes. In continuation with our quest for developing anti-inflammatory and antimicrobial agents bearing pyrazole scaffold, a series of N-pyrazolylbenzamides 1-22 were synthesized. Methods: All the desired compounds have been synthesized by following reported chemical reactions and upon confirmation of structure of compounds through spectral data, all the compounds were screened for antibacterial including resistant strains, antifungal, antitubercular activity and antiinflammatory activity. Results: In the antibacterial activity screening four compounds exhibited potent antibacterial activity and admirable antifungal activity. Compounds 7 and 17 demonstrated potent activity with MIC of 3.12 μg/mL against Bacillus subtilis and compounds 3 and 17 were found to be highly potent against some of resistant strains with MIC value of 3.12 μg/mL. Compounds 5 and 17 showed antitubercular activity with MIC value of 6.25 μg/mL. All the compounds were also subjected for anti-inflammatory activity at 50 mg/Kg dose, three compounds 8, 12 and 16 produced significant anti-inflammatory activity over 50% in the third hour of observation. Conclusion: Structurally characterized compounds have been screened for anti-inflammatory and antimicrobial activities. Compounds 7 and 17 were found to be potent antibacterial compounds and 17 emerged out as one of the potent compounds with activity against MRSA, VRSA and E. faecium and 5 and 17 showed MIC value of 6.25 μg/mL against H37Rv mycobacterial strain. Compounds 4, 7, 8, 12 and 16 exhibited anti-inflammatory activity.

Background: The involvement of 3α-hydroxysteroid dehydrogenase (3α-HSD AKR1C2) in the processes of liver metastasis and prostate cancer has been previously reported. Increased 5α- reductase 1 (5α-R1) activity in prostate cancer has also been reported. Therefore, overexpression of 3α-HSD and 5α-R1 could be related to drug resistance and disease progression of liver and prostate tumors. Aim: The aim of this study was to identify the in vitro activity of 13 different 17β-Narylcarbamoylandrost- 4-en-3-one derivatives as inhibitors of 3α-hydroxisteroid dehydrogenase (AKR1C9) and 5α-R1 present in rat liver microsomes. Methods: The methods for synthesis, molecular docking, and identification 13 different 17β-Narylcarbamoylandrost- 4-en-3-one derivatives as specific inhibitors of the activity of 5α-R1 or 3α-HSD (AKR1C9) were detailed in this paper. The activity of these enzymes was obtained using solubilized microsomes of rat liver in the presence or absence of each novel steroid. Results: Data indicated some of these derivatives specifically inhibited the activity of 5α-R1, with a parallel decrease in 3α-diol formation. In addition, the other steroids prevented 3α-HSD activity, inducing the accumulation of 5α-DHT under conditions of reduction of the reaction. The steroid that inhibited 3α-HSD activity most strongly was 17β-N-(4-methoxyphenylcarbamoyl)androst-4-ene-3-one, since this compound performed key interactions; a hydrogen bond between the p-OCH3 group, and the side chain Arg133 present in 3α-HSD (AKR1C9). In addition, we identified the most potent inhibitors of 5α-R1 activity of this series as the 17β-N-(3-methoxyphenylcarbamoyl)androst-4-ene-3-one, and 17β-N-(3-fluorophenylcarbamoyl)androst-4-ene-3-one, which have hydrogen-bond-acceptor groups and the best molecular spatial arrangement to inhibit this enzyme. Conclusion: The results suggested that inhibitors should be dual to prevent 5α-reductase 1 and 3α- HSD activity, since it should be considered the latter enzyme could increase intraprostatic 5α-DHT under oxidizing reaction conditions, whereas to prevent metastasis, it would be appropriate to use 3α- HSD inhibitors.

Background: Depression associated with asthma enhances asthma-related morbidity and mortality. While antidepressants (AD) are prescribed in depression, β2-adrenergic agonists (BAA) and xanthines are used in asthma. Asthma treatment side effects include depression and suicidal ideation. Objective: Here, we identified a possible mechanism of BAA and xanthines to induce depressant or antidepressant responses by advanced methods of computational pharmacology correlated with clinical studies. Methods: Based on 18 AD, 7 BAA and two xanthines, here were generated quantitative structureactivity relationship (QSAR) models establishing the contribution of drugs molecular descriptors to the binding affinity for two membrane receptors deeply involved in depression, namely serotonin transporter SERT and serotonin receptor 5-HT1A. Results: QSAR models with good statistical validation parameters (q2 (cross-validated r2) higher than 0.70 and fitted correlation r2, higher than 0.80) were obtained considering the critical molecular descriptors: solvent accessible surface areas, energy of solvatation, hydrophobicity and count of rotatable bounds. The results suggest that: (i) clenbuterol should exert middle antidepressant effects, (ii) theophylline could induce suicidal ideation at the beginning of treatment due to its similarity with escitalopram, (iii) salbutamol may be safely used in depressive asthmatic patents, (iv) indacaterol antidepressant effects should be more significant than those of other long-acting BAA, and (v) the usage of fenoterol and formoterol may induce mania, delirium, etc. Conclusion: The molecular mechanisms of BAA and xanthines evaluated here represent important resources for future studies focused on depression in asthma.

Background: Nowadays molecular modeling is widely used in different areas of scientific research. Especially in medical and pharmaceutical research molecular modeling allows saving time and money in conception of new drugs by comprehension of interaction between disease's enzymes and inhibitors for probable formation of stable complex. Cinnamon as famous plant and culinary spice is highly recommended in treatment of type 2 diabetes by many researchers. Methods: By molecular modeling and molecular docking, interactions between type 2 diabetes enzyme (DPP-4) and characteristically molecules of cinnamon are studied. Results: Molecules from different parts of cinnamon interact differently with diabetes type 2 enzyme (DPP-4) and confirm primary studies concerning cinnamon anti-diabetic effect. Conclusion: Buds and flowers molecules of cinnamon inhibit DPP-4 enzyme better than barks commonly used as spices and traditional medicines.

Background: Many peptides are produced from food proteins during the manufacturing of various functional foods; unexpected and valuable physiological activities are frequently identified in such released peptides. Elastin, which normally exists as an insoluble elastic fiber, is being used as a new health food material in accordance with the progress in solubilization techniques for elastin. Objective: To evaluate the usefulness of elastin as a material for functional foods, we prepared highly pure, water-soluble elastin from pig aorta and evaluated its angiotensin-converting enzyme (ACE)- inhibitory activity. Method: Pure, water-soluble elastin was prepared from pig aorta using a hydrolyzing method employing a hot alkali reagent. Efficient enzymatic degradation of the elastin was achieved by using elastase that is specific for elastin. The ACE-inhibitory activities of elastin and of peptides obtained via enzymatic degradation were investigated. Three novel ACE-inhibiting peptides were purified from the degradation, and we investigated their ACE-inhibitory activities. Results: Highly pure, water-soluble elastin was prepared from pig aorta; this elastin preparation showed weak inhibitory activity (8.4% inhibition) against ACE. Surprisingly, 6-fold greater enzymeinhibitory activity was observed for elastin peptides obtained from elastase-mediated degradation of the soluble elastin (48.0% inhibition). Among the enzymatically degraded elastin peptides, three were purified and their primary structures were newly characterized as Val-Tyr-Pro-Gly, Val-Gly-Val-Ala- Pro-Gly, and Gly-Tyr-Pro-Ile. All three peptides showed apparent ACE-inhibitory activity, and Val- Tyr-Pro-Gly exhibited the highest inhibitory capacity among them (60.6% inhibition). Conclusion: These results suggest that water-soluble elastin may serve as a functional food to exert a blood pressure-lowering effect in the body.

Background: Trypsin Inhibitors are one of the most promising and investigated subject for their role in pharmacognostical and pharmacological studies. Aim: The paper describes purification and characterization of trypsin inhibitor obtained from blackeyed cowpea (Vigna unguiculata). Methods: The purification procedure of Vigna unguiculata trypsin inhibitor (VUTI) includes homogenization followed by ammonium sulphate precipitation. The protein thus precipitated was further dialysed and purified by ion exchange chromatography and gel permeation chromatography. The molecular weight was determined by SDS-PAGE. The protein thus purified was characterized biochemically to demonstrate curative potential as strong antioxidant, anti-inflammatory and antimicrobial agent. Results: The 15 kDa VUTI obtained showed IC50 values 490 μg/ml compared to standard which was 254μg/ml in 1, 1-diphenyl-2-picrylhydrazyl (DPPH) assay. Also, the highest ferric reducing antioxidant power (FRAP) results confirmed the highest FRAP value of 0.405 mM at 1000 μg/ml and the lowest value of 0.113 mM at 100 μg/ml which were quite comparable to ascorbic acid (standard). Anti-inflammatory activity of VUTI was depicted by the method of inhibition of albumin denaturation where, VUTI showed high IC50 value of 696.46 μg/ml. Also, VUTI showed good antibacterial potential by inhibiting all tested bacterial strains with maximum inhibition against Bacillus subtilis (99.62%) and minimum against Staphylococcus aureus (34.62%). The results were quite comparable with standard drug ampicillin (5 mg/ml). Unfortunately, VUTI failed to show any activity against fungi. Conclusion: Thus, the results obtained depict that VUTI additionally be a wonderful candidate for development of novel antibacterial drugs, and it can also be used to reduce the deletorious effects of free radicals.