Current Enzyme Inhibition - Volume 15, Issue 1, 2019

Alzheimer’s disease (AD) is a complex neurological disorder characterised by decrease level of ACh and increased AChE expression. Inhibition of AChE is one of the common strategies to treat AD as it leads to increase Ach level quantitatively at the synaptic cleft. Acetylcholinesterase inhibitors (AChEIs) are used to treat various neurodegenerative disorders, and many are FDA approved for the management and cure of AD. AChEIs produce long term symptomatic effect, that contribute in other pathological mechanisms of the disease (e.g. formation of amyloid–β plaques) and have provided a rationale to the discovery of this class of inhibitors. Currently prescribed AChE inhibitors are Galantamine (natural alkaloid) and Rivastigmine (synthetic alkaloid compound) and have been considered beneficial for the treatment of mild to moderate AD. However, there is a need for the discovery of more effective compounds derived from natural sources as well as form synthetic sources as potential AChEIs. Findings and advances about natural and synthetic derivatives as potential sources of AChEIs will be collectively summarised in this review paper.

Background: The genus Linaria belongs to the Scrophulariaceae family. It is a large genus comprising about 200 species. Various parts of several Linaria species have been reported to exhibit various biological effects. In Algeria especially in the Sahara and steppe regions, the different species of Linaria have several uses in dietary application. Objective: The aims of this study are to evaluate the α-Glucosidase and α-Amylase inhibitory effects and the antioxidant activity using in vitro assays by an organic extract of the aerial part of Linaria aegyptiaca collected in two months, April and June, from southern Algeria. Methods: The extracts were obtained with successful maceration in (hexane, dichloromethane, acetone and methanol). The phenolics and flavonoids contents of L. aegyptiaca extracts were evaluated with Folin- Ciocalteu and aluminum chloride reagents, respectively. Then, we studied their inhibitory effects on α-Glucosidase and α-Amylase enzymes. The antioxidant potential was determined in vitro with DPPH, ABT and Phosphomolybdate tests. Results: The highest phenolic and flavonoid content were detected in the methanolic extracts of Linaria aegyptiaca collected in April. All the extracts showed good inhibitory activity on both enzymes, where the best activity was against α- amylase by acetonic extract collected in June with an IC50 = 95.03 μg/ml. The evaluation of antioxidant activity showed that all the extracts exhibited a good antioxidant capacity compared to standard antioxidants. Conclusion: The aim of this research is to establish the anti-diabetic properties and the probable alpha glucosidase and alpha amylase inhibitory activities of Algerian Linaria aegyptiaca species. These results show that this species has good antioxidant properties and a good potential for hyperglycemia management, too. The Algerian Linaria aegyptiaca can be considered as a natural source of anti-hyperglycemic treatment and might be interesting for the prospect of new molecules with antidiabetic effect.

Background: Several biological activities like anticancer, anti-inflammatory, analgesic, antitubercular activities are reported for pyrimidine scaffolds. Extensive work on pyrimidine indole scaffolds is required for antimitotic activity. Objective: To synthesize a novel Indole Pyrimidine scaffold via an efficient synthetic method and to evaluate cytotoxic activity using various human cancer cell lines. Methods: 4,4-(3-substituted phenyl)-6-methyl-N-[(Z)-(5-methyl-2-oxo-indolin-3-ylidene)amino]-2- oxo-3,4-dihydro-1H-pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated for cytotoxic activity. The structures were confirmed by IR, 1H NMR, C13NMR and Mass spectroscopy. The antiproliferative activities of the synthesized compounds were evaluated in vitro against human cancer cell lines including HeLa and MCF-7. Results: The results revealed that most of the compounds possessed moderate to excellent potency. Three among 10 molecules, showed more than 70% growth inhibition against all tested cancer cells. The nature of the substituent group (R) on the indole ring affected significantly the anti-proliferative activity of the molecules. The IC50 values of the most promising compound 4h are 76.4μM and 88.2μM against HeLa and MCF-7 respectively, which are closer to the standard compound doxorubicin. Conclusion: Molecular docking analysis demonstrated that 4b and 4d interact and bind efficiently with KSP binding site. The preliminary results made us investigate for further development of potent indole-pyrimidine scaffolds as cytotoxic agents.

Background: In the development and maintenance of male reproductive function and fertility, steroidogenesis plays a key role. Aims: The aim of the present study was to investigate the effect of the betel leaf stalk extract on 17β- hydroxy steroid dehydrogenase activity levels. Methods: The observed elevation in testicular cholesterol levels may be due to decreased androgen production, which resulted in impaired spermatogenesis. The decreased steroidogenic enzyme 17β- HSD activity represents decreased androgen production by the extract administration. Reduction in enzyme active site density and Km value revealed that there was a reduction in enzyme-substrate affinities and rate of E-S complex breakdown in the administered rat testes. Results & Conclusion: The administration of betel leaf stalk extract resulted in decreased enzyme content probably through impaired synthesis.

Background: Diabetes mellitus is the most common and fastest growing disease in the world. One of the therapies to treat diabetes is the inhibition of α-amylase activity by inhibitors from microbial and plant source. Actinomycetes are potential sources of enzyme inhibitors, drugs, amino acids, vitamins etc. Objective: Our work mainly highlights the isolation of actinomycetes from soil samples of different habitats and screening of α -amylase inhibitors. Methods: Actinomycetes were isolated from soil samples of different habitats by different methods; these include a variety of pre-treatment of soil samples in combination with an appropriate supplement medium with selective antibacterial agents. Isolated actinomycetes grown in fermentation condition and metabolites were extracted with Isopropyl alcohol and concentrated to obtain solid material. The extract of each isolate was tested for α -amylase inhibition using starch Iodine plate method and DNS- spectroscopic method. Results: Total 110 actinomycetes strains were isolated from various sources. Among 110 extracts of actinomycetes, eight extracts have shown positive results for α-amylase inhibition in starch Iodine plate assay method. Extracts selected from primary results were used for the confirmation of inhibitory activity using DNS- spectroscopic method. Out of eight extracts, six extracts showed Porcine pancreatic α -amylase inhibitory activity ranging from 40-86%. The actinomycetes strains that produce α -amylase inhibitory activity are A-24, A-29, B-5, B-18, C-15 and D-24. Conclusion: These results show that actinomycetes are a potential source for α -amylase inhibitors, which may lead to valuable novel drugs for diabetic treatment.

Background: Cells have specific enzymes (nucleoside triphosphate pyrophosphohydrolase) that hydrolyze non-canonic nucleoside triphosphates into nucleoside monophosphophates and pyrophosphate, thus removing them from the metabolic processes. This class of enzymes includes inosine triphosphate pyrophosphatase (ITPA) which has specificity to ITP, dITP, XTP and dXTP. Objective: The mutation (94C→A) rather often occurs in humans and can affect the sensitivity of patients to medicines. This mutation leads to a Pro32Thr substitution in the human ITPA protein. The mechanism for the inactivating effect of the mutation is unknown yet. Methods: Molecular modeling of the polymorphic form of inosine triphosphate pyrophosphohydrolase Р32Т-hITPA showing the greatest decrease in the enzyme activity is performed. The analysis is given for four dimer variants: wild-type (P32/P32) and mutant (T32/T32) homodimers and two mutant heterodimers (Р32/Т32 and Т32/Р32). Results: The analysis does not show the motion of the loop between α2 and β2 where mutation localized. Thus, the hypothesis of the flipped-out hydrophobic residue and subsequent of protein degradation have not been confirmed. Dimer displacements were much higher than subunit displacements. The analysis of hydrogen bonds between subunits shows that there are the more stable hydrogen bonds in the wild-type homodimer and fewer in the mutant homodimer, while heterodimers have intermediate stability. Conclusion: The results confirm the assumption of possible weakening of bonds between the mutant subunits.

Introduction: Plants supply traditional Algerian medicines for the treatment of antiinflammatory effect. The reasons for the use of traditional treatments were that pure compounds obtained were also effective in reducing the toxicities of toxic agents or other drugs. Methods: In this study, we explore the phytochemical composition and the phenolic content by indirect method to evaluate the antioxidants and the anti-inflammatory capacities of twelve extracts from three plants. Results: The total phenolic content ranged from 0.168 ± 0.020 to 4.166 ± 0.124 mg per gram of dry weight. Phytochemical screening revealed that tannins, C-heterosides, O-reduced heterosides and reducing compounds are the most common chemical groups. The highest antiradical activity was achieved with methanolic extract of Hammada elegans (EC50 = 0.551 ± 0.171mg/mL). However, the acetonic extract of Hammada elegans represents the most important reducing activity (EC50 = 0.747 ± 0.004mg/mL). Moreover, this extract also displays the highest chelating ferrous ions effect (EC50 = 5.749 ± 0.009 mg/mL) while the hydromethanolic extract of Cleome arabica has the best antilipoperoxidative effect (EC50 = 0.031 ± 0.000mg/mL). Furthermore, all extracts inhibit the activity of lipooxygenase and cyclooxygenase with IC50 values less than 19.210 ± 0.297 mg/mL. Therefore, the acetonic extract of Hammada elegans appears to be twice greater than that of standard inhibitors. Conclusion: The fractionation of the acetonic extract of Hammada elegans has given a potent bioactive compound which seems to have potential therapeutic possibilities for the prevention of the inflammatory effects.

Introduction: In recent times, a new very significant research area has developed and obtained the potential use of Carbonic Anhydrase inhibitors as Antitumor agents. Methods: A series of sulfonamides and Benzenesulfonamides with benzimidazole moieties to inhibit CSXII was considered in this study. Results and Conclusion: The best model was obtained with a predictive r2 value of 0.678 and cross validated coefficient q2 value as 0.529 in tripos CoMFA region. The paper shows that the electrostatic and steric effects are important features in Carbonic Anhydrase XII inhibition for the investigated compounds. The effort has been undertaken to search for the structural aspects of bioactive molecules.