Medicinal Chemistry - Volume 13, Issue 7, 2017

Secretory phospholipase A2 group IIA (sPLA2-IIA) is an enzyme that hydrolyzes the sn-2 ester bond in glyceroacyl phospholipids present in lipoproteins and cell membranes. As many immunohistochemical studies reveal that the high expression of sPLA2-IIA in the tumorous tissue or plasma of cancer patients, though low expression in other cases, the enzyme is considered highly relevant with cancer development. Effort has been made to establish the mechanism of how sPLA2- IIA is involved in various cancers in order to understand its pathogenic role and to utilize it as a target for cancer diagnosis and therapy. This article specifically reviews recent studies regarding the relevance of sPLA2-IIA with various cancers and reported inhibitors of the protein.

Background: N-substituted 3-amino-1H-indazoles represent an interesting class of biologically active compounds. Among them, derivatives containing phenylurea moiety are of particular interest. Such compounds have been found to possess inhibitory activity against cancer cell growth. Additionally, various oxazoline-containing compounds have also been designed as potential anticancer agents. Objective: The aim of this work was to obtain a new class of N-substituted 3-amino-1H-indazole derivatives with cytotoxic activity towards cancer cells. Method: Two series of 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylurea and 3- phenylthiourea derivatives 7-17 and 18-22, respectively, were prepared and screened for their potential in vitro cytotoxic activities against lung carcinoma LCLC-103H cell line using a crystal violet microtiter plate assay. Results: All the urea derivatives, except the compound 8, were inactive at a concentration of 20 μM attainable in cancer cells, while the thiourea derivatives showed a pronounced cancer cell growth inhibitory effects. The most potent 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-ptolylthiourea (19) exhibited cytotoxicity on the lung cancer LCLC-103H and cervical cancer SISO cell lines at a concentration of 10 μM. Moreover, compound 19 displayed cytostatic activity against pancreas cancer DAN-G cell line. Conclusion: The 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylthiourea derivatives described herein may serve as a useful scaffold for the search for novel anticancer agents.

Background: The synthesis of 1,2-oxazine-fused linear furocoumarins was performed involving the transition metal catalysis reaction of plant coumarin oreoselone derivatives. Objective and Method: The Pd-catalyzed desulfonative cross-coupling reactions of 2-(tosyl)oreoselone with terminal alkynes and the successive treatment of the obtained 2-(arylethynyl)furocoumarins with an excess of hydroxylamine gave the expected (Z,E)-3-(hydroxyimino)-2-(arylethynyl)furocoumarins with an (Z:E) ratio of about 1:0.5. The gold(III)-catalyzed cycloisomerization of furocoumarin α,β-acetylenic (Z)-oximes led to a new group of heterocyclic compounds - chromeno[6',7'4,5]furo[3,2-c][1,2]oxazine. The (E)-isomer in this condition was transformed into (E)-3-(hydroxyimino)-2-(propan-2-ylidene) furocoumarin. Results: Pharmacological screening of the synthesized 1,2-oxazine-fused linear furocoumarins for anti-inflammatory and analgesic activity in vivo revealed that this compounds possessed high activity which was depend on the substitution in the aromatic ring of the oxazine unit. The results of experimental studies were found to be in accordance with that of the in silico docking results. Conclusion: The moderate toxicity of compounds (LD50 value was more than 2000 mg/kg) encouraged the further design of therapeutically relevant analogues based on this novel type of fused linear furocoumarins.

Background: Mangiferin, was identified in the crude methanol extract, ethyl acetate, and n-butanol fractions of Aphloia theiformis (Vahl.) Benn. Objective: This study aimed to analyze the plausible binding modes of mangiferin to key enzymes linked to diabetes type 2 (DT2), obesity, hypertension, Alzheimer';s disease, and urolithiasis using molecular docking. Method: Crystallographic structures of α-amylase, α-glucosidase, glycogen phosphorylase (GP), pancreatic lipase, cholesterol esterase (CEase), angiotensin-I-converting enzyme (ACE), acetyl cholinesterase (AChE), and urease available on the Protein Databank database were docked to mangiferin using Gold 6.0 software. Results: We showed that mangiferin bound to all enzymes by π-π and hydrogen bonds mostly. Mangiferin was docked to both allosteric and orthosteric sites of α-glucosidase by π-π interactions. However, several hydrogen bonds were observed at the orthosteric position, suggesting a preference for this site. The docking of mangiferin on AChE with the catalytic pocket occupied by paraoxon could be attributed to π-π stacking involving amino acid residues, Trp341 and Trp124. Conclusion: This study provided an insight of the molecular interaction of mangiferin with the studied enzymes and can be considered as a valuable tool for designing new drugs for better management of these diseases.

Background: Aging is a risk factor of age-related diseases. With the increasing number of patients, serious consequences, and heavy economic burden, demands for drugs used to treat agerelated diseases have increased. As such, anti-aging substances should be isolated to develop drugs for the prevention and treatment of age-related diseases. Method: In this study, a methanol extract of immature Arabidopsis thaliana seeds with coat was separated by using a K6001 yeast bioassay system. In order to investigate the action mechanism, four mutants, namely, Δuth1, Δskn7, Δsod1, and Δsod2 with K6001 background were employed and the anti-oxidative stress assay was performed. Results: One new anti-aging lysophosphatidic acid (LPA) was obtained, and its structural and stereochemical characteristics were elucidated through spectroscopy and chemical derivatization. LPA can extend the replicative lifespan of K6001 at 10 and 30 μM (p < 0.001 and p < 0.01, respectively). This finding was comparable to the effect of resveratrol, a well-known anti-aging substance. However, the anti-aging activity of the compound on the four mutants was diminished. In the antioxidative stress assay, LPA improved the oxidative resistance of yeast cells. Conclusion: The new LPA may exert its anti-aging effect by improving the anti-oxidative ability of yeast cells. The genes of UTH1, SKN7, and SOD may also be involved in the action.

Background: Alzheimer's disease is caused by the destruction or loss of cholinergic cells that produce or use ACh in the brain, thereby reducing the availability of enzyme to other cells. The major treatment strategy for AD is to decrease the level of cholinesterase in the brain. Objective: The aim of this study was to describe the effect of novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) as cholinesterase inhibitors (CEIs). Method: A novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) was synthesized by treating 3-chloropentane-2,4-dione (1) with urea followed by reaction with suitably substituted benzaldehydes. Structural confirmation of all the synthesized compounds was carried out by spectroscopic techniques (FTIR, 1H and 13CNMR) and elemental analysis. Furthermore, these derivatives were subjected to biological evaluation as potential inhibitors of cholinesterases i.e. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Results: In all synthesized compounds except two compounds i.e. 3a and 3f, all compounds were identified as selective inhibitors of AChE. Compound 3a exhibited potent inhibitory values against AChE (IC50± SEM = 1.78±0.11 μM), exhibiting ≈7 times greater selectivity for AChE over BChE. Kinetics studies were performed to find out the mechanism of inhibition against respective enzyme. In addition, molecular docking studies of most potent inhibitors were also carried out to determine the binding interactions with AChE and BChE, respectively. Conclusion: In this study, novel thiazole derivatives i.e. arylidene aminothiazolylethanones were successfully synthesized, characterized and further screened for threir potential as cholinesterase inhibitors. All compounds were found as potent selective inhibitors of AChE except two compounds which exhibited dual inhibitory activities but both of these compounds were highly selective toward AChE as compared to BChE.

Background: Acetylcholinesterase (AChE) is an important target in the development of drug to treat Alzheimer's disease (AD). In this work, we investigated the effect of twenty-two synthesized chalcones on AChE activity. Objective: This work is aimed to synthesize and evaluate the effect of chalcones on the AChE activity, as well as anti-oxidant activity and predict their pharmacokinetic profile. Method: Chalcones were synthesized through a Claisen-Schmidt condensation and their inhibitory effect on the AChE was evaluated by the Elmann's colorimetric method. To determine the anti-oxidant activity the DPPH radical scavenging method was chosen. Results: We found that all chalcones inhibit this activity, with IC50 values ranging from 0.008 to 4.8 μM. We selected the most active compound 19 with an IC50 value of 0.008 μM for a kinetic study demonstrating a competitive inhibition mode. Molecular docking simulations showed a good interaction between 19 and the active site of AChE. Considering the prediction of pharmacokinetic parameters being a useful tool for selecting potential drug candidates, our study results suggest that the majority of chalcones, including the most active one, have a promising pharmacokinetic profile and blood-brain barrier permeability. The involvement of reactive oxygen species (ROS) in AD-related events has encouraged us to evaluate these chalcones as radical scavengers. Conclusion: We have found that compound 19 is a potent AChE inhibitor, and based on kinetic studies, it acts as a competitive inhibitor.

Background: To know the ability of a compound to penetrate the blood-brain barrier (BBB) is a challenging task; despite the numerous efforts realized to predict/measure BBB passage, they still have several drawbacks. Method: The prediction of the permeability through the BBB is carried out using classification trees. A large data set of 497 compounds (recently published) is selected to develop the tree model. Results: The best model shows an accuracy higher than 87.6% for training set; the model was also validated using 10-fold cross-validation procedure and through a test set achieving accuracy values of 86.1% and 87.9%, correspondingly. We give a brief explanation, in structural terms, of how our model describes the passage of molecules through the BBB. Additionally, the obtained model is compared with other approaches previously published in the international literature showing better results. Conclusion: Finally, we can say that, the present model would be a valuable tool in the early stages of drug discovery process of neuropharmaceuticals.

Background: Intrigued by the fact that aminoadamantane derivatives, bearing the active 1,2-ethylenediamine moiety, are promising antitubercular agents, we report herein the synthesis and the antitubercular evaluation of N,N'-substituded-4,4'-[adamantane-2,2-diyl]bis(phe-noxyalkylamines)1a-g, N,N'-substituded-4,4'-[adamantane-1,3-diyl]bis(phenoxyalkylamines) 2a-f, N,N'-substituded-[4-(1-adamantyl)phenoxy]alkylamines 3a-d and N,N'-substituded-[4-(2-adamantyl)-phenoxy]alkylamines 4a,b. Method: A substituted diarylmethane moiety was introduced on the adamantane skeleton of the new derivatives. The synthesis of the above compounds involved the nucleophilic attack of the corresponding phenoxide, to the appropriate aminoalkylchloride hydrochloride under heating. Results: The double substituted adamantane derivatives with an aminoether side chain exhibit significant activity against Mycobacterium tuberculosis. Conclusion: The length and the nature of the amino end of the side chain influence the antitubercular activity. The double phenolic substitution of the adamantane scaffold and the aminoether side chain with a three-methylene spacer between the phenoxy group and the nitrogen atom present the better results. (analogues 1f,g and 2e,f). These findings merit further investigation aiming at the design of more potent adamantane antituberculars, bearing a number of different substituents on the diarylmethane pharmacophore, which will also be translocated to other posititions on the adamantane ring.

Background: Pectin is a heterogeneous polysaccharide present in plants and citrus fruits. It exhibits different beneficial biological activities. Conflicting reports exist about the antimicrobial effect of pectin and its derivatives. Objective: In this study, we investigate the antimicrobial effect of Modified Citrus Pectin (MCP) against Staphylococcus aureus, a pathogen showing increasing rates of antimicrobial resistance worldwide. Method: Forty-three clinical isolates of S. aureus were obtained from a hospital in North Lebanon. Minimum Inhibitory Concentrations (MICs) and Minimum Bactericidal Concentrations (MBCs) were determined using MCP after determining its optimum pH activity. The combination between MCP and cefotaxime was then investigated for S. aureus isolates using the checkerboard technique. Results and Discussion: The optimum pH for the activity of MCP was 6.0. MIC and MBC values against S. aureus ranged between 0.39-50 μg/μl and 3.13-50 μg/μl, respectively. These values are promising for using MCP in the inhibition of some S. aureus isolates at relatively low concentrations. Combination experiments showed an additive effect in most S. aureus strains between MCP and cefotaxime, and a synergistic effect in two strains. These preliminary findings open the way for further investigation into the therapeutic potential of MCP in the treatment of S. aureus infections. Conclusion: MCP demonstrates in vitro antimicrobial activity alone and in combination with cefotaxime against S. aureus.

Background: Endophytic fungi are being recognized as vital and untapped sources of a variety of structurally novel and unique bioactive secondary metabolites in the field of natural products drug discovery. Herein, this study reports the isolation and characterization of secondary metabolites from an endophytic fungus Penicillium polonicum (NFW9) associated with Taxus fuana. Method: The extracts of the endophytic fungus cultured on potato dextrose agar were purified using several chromatographic techniques. Biological evaluation was performed based on their abilities to inhibit tumor necrosis factor-alpha (TNF-α)-induced nuclear factor-kappa B (NF-ΚB) and cytotoxicity assays. Results: Bioactivity-directed fractionation of the ethyl acetate extract of a fermentation culture of an endophytic fungus, Penicillium polonicum led to the isolation of a dimeric anthraquinone, (R)- 1,1',3,3',5,5'-hexahydroxy-7,7'-dimethyl[2,2'-bianthracene]-9,9',10,10'-tetraone (1), a steroidal furanoid (-)-wortmannolone (2), along with three other compounds (3−4). Moreover, this is the first report on the isolation of compound 1 from an endophytic fungus. All purified metabolites were characterized by NMR and MS data analyses. The stereo structure of compound 1 was determined by the measurement of specific optical rotation and CD spectrum. The relative stereochemistry of 2 was confirmed by single-crystal X-ray diffraction. Compounds 2−3 showed inhibitory activities in the TNF-α-induced NF-ΚB assay with IC50 values in the range of 0.47−2.11 μM. Compounds 1, 4 and 5 showed moderate inhibition against NF-ΚB and cancer cell lines. Conclusion: The endophytic fungus Penicillium polonicum of Taxus fuana is capable of producing biologically active natural compounds. Our results provide a scientific rationale for further chemical investigations into endophyte-producing natural products, drug discovery and development.

Background: α-Glucosidase inhibitors (AGIs) have been reported for their clinical potential against postprandial hyperglycemia, which is responsible for the risks associated with diabetes mellitus 2 and cardiovascular diseases (CVDs). Besides, a number of compounds have been reported as potent AGIs, several side effects are associated with them. Methods: The aim of present work is to explore new and potent molecules as AGIs. Therefore, a library of dibenzoazepine linked triazoles (1-15) was studied for their in vitro α-glucosidase inhibitory activity. The binding modes of potent compounds in the active site of α-glucosidase enzyme were also explored through molecular docking studies. Results and Conclusion: Among the reported triazoles, compounds 3-9, 11, and 13 (IC50 = 6.0 ± 0.03 to 19.8 ± 0.28 μM) were found to be several fold more active than the standard drug acarbose (IC50 = 840 ± 1.73 μM). Compound 5 (IC50 = 6.0 ± 0.03 μM) was the most potent AGIs in the series, about 77- fold more active than acarbose. Therefore, dibenzoazepine linked-triazoles described here can serve as leads for further studies as new non-sugar AGIs.