Medicinal Chemistry - Volume 9, Issue 6, 2013

The pathophysiology of schizophrenia has not been fully elucidated but there are converging leads to understanding this complex psychiatric disorder. One family of molecules that may play a crucial role in the development of schizophrenia is the eicosanoids. Review of the literature on eicosanoids in patients with schizophrenia points to findings in three areas: precursor molecules such as polyunsaturated fatty acids (PUFAs) and specifically arachidonic acid (AA), the actions of specific eicosanoids such as thromboxane A2 (TxA2), thromboxane B2 (TxB2) and prostaglandin E2 (PGE2), and enzymes with important functions in eicosanoid metabolism such as cyclooxygenase 2 (COX-2). It has also been found that classical as well as second generation antipsychotics, drugs used to treat schizophrenia, influence eicosanoid metabolism. For example, clozapine and its metabolite N-desmethylclozapine (NDMC) decreased TxB2 production in vitro. Eicosanoids and the enzymes involved in their metabolism may provide novel future drug targets. Therapeutic response to COX-2 inhibitors has already been demonstrated in patients at an early stage of schizophrenia. COX-2 inhibitors may exert this therapeutic action through their effects in reducing PGE2, type-2 cytokine and kynurenic acid production and strengthening glutamatergic neurotransmission.

Hepatitis C virus (HCV) is a Hepacivirus that causes chronic liver disease, leading to hepatocellular carcinoma, cirrhosis, and chronic hepatitis in about 3% of the world population. In this study, novel HCV NS3 serine protease inhibitors based on 93 boceprevir analogs were studied by QSAR analyses using thermodynamic, structural and topological descriptors, including E-state descriptors. Novel compounds were proposed using the QSAR models. Both models were highly predictive, with calibration, leave-one-out validation and external validation R2 of 0.66, 0.65 and 0.52, respectively. The most promising structures were docked into the HCV NS3 serine protease active site demonstrating, then, the high affinity of some new structures.

Series of new benzyl 2H-chromenones 6a-n was synthesized by Pechmann condensation of substituted benzyl resorcinols 2a-c and 3a with various β-ketoesters such as ethyl 3-oxobutanoate, ethyl 3-oxo-3-phenylpropanoate, ethyl 4- chloro-3-oxobutanoate, ethyl 4,4,4-trifluoro-3-oxobutanoate and ethyl 2-chloro-3-oxobutanoate 5a-e in very good yields. Synthesized compounds 6a-n were screened for their α-amylase inhibitory, and ABTS.+ scavenging activities. In the present series of compounds, compound 8-benzyl-7-hydroxy-4-phenyl-2H-chromen-2-one 6c and 8-benzyl-7-hydroxy-4- methyl-2H-chromen-2-one 6a were most potent ABTS.+ radical scavenging and α-amylase inhibitor. Although compound 6,8-dibenzyl-7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one 6h displayed potent ABTS.+ free radical scavenging potential, it was found poor in inhibiting pancreatic α-amylase.

Mitoxantrone is an anthracene-based anticancer agent whose efficacy in treating autoimmune diseases is believed to be due to cytotoxicity and inhibition of proliferation of cells. Several novel anthraquinone derivatives, analogs of mitoxantrone, were designed and synthesized. Lipophilic and functionalized mitoxantrone analogs were prepared by a simple methodology and the cytotoxicity and the inhibitory effect on nitric oxide release of these compounds were demonstrated in vitro on J774A.1 macrophages. Interestingly compounds 3, 4, 5, 6, 7, and 8 exhibited reduction in NO release (62.4%, 92.6%, 73.4%, 58.4%, 57.8% and 53.4%, respectively) in comparison to NG-n-methyl-arginine treated control, without cytotoxicity. In conclusion, anthraquinone derivatives were prepared in a good yield and showed promissory antiinflammatory properties.

Plants have always been a supreme source of drugs and India is endowed with a wide variety of them with high medicinal values. The Quorum Sensing (QS) quenching efficiency of various solvent extracts of Melia dubia seeds was investigated against uropathogenic Escherichia coli (UPEC) to screen the competitive inhibitor of SdiA, a transcriptional activator of quorum sensing in E. coli. In this study, potentiality of five different extracts of Melia dubia seeds for quorum sensing inhibitory activity was investigated against uropathogenic Escherichia coli (UPEC). Assays such as cell density, swarming motility, protein, protease, hemolysis, hemagglutination, hydrophobicity and biofilm inhibition were performed. Biofilm, hemolysis and swarming motility were found to be inhibited by 92.1%, 20.9 % and 48.52% respectively, when the medium was supplemented with 30 mg/ml of the ethanolic extract. GC-MS spectrum of the ethanolic extract showed an array of 27 structurally unlinked compounds with natural ligand C8HSL. The docking against QS transcriptional regulator SdiA was predicted by in silico studies and the ligand C6 showed significant activity with -10.8 GScore. In vitro and in silico docking analysis showed fairly a good correlation, suggesting that the ethanolic extract showed potency to attenuate quorum sensing of uropathogenic E. coli. Further studies by in vitro and in vivo strategies are necessary to foresee the quorum quenching effect of the ligands.

Diabetes mellitus is a group of metabolic disorders characterised by chronic hyperglycemia resulting either from a deficiency of insulin, or decreased ability to transduce the insulin signal, or both. Insulin resistance and β-cell dysfunction are two fundamental defects known to precede the onset of type 2 diabetes. PTP 1B is considered to function as a negative regulator of insulin signal transduction by dephosphorylating phosphotyrosine residues. 2,4-Thiazolidinediones (TZDs) have long been considered as antihyperglycemic agents which act by ameliorating insulin resistance and thereby normalizing elevated blood glucose level. A three dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a novel class of thiazolidinedione derivatives using self-organizing molecular field analysis (SOMFA) to correlate their molecular architecture with observed PTP 1B inhibitory activities. The master grid maps derived from the best model were used to display the contribution of both electrostatic and shape potential that can be mapped back onto structural features relating to the trends in inhibitory activities. The present SOMFA study indicated the indispensable molecular features which can be further explored for structural modifications of these lead molecules in order to optimize PTP 1B inhibitory activity.

Using cholesterol, β-sitosterol, dehydroisoandrosterone and pregnenolone as starting materials, a series of 6- hydroximino analogs of ring B abeo-sterols were synthesized and characterized. The antiproliferative activity of analogs was evaluated against SGC 7901 (human gastric carcinoma), HeLa (human cervical carcinoma) and Bel 7404 (human liver carcinoma) cells. The results showed that the presence of a alkyl side chain was very important for their cytotoxicity. However, the presence of 6-hydroximino cannot increase the cytotoxicity of compounds compared with 6-hydroxy group. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.

Bisphosphonate drugs are well known to inhibit osteoclastic activity and have been proposed for the management of bone diseases, including periodontitis which is associated with alveolar bone destruction. In this study, we evaluated the effects of four arylsulfonamide bisphosphonates on growth of the periodontopathogenic bacterium Porphyromonas gingivalis as well as their capacity to reduce cytokine secretion by lipopolysaccharide (LPS)-stimulated oral epithelial cells. The growth of P. gingivalis was inhibited by (4’-Chloro-biphenyl-4-sulfonylamino)methyl-1,1- bisphosphonic acid while the three other arylsulfonamide bisphosphonates ((4-Methoxy-phenylsulfonylamino)methyl-1,1- bisphosphonic acid, (4-Nitro-phenylsulfonylamino)methyl-1,1-bisphosphonic acid, and (Biphenyl-4-sulfonylamino) methyl-1,1-bisphosphonic acid) had no effect. Growth inhibition was more pronounced under an iron-restricted condition. All four arylsulfonamide bisphosphonates decreased the production of the pro-inflammatory cytokines IL-6 and IL-8 by Aggregatibacter actinomycetemcomitans LPS-stimulated oral epithelial cells. In conclusion, we uncovered additional properties of bisphosphonates that may be beneficial for the treatment of periodontal diseases. In particular, (4’-Chlorobiphenyl- 4-sulfonylamino)methyl-1,1-bisphosphonic acid combines the already disclosed antiresoptive activity with antiinflammatory and antibacterial properties

With this study we intend to evaluate the effects of 8 different glucosinolate hydrolysis products including isothiocyanates as antibacterial compounds against Aeromonadaceae, isolated from intestinal segments of pigs collected directly from slaughter-houses in the North of Portugal. Four Aeromonas species, A. allosaccharophila, A. hydrophila, A. media and A. veronii were identified. Using disc-diffusion bioassay all compounds were tested at 6 different doses (0.015, 0.15, 0.75, 1.5 and 3.0 µmoles) in dimethyl-sulfoxide (DMSO). Antibiotic standard (gentamicin) and DMSO (negative control) were included in all experiments. Minimum and maximum dose inhibitions (in µmoles) were assessed. To our knowledge, this is the first study of antimicrobial activity of glucosinolate hydrolysis products against Aeromonas species. The results showed that glucosinolate hydrolysis products and particularly the isothiocyanates have antimicrobial activity, which was proportional to the concentration used. However, not all revealed the same tendency, which means that the chemical structure of each compound is fundamental to understand their effectiveness. Among the different isothiocyanates the benzylisothiocyanate, sulforaphane and 2-phenylethylisothiocyanate were the most effective in vitro inhibitors of bacterial growth. This in vitro study provides enough data to demonstrate the potential use of these natural dietary chemicals for treating infectious diseases caused by Aeromonas spp.

The structure glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), acid phosphatase (ACP), alkaline phosphatase (ALP) and glutamate dehydrogenase (GlDH) activity relationships of 2H-pyran-2- ones polysubstitutes being a new class of hepatoprotective agents have been investigated by means of the Electronic- Topological Method (ETM) and two Statistical Analysis. Molecular fragments specific for active compounds were calculated for 2H-pyran-2-ones polysubstitutes by applying the ETM. QSAR descriptors such as molecular weight, EHOMO, ELUMO, ΔE, chemical potential, softness, electrophilicity index, dipole moment, etc were calculated. In order to examine the relationship between independent and dependent variables, both Partial Least Squares Regression and ANNs are employed to determine the relationship since the data set consists of highly nonlinearity and multicolinearity. It is observed that ANN has surpassed both PLS2 and PLS1 in terms of better modeling and validation.

In order to search for novel potential agents for the treatment of chronic kidney diseases (CKD), nitric oxide (NO)-releasing derivatives (5a-c) of ferulic acid were synthesized and characterized by MS, 1H NMR, and elementary analysis. They showed different NO-releasing rate in the absence or presence of L-cysteine in vitro. In the adenine induced CKD rats, these compounds revealed reno-protective effect via lowering blood urea nitrogen (BUN), creatinine (Cr) in serum and malondialdehyde (MDA) in kidney, increasing NO and superoxide dismutase (SOD) level in kidney. Among them, 3-methoxy-4-(nitrooxy)ethoxy cinnamic acid (5a) was confirmed to have a higher NO-releasing rate in vitro and better effect in ameliorating adenine-induced kidney damage in rats.

Starting from cyclopentadiene, two racemic mixtures of 4-aminocyclopentane-1,3-diols were prepared in 8 steps and characterized. Structure determination proved the anticipated trans-orientation of the two oxygen atoms with respect to the plane of the ring. The fragment-like new compounds are small and hydrophilic, devoid of rotatable bonds, and offer stereochemically defined attachment points for substituents. Thus, these platforms for diversity are suitable starting points for the construction of combinatorial libraries of lead-like 4-amidocyclopentane-1,3-diols or natural product analogs. As a proof of concept, cyclopentanoid anandamide analogs were prepared using these molecular platforms and evaluated as tools for the investigation of unresolved issues in the molecular biology of anandamide.

Fourteen Hantzsch adducts with different substituents at the C-4 position were synthesized through multicomponent reactions by using citric or lactic acid as catalysts. To the best of our knowledge, this is the first report on the synthesis of such a class of compounds based on multicomponent reactions catalyzed by non-toxic organic acids. The potential to scavenge reactive nitrogen/oxygen species (RNS/ROS) and the ability to inhibit cancer cell growth were then investigated. Among the synthesized compounds, adduct 15 was the most promising free radical scavenger, while adduct 20 was shown to have a wider spectrum of action on the cancer cells studied. These results highlight Hantzsch adducts as lead compounds for obtaining new free radical scavengers and anticancer agents.