Letters in Drug Design & Discovery - Volume 14, Issue 9, 2017

Objective: We aim to provide new insight and scientific evidence for rational design and discovery of phosphodiesterase-9A (PDE9A) inhibitors with remarkable potency and weak side effect to treat CNS diseases such as Alzheimer's disease. Methods: Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of PDE9A inhibitors. Moreover, two different alignment methods, docking-based structural alignment (DCBA) and local lowest energy structure based alignment (LESBA), were employed to scrutinize their effects on the robustness and predictive capability of 3D-QSAR models. Results: The models generated by CoMFA had a cross-validated coefficient (q2) of 0.771 and a regression coefficient (r^{2) of 0.983. The CoMSIA models had a (q2) of 0.776 and (r2) of 0.960. The external predictive capability of the built models was evaluated by using the test set of nine compounds. From obtained results, the CoMSIA models were found to have highly predictive capability in comparison with CoMFA models. Contour maps of CoMSIA models provided many helpful structural insights, including N1-bulkier hydrophobic group such as cyclopentyl group better filling the metal binding pocket in the PDE9A to show stronger inhibitory activity.} Conclusions: Docking-based 3D-QSAR studies is helpful to improve the design of pyrazolopyrimidinone derivatives as PDE9A inhibitors to develop new chemical entities with higher selectivity.

Background: P-glycoprotein (p-gp) is one of the membrane transporter protein belong to the ATP-binding cassette which can efflux drugs to the out of the cell and cause drug resistance. Therefore, designing of new compounds with p-gp inhibitory activity can reduce drug resistance. Objective: Our aim is to introduce quantitative structure activity relationship (QSAR) models for predicting the p-gp inhibitory activity of the methylated polyphenol derivatives. Methods: Structure and activity of 52 compounds were obtained from the literature. Structure of the molecules were optimized using Hyperchem software, and molecular descriptors were calculated by the Dragon software. For external validation of the QSAR models, the data split to training and test sets using random sampling and rational methods (activity sampling and Kennard-Stone algorithm). The QSAR models were established by using both linear methods, i.e., multiple linear regression (MLR) and non-linear methods, i.e., artificial neural networks (ANN) and support vector machine (SVM). Results: Non-linear models and rational training and test set selection methods can introduce better results for predicting the activity. Conclusion: The developed QSAR models were able to predict the p-gp inhibitory activity of the studied compounds with good accuracy.

Introduction: According to WHO, cancer is one of the most leading causes of death. Development of anticancer drugs draw considerable attention. Pyridazinones analogues were reported to possess anticancer properties. Chemical modification of pyridazinone may lead to potential anticancer agent. Objective: The objective of this article is to develop new pyridazinone deriatives and evaluate their anticancer activities. Results: The target compounds were synthesized using Palladium cross coupling reactions, Buchwald and Suzuki, the synthesized compound were evaluated against BT-549, KB and SK-MEL cell lines. Some compounds showed moderate to significant inhibitory activity. Conclusion: Novel pyridazinone derivatives were synthesized in a good yield. Some of the synthesized analogues showed good anticancer properties against BT-549, KB and SK-MEL cell lines.

The amine (2) was prepared starting from 1-(4-fluorophenyl) piperazine via two steps, and then converted to the corresponding hydrazide (4). The reaction of hydrazide (4) with carbon disulfide generated the corresponding 1,3,4-oxadiazole (5), while the treatment of hydrazide with ethyl bromoacetate produced 4-oxo-2-thioxo-1,3-thiazolidine compound (6). The fourcomponent condensation of 4 with several aldehydes gave the corresponding 4-oxo-2-thioxo-1,3-thiazolidinglycinamides (7a-f). The synthesis of 4-oxo-1,3-oxazolidines (9a,b), 1,3-oxazoles (10a,b) and 1,3,4-triazoles (11a,b) was carried out starting from compounds 8a,b. Mannich bases (12a-d and 13a-f) were prepared using three component condensation of compounds 5 and 12a,b and corresponding amines. The synthesis of 16a-c, which were considered as the new analogues of azole class antifungals, was performed starting from the compound 14a via three steps. Results and Conclusion: All the reactions were examined under traditional and microwave irradiation conditions, and optimum conditions were defined. The antimicrobial activities of the newly synthesized compounds were screened and some of the tested compounds were displayed good-moderate antibacterial activity.

Background: A new series of aurone-hydrazones have been designed and synthesized in order to explore new bioactive compounds, which could have potential to be used as active drugs against Alzheimer's disease. Methods: The newly synthesized compounds were characterized by various spectroscopic techniques (IR, mass spectrometry and NMR spectroscopy) and evaluated in vitro for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. All target compounds exhibited varied degree of IC50 values compared to standard Donepezil. Among the series, the compound 6c was found as a potent dual inhibitor of AChE and BChE having IC50 values 0.92±0.01 and 2.25±0.01 μM respectively. Results and Conclusion: The experimental results were further supported by molecular docking analysis. Both studies showed that some of these compounds are interesting inhibitors against AChE and BChE enzymes.

Background: This study evaluated the biological properties of twelve 1,3-thiazolidin-4- ones by assessing antifungal and antibacterial activities. Methods: All compounds were tested against three fungi and two bacteria. The lowest concentration that produced a ≥50% inhibition of the growth of yeast in comparison with positive control was identified as MIC50. Compound 1b showed the best antifungal result against Candida albicans with MIC50 100 μg/ml (52.38% of growth inhibition). In the antifungal Rhodotorula assay, two compounds showed good antifungal activity with MIC50 100 μg/ml (1f: 82.91% and 1i: 61.91%). For C. parapsilosis compound 1i has MIC50 200 μg/ml. Results and Conclusion: No antibacterial activity was found for Staphylococcus aureus and Escherichia coli at the highest concentration tested (400 μg/ml). The cytotoxicity study for three compounds was carried out against primary astrocyte cells and no toxic effect was found at 400 μM. This study discovered at least two potential compounds that will guide further chemical modification to search for better results.

Background: Preclinical therapeutic efficacy of new anti-TB molecules is normally assessed by examining reduction in the bacterial load in different organs of mice infected with M. tuberculosis. However, since infection in the peripheral blood can mirror overall bacillary load in the body, assessment of bacteremia may reflect the treatment outcome in a more reliable manner while obviating the need to examine different organs. Objective: This study was aimed at determining the effect of anti-TB drugs on bacteremia in mice infected with M. tuberculosis. Methods: BALB/c mice were intravenously infected with M. tuberculosis and effect of oral treatment with Isoniazid (INH) and Rifampicin (RFM) on bacilli present in the peripheral blood, lungs, spleen and liver was determined. Colony forming units (CFUs) were enumerated by plating the lysed blood sediments or tissue homogenates, onto Middlebrook 7H11 agar. Drug efficacy was assessed as log reduction in CFUs in different tissues. Results: A progressive increase in M. tuberculosis CFUs was seen in the blood of untreated mice. Upon treatment with INH and RFM, respectively, 1.77 and 1.97 log reductions in blood CFUs were seen. Multiplication and killing (after drug treatment) of M. tuberculosis in the blood and other tissues of mice were comparable. Conclusion: Determination of M. tuberculosis CFUs in the blood of mice can serve as a simple and efficient method for primary selection of in vivo active molecules.

Background: Virgin olive oil, the main source of lipids in a mediterranean diet, is broadly recognised to possess health-beneficial features, namely a protective role against cancer. It comprises several phenolic compounds, the major ones being tyrosol (p-hydroxyphenylethanol), hydroxytyrosol (3,4-dihydroxyphenylethanol), lignans and secoiridoids, namely oleuropein (OP) and the oleuropein aglycones 3,4-(dihydroxyphenyl) ethanol elenolic acid ester and 3,4-(dihydroxyphenyl)ethanol elenolic acid di-aldehyde. Objective: The goal of this work is the in vitro evaluation of the anti-proliferative activity against human amelanotic melanoma (C32 cell line) for hydroxytyrosol and the most important secoiridoids of olive oil. The effect of hydroxytyrosol on non-neoplastic cells (BJ fibroblass) was also investigated. Methods: Inhibition of cell proliferation was assessed by the Sulforhodamine colorimetric method, in both neoplastic and non-tumorigenic cells. Results: 3,4-(Dihydroxyphenyl)ethanol elenolic acid di-aldehyde and 3,4-(dihydroxyphenyl)ethanol elenolic acid ester secoiridoid aglycones were found to display growth-inhibiting activity (at ca. 100 μM), as opposed to oleuropein that elicited a strong protective effect at all concentrations (100 to 1000 μM). 3,4-Dihydroxyphenylethanol evidenced a dual effect (strongly dose-dependent) - cytoprotective for lower dosages and cytotoxic at high concentrations. Conclusion: Attending to the recognised structural dependence of the biological activity of phenolic derivatives, the previously gathered conformational data on the olive oil constituents presently investigated assisted the interpretation of their biological properties. This type of studies, coupling structural characterisation to biological assessment, allows the establishment of reliable structure activity relationships for polyphenolic compounds, ruling their cytoprotective vs cytotoxic activity and therefore their potential use as natural-based pharmacological agents.

Background: Endothelial dysfunction is an initial step for atherosclerotic cardiovascular disease and highly prevalent in high-risk patients, such as those with hypertension or chronic kidney disease. Decreased nitric oxide production and/or impaired bioavailability are involved in endothelial dysfunction. Since blood pressure lowering significantly reduces the risk for future cardiovascular events in hypertensive patients, several guidelines recommended combination of anti-hypertensive drugs that had complimentary mode of actions for the treatment of patients with moderate or severe hypertension. However, effects of combination therapy on nitric oxide generation by endothelial cells are not fully understood. Methods: In this study, we examined the effects of amlodipine, a calcium channel blocker, and irbesartan, an angiotensin II type 1 receptor blocker on nitrate/nitrite generation in angiotensin IIexposed human umbilical vein endothelial cells. Compared with control, angiotensin II at 100 nM significantly increased reactive oxygen species generation and reduced mRNA levels of endothelial nitric oxide synthase in endothelial cells, both of which were prevented by 10 nM irbesartan, but not 1 nM amlodipine. Combination of irbesartan with amlodipine further ameliorated the deleterious effects of angiotensin II on endothelial cells. Moreover, although amlodipine or irbesartan treatment alone did not increase nitrate/nitrite generation, combination therapy significantly restored the decreased nitrate/nitrite production by angiotensin II-exposed endothelial cells. Results and Conclusion: The present study suggests that combination of irbesartan with amlodipine could be beneficial against endothelial dysfunction, whose effects may partly be independent on its blood pressure-lowering properties.

Background: L-ascorbic acid and organic amine showed a good brain targeting ability. However, there was no report on the combination of L-ascorbic acid and organic amine as a carrier for central nervous system (CNS) drug delivery. Objective: To synthesize the ibuprofen prodrug co-modified by organic amine and L-ascorbic acid, and evaluate its brain targeting ability. Methods: A dual-targeting ibuprofen prodrug 2 co-modified by organic amine and L-ascorbic acid was designed and synthesized. HEK293T cells were used to evaluate the cytotoxicity. The chemical and metabolic stability was investigated in buffer solutions, plasma and brain homogenate, respectively. Furthermore, the brain targeting ability of the prodrug was evaluated in vivo compared with prodrug 1 and naked ibuprofen. Results: The novel prodrug 2 exhibited excellent ability to penetrate the brain-blood barrier (BBB) and significantly increased the level of ibuprofen in brain. The relative uptake efficiency and concentration efficiency were enhanced by 3.16 and 4.92 times than that of naked ibuprofen, respectively. Conclusion: The results of this study indicated that organic amine and L-ascorbic acid was a splendid carrier to enhance the delivery of CNS drugs into brain. These results provided an effective entry to the development of new brain targeting drugs.

Background: A series of newly synthesized compounds structurally related to Aripiprazole and Brexpiprazole, atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, depression and bipolar disorder have been prepared and characterized by Elemental analysis, FT-IR, ¹H NMR, ¹³C NMR, HSQC (2D NMR) and Mass spectrometry. All the compounds have been docked against, human A2A Adenosine receptor, human β2-Adrenergic G-Protein Coupled Receptor (GPCR) and ADME properties ware also evaluated. Objective: We focused on screening the neuroleptic activity of the synthesized drug molecules with different anti-psychotic animal models. Methods: All the drug molecules (10mg/kg) and also standard drug Aripiprazole (5mg/kg) were administered to their individual groups with 8 different animal models. Docking studies were carried out by Schrodinger 9.5 software to predict the antipsychotic activity and the pharmacokinetic properties were subjected to QIKPROP3.7 (Qikprop) module of Schrödinger software to determine ADME property.. Results: Both the receptor and ligand interaction shows an excellent dock score. ADME properties were also evaluated in the desirable range; finally these compounds have orally drug-likeness property. The results basically pointed out the fact that mutually the test molecules and control group may have the property to improve the positive symptoms of schizophrenia by reducing the dopamine levels of dopaminergic neurons of the brain. Conclusion: Docked against the protein to determine the Binding Energy, Glides core, Hydrogen bond, Total Intermolecular Energy and Interacting residues. ADME properties have been determined and obey the Lipinski's rule of five for drug likeness property. The synthesized compounds are used against Aripiprazole as a standard drug. The result has shown a promising effect in reducing the positive symptoms of psychosis in rats by sinking the dopamine levels in the frontal cortical region of the brain.

Background: The present review article is related to the synthesis and medicinal importance of benzoxepine and its derivatives. The study of heterocycles is an evergreen field in the branch of organic / medicinal chemistry and always attracts the attention of chemists working not only in the area of organic synthesis but also in natural products. Methodology: The derivatives of benzoxepine exhibit a wide range of pharmacological properties such as antibacterial, anticancer, antioxidants, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis, antispermetogenic and antipsychotic activities. Consequently, their syntheses have attracted significant interest. Various methodologies have been developed for the synthesis and functionalization of this class of compounds. Conclusion: In the present article, the relevant and recent advances in the field will be briefly covered.

Background: The continual evolution of the world is closely chaperoned by the emergence of deadly diseases, which presents itself at every turn thus determining the 3D structure of a protein drug target plays a crucial factor in the process of effective drug design and discovery. Methods: The 3D structure of a protein is an essential component that must be considered when establishing the functional domain of a protein, enabling the structural dynamic interactions with specified ligands and proteins to be studied and understood on a molecular level. Integrating the application of homology modeling which is also regarded as comparative modeling, may enable the provision of low-resolution 3D protein structures with enhanced accuracy made viable by a costeffective protocol. Results: The application of homology modeling has already impacted many fields of research, which is presented in this review and continues to aid all of spheres of science and medical research, such as molecular biologists and pharmaceutical scientists with considerable insight regarding the spatial conformation of important residues within the protein structure in addition to providing a template for the design of new innovative drugs with enhanced specificity and effectivity. Conclusion: This review provides a conclusive route map of the process of homology modeling that can be followed, limitations associated with the application of homology modeling and potential solutions. This review incorporates various tools that can be utilised. Highlighting the features of each tool enabling the construction of the most accurate model, that may aid in next generation drug discovery.