Letters in Drug Design & Discovery - Volume 14, Issue 8, 2017

Background: This work showed the use of 0-2D Dragon molecular descriptors in the prediction of α-amylase and α-glucosidase inhibitory activity. Methods: Several artificial intelligence techniques are used for obtaining quantitative structure-activity relationship (QSAR) models to discriminate active (inhibitor) compounds from inactive (non-inhibitor) ones. The machine learning methodologies such as support vector machine, artificial neural network, and k-nearest neighbor (k-NN) were employed. The k-NN technique had the best classification performances for both targets with values above 90% for the training and prediction sets, correspondingly. Results and Conclusion: These results provided a double target modeling approach for increasing the estimation of antidiabetic chemicals identification aimed by double-way workflow in virtual screenings pipelines.

Background: Thioether pleuromutilin derivatives play a dominant role in the epidemic of bacterial resistance to antibacterial agent, and the novel antibacterial compounds would exhibit fresh mechanism of function. Objective: The aim of this study was to determine the connection between thioether pleuromutilin derivatives and 50S ribosomal protein L3, discovering more potent and selective molecules. Methods: We used the 3D-QSAR and Topomer CoMFA to build molecular modeling, obtaining structure characterization required for activity. Molecular docking was conducted to observe the binding model. Besides, the ADMET descriptors were performed to predict the pharmacokinetic properties of new designed agents. Results: The models we built yield reliable statistical information: the values of correlation coefficients and cross validation coefficient are admirable. The results of molecular docking indicate that the designed compounds could bind with receptor more strongly, and that might form greater numbers of hydrogen-bonding with larger amount of residues. Finally, several newly discovered inhibitors were found to pass the entire ADMET test. Conclusion: The CoMFA/CoMSIA and Topomer CoMFA models suggest the vital factors to confirm bactericidal activity of the pleuromutilin derivatives, providing momentous guidance for designing more robust antibacterial agents. From the results of molecular docking and ADMET prediction, we detect that the introduction of F atom or gem-difluoro groups could obviously enhance inhibitory activity.

Background: Currently, aromatase inhibitors (AIs) have been developed for the treatment of breast cancers and other estrogen-related conditions. However, searching for more and new classes of AIs is being investigated. 8-Aminoquinoline (8AQ) is an interesting scaffold to be explored. In particular, 8AQ as its mixed ligands (5-nitrouracil, 5Nu and 5-iodouracil, 5Iu) metal complexes are potential compounds to be studied. Objective: Metal complexes of 8AQ-5Nu/5Iu were investigated for aromatase inhibitory activity and cytotoxicity. Methods: Metal complexes (1-6) and free ligands were evaluated for aromatase inhibitory and cytotoxic activities. Aromatase inhibitory activity of the metal complexes was performed according to a guideline of BD Gentest™ kit using CYP19 enzyme and O-benzyl fluorescein (DBF) as a substrate. Cytotoxic effect of the compounds was tested against normal embryonic lung cell line (MRC) using the MTT assay. Results: Significantly, copper complexes 3 (IC50 = 0.7 μM) and 6 (IC50 = 1.7 μM) were shown to be active aromatase inhibitors with selectivity indices of 24.74 and16.40, respectively. Conclusion: Copper complexes of 8AQ-5Nu (3) and of 8AQ-5Iu (6) were highlighted as novel aromatase inhibitors that could be further developed for therapeutic applications.

Background: Regulation of pro-inflammatory cytokines especially TNFα can have therapeutic effects in inflammatory diseases and this approach has attracted much attention for drug discovery for diseases such as rheumatoid arthritis. Objective: In the present contribution, 16 derivatives of 3,4-dihydropyrimidin-2(1H)-one(thione) C5 amide were synthesized and their anti-inflammatory activities were investigated. Methods: We synthesized 3,4-dihydropyrimidin-2(1H)-one(thione) C5 amide derivatives according to Biginelli method. Inhibitory effect of newly synthesized derivatives was evaluated on TNF-α production in lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs). Results: Most of these compounds demonstrated good inhibition of TNF-α production in lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs). Compounds 6k and 6c showed the highest levels of TNFα inhibition (74.9% and 72.2% at 50 μM, respectively). Molecular modeling study revealed that compound 6k formed a stable complex with the active site of p38α MAPK. Conclusion: The common structural feature of two most potent compounds was the presence of 6-ethoxybenzothiazol moiety on the carbamoyl group at position 5 of the DHPM ring. The findings of this study provide evidence that DHPM derivatives might be considered as promising compounds for the discovery of novel anti-cytokine agents. Amino acid decomposition analysis showed that DHPM scaffold had essential pharmacophore components of p38α MAPK inhibitors

Background: The endogenous cannabinoid system (eCB) has been shown to play an important role in the extinction of aversive memories. AM404, the metabolite of paracetamol, was shown to enhance eCB signaling. Objective: The present study was designed to pre-clinically evaluate the effectiveness of paracetamol against Post-traumatic stress disorder (PTSD). Methods: Contextual Fear conditioning (CFC) was used as animal model of PTSD. The behavioral and biochemical indicators of anxiety were also measured using elevated plus maze (EPM) and corticosterone levels, respectively. Results: Our data showed that the paracetamol treatment (100, 250 and 500 mg/kg) caused significant dose dependent decrease in animal’s freezing behavior in fear conditioned rats. The EPM data revealed that the treated rats spent more time in the open arm of elevated plus maze. However, the corticosterone levels remained unaltered. Conclusion: The present study provide robust evidence that the paracetamol, having established safety in humans, holds promise against PTSD and merits further investigation as potential lead compound in anti-PTSD drug development program.

Background: Tetrahydroxystilbene glucoside (TSG), the main active ingredient derived from the dried tubor root of Polygonum multiflorum, presents different pharmacological activities such as anti-oxidant and anti-inflammation. Recent studies indicated that TSG produced neuroprotection against Parkinson's disease (PD). However, few researches focusing on the effects of TSG on the liver cytochrome P450 (Cyp) enzyme expressions in PD animal model were also shown. Objective: This study aimed to detect the effects of TSG on liver Cyp protein expressions in lipopolysaccharide (LPS)-induced PD rat model. Methods: Male rats were randomly divided into control, model (LPS, 5μg), LPS+TSG (10 mg/kg) and LPS+TSG (50 mg/kg) groups. The dopaminergic neuronal damage rat model was induced by single direct injecting LPS into the brain substantia nigra. After seven daily intraperitoneal injection of TSG, rats were sacrificed and the livers were collected. The protein levels of liver Cyp1a2, Cyp2e1 and Cyp3a and several transcription factors, such as peroxisome proliferator-activated receptor α (PPARα ), aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), were detected by western blotting assay. Results and Conclusion: TSG (10 and 50 mg/kg) significantly increased Cyp1a2 protein expression and decreased Cyp2e1 and Cyp3a protein levels in the LPS-induced dopaminergic neuronal damage rats. Moreover, TSG (10 and 50 mg/kg) inhibited LPS-induced increase in the AhR protein level and TSG (50 mg/kg) suppressed LPS-increased PXR and PPARα protein expressions after TSG treatment for 7 days. TSG increased Cyp1a2 and decreased Cyp2e1 and Cyp3a protein expressions through the regulatory effects on AhR, PXR and PPARα activation in the LPS-induced dopaminergic neuronal damage rat liver.

Background: Compounds bearing ortho-hydroxy N-acyl hydrazone moiety have been reported with high anticancer activity acting by increasing the enzymatic activity of procaspase-3 in cancer cells and therefore inducing apoptosis in some tumour models. Methods: Considering this subunit's proclivity for anticancer activity we have synthesized novel N'-arylidene-2-[(4-nitrophenyl)piperazin-1-yl]acetohydrazide derivatives (3a-3n) including N-acyl hydrazone moiety with a well-known three step synthetic procedure. The antiproliferative activity of the compounds were investigated using MTT method and xCELLigence real time cell analysis system against NIH/3T3 (Mouse embryo fibroblast cell line) as healthy cell line and A549 (Human lung adenocarcinoma ephitelial cell line) as tumour cell line. Results and Conclusion: The IC50 values of final compounds were determined for 24h and 48h incubation periods. As a second stage, flow cytometric analysis was performed for selected highly active compounds (3g, 3i, 3j, 3n) on A549 cell line. Compound 3i bearing 3-chlorophenyl moiety was detected to cause apoptosis in a ratio of 54.7 %.

Background: A series of ferulic acid-donepezil hybrids were designed, synthesized and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. Methods: Among the synthesized compounds, compound TM-I-3 acted as an antioxidant (1.1eq of Trolox), showed the highest BuChE inhibitory activity with IC50 value of 3.4 ± 0.21 μM, the result of molecular provided a possible mechanism for its unexpected inhibitory activity against BuChE. In addition, compound TM-I-3 inhibited and disaggregated self-induced Aβ1-42 aggregation by 61.1±1.8% and 53.1 ±3.4% at 25μM respectively, which was consistent with the transmission electron microscopy (TEM) and molecular modeling study. Moreover, TM-I-3 exhibited a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in PC12 cells. Furthermore, our investigation proved that TM-I-3 could penetrate the blood-brain barrier (BBB) in vitro, and abided by the Lipinski’s rule of five. Results and Conclusion: These data suggest that compound TM-I-3, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drugdiscovery development against the advanced stages of AD.

Background: A series of 5-(arylideneamino)-1H-pyrazole-4-carbonitriles 8a-h was synthesized via reaction of triethylorthoformate 1 with malononitrile 2 in presence of acetic anhydride to give ethoxymethylenemalononitrile 3. Compound 3 was reacted with 4-methanesulfonylphenylhydrazine 4 to give 5-amino-1H-pyrazole-4-carbonitrile 5 that condensed with different aromatic aldehydes 6a-h in presence of the ionic liquid morpholinium hydrogen sulphate 7 to form the target 5-(arylideneamino)-1H-pyrazole-4-carbonitrile compounds 8a-h. Methods: All the synthesized compounds were evaluated for their cyclooxygenase selectivity, antiinflammatory, and molecular docking study for COX 2 enzyme. 8a and 8e were the most potent COX-2 inhibitors (IC50 = 0.98, 1.3 μM respectively). Results: While most compounds showed good anti-inflammatory activity at all time intervals (1, 3 and 5 h), 8d derivative displayed the highest anti-inflammatory activities (94.61, 98.35, and 99.92%, respectively) and the most COX-2 selective derivatives 8a and 8e showed considerable potency (47.43, 88.94, and 98.44% respectively for 8a and 51.90, 89.13, and 98.20% respectively for 8e) comparable to that of celecoxib (92.77, 97.77, and 99.51% respectively). Also, 8d showed less ulceration effect (ulcer index = 2.9) than celecoxib (ulcer index = 3.35) and aspirin (ulcer index 22.75). Conclusion: Additionally, all the tested compounds showed good binding affinity for COX 2 enzyme in the molecular docking studies.

Background: In this work, 2-[[5-(4-aminophenyl)-4-(4-substituted phenyl)-4H-1,2,4-triazol-3-yl]thio]-1-(4-substituted phenyl)ethan-1-one derivatives (1-15) and 2-[[5-(4-aminophenyl)-4-(4-substituted phenyl)-4H-1,2,4-triazol-3-yl]thio]-N-(4-substituted phenyl)acetamide derivatives (15-30) were synthesized using 4-aminobenzohydrazide as starting material. Methods: These compounds were screened to determine their antimicrobial activities against Grampositive bacteria B. cereus, S. aureus, E. faecalis, L. monocytogenes; Gram-negative bacteria E. coli, P. aeruginosa, K. pneumoniae, S. typhimurium, yeasts C. parapsilosis, C. albicans, C. glabrata, C. krusei; molds A. niger, A. flavus, A. parasiticus, A. fumigatus, Rhizopus sp., A. alternate, S. rolfsii and a mycobacteria M. tuberculosis. Results and Conclusion: Compounds 2, 6, 7, 8 have displayed antituberculotic potential as much as standard drug, rifampicin. Also, compounds have exhibited moderate antibacterial and antifungal activities, contrary to expectations.

Background: The cyclooxygenase (COX) enzymes are important biological targets for non-steroidal anti-inflammatory (NSAID) drugs because they can inhibit the prostaglandin synthesis during the inflammatory process. Although COX enzymes are structurally well characterized, accurate ligand docking studies are challenging due to their varied structural and chemical properties. Methods: We conducted molecular docking studies of 30 structurally diverse NSAIDs using two different software packages in an effort to examine if a linear dependency between experimental IC50 values (50% binding inhibition) and binding energies is realistic for this class of compounds. Results: Results showed that the docking technique can approximate the selectivity of NSAIDs via energetic terms but not the IC50. Evaluation of ADME parameters coupled with multiple linear regression was performed to create statistically significant QSAR models correlating IC50 values to physicochemical and biological parameters for the COX-2 enzyme. Conclusion: The distribution of the electrostatic potential, nucleophilicity and electrophilicity was found to be the most important descriptor for drug-enzyme interactions.

Background: Recent studies indicated that indole biphenylcarboxylic acids exhibited antidiabetic properties in diet-induced obese mice through antagonism of PPAR.γ Objective and Method: In order to explore structure activity relationship and the interactions with PPARγ, thus finding new active compounds, we carried on some researches by molecular docking and 3D-QSAR studies. We also explored structure activity relationship of these compounds by 3DQSAR studies. A Partial Least Squares (PLS) model was built using energy grids as descriptors. Results and Conclusion: This model of training set r2 is 0.995, test set r2 is 0.614, the model also has a cross-validation q2 value of 0.556. According to the molecular docking results and contour maps derived from the 3D-QSAR model, we carried out structural optimization and designed several new compounds to improve the predicted biological activity and dock scores of original ones. The new compounds could offer a possible orientation for finding potential drugs.

Background: Depressive disorders are among four leading causes of burden among the most disabling medical illnesses and antidepressant drugs (AD) occupying leading positions in the worldwide pharmaceutical market. However, typical AD show prolonged delay, refractory and adverse side effects. Methodology: The review analyzes experimental data and theoretical models of possible antidepressant effect of benzopentathiepine, 8-(trifluoromethyl)-1,2,3,4,5 - benzopentathiepin-6- amine hydrochloride (TC-2153). The antidepressant effect of TC-2153 is based on its ability to inhibit striatal enriched protein tyrosine phosphatase (STEP)- an enzyme that plays a key role in the intraneuronal transduction of signals from receptors of classic neurotransmitters and the brain derived neurotrophic factor (BDNF). The mechanism underlying antidepressant effect of TC-2153 includes increase in production as well as intracellular effect of BDNF on neuronal survival and neurogenesis. Results and Conclusion: There is no visible mechanisms of delay, refractory and adverse side effects of TC-2153. Thus, TC-2153 is a promising drug of new generation of atypical AD.