Letters in Drug Design & Discovery - Volume 11, Issue 5, 2014

Gram-positive bacteria are the most common cause of skin infection in hospitalized patients, with Staphylococcus aureus being the principal pathogen responsible for deaths. A series of poly-oxygenated chalcones was synthesized and assayed for anti-staphylococcal activity. Hydroxylated chalcones were more effective in the inhibition of microbial growth than methoxylated analogues. The compound 3’,5’,4-trihydroxychalcone is the most promising compound among those evaluated, showing a much broader antimicrobial spectrum than oxacillin and a MIC of 64 μg/ml to a multidrug- resistant hospital clinical strain of S. aureus.

5-Nitroimidazoles are drugs having both antiprotozoal and antibacterial activity, but show mutagenicity and development of resistance particularly with metronidazole. For the development of new potentially safer derivatives, we investigated new strategies of synthesis: such as Vicarious Nucleophilic Substitution of hydrogen (VNS), palladiumcatalyzed cross-coupling reactions (Suzuki-Miyaura, Sonogashira…) and electron transfer reactions (Unimolecular Radical Nucleophilic Substitution (SRN1), TDAE methodology) applied in 5-nitroimidazole series.

In an attempt to control multidrug resistant dilemma, a library of quinazolinone based on two novel series was rationalized and synthesized with simple and efficient etiquette. A number of compounds encompass ethyl thioureidic backbone, structurally related to PETT (Phenyl Ethyl Thiazolyl Thiourea) congeners. All the final synthesized compounds were characterized by IR, 1H NMR, 13C NMR, mass and elemental analysis. The newly synthesized compounds were studied for efficacy against several bacteria (Staphylococcus Aureus, Bacillus Cereus, Escherichia Coli, Pseudomonas Aeruginosa, Klebsiella Pneumoniae, Salmonella Typhi, Proteus Vulgaris, Shigella Flexneria) and fungi (Candida Albicans, Aspergillus Niger, Aspergillus Clavatus) using the broth dilution technique. Moreover, these compounds were also screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using the BACTEC MGIT method.

A series of novel 4-bromo-2-(3-methyl-1-(substituted-phenylsulfonyl)-4,5-dihydro-1H-pyrazol-5-yl) phenol derivatives were synthesized and characterized by NMR, ESI-MS. Compound 3c was determined by X-ray. Biological activity tests results show that compound 3h displayed activity with MIC of 0.39, 0.78, 1.562 μg/mL against B. subtilis ATCC 6633, S. aureus ATCC 6538, P. fluorescens ATCC 13525 and could strongly inhibit S. aureus DNA gyrase and B. subtilis DNA gyrase with IC50s of 0.25 and 0.18 μg/mL respectively.

The synthesis of 2-[3/4-(2-substituted phenyl-2-oxoethoxy)benzylidene]-6-substituted-2,3-dihydro-1H-inden-1- one derivatives and the investigation of their anticancer activity were studied. 2-(3- or 4-Hydroxybenzylidene)-6- substituted-2,3-dihydro-1H-inden-1-ones were reacted with suitable 2-bromoacetophenones to give 2-[3/4-(2-substituted phenyl-2-oxoethoxy)benzylidene]-6-substituted-2,3-dihydro-1H-inden-1-one derivatives. The structure elucidation of the synthesised compounds was performed by IR, 1H-NMR, mass spectroscopic data and elemental analyses. The anticancer screening was carried out in National Cancer Institute (NCI), USA. Notable activity was obtained for some compounds.

The α-Mangostin and -Mangostin were mainly isolated from Garcinia Mangostana L. as representative Xanthone's natural products of plant origin, revealed high activity of antitumor, antioxidation and other diverse pharmacological activities. A series of α, γ-Mangostin derivatives LT-1~17 has been synthesized, and confirmed by 1H NMR, 13C NMR, MS(supplement file). Compounds LT-2~17, as novel Xanthone, have been reported for the first time. Their antitumor activities have been investigated by MTT method in cell lines: A549, K562, CNE, KB-3-1, MCF-7 and HepG2. A number of compounds showed potent anti-tumor activity, in some cases even higher (more effective) than Mangostins. Compound 3 with an IC50 value of 1.73 μM in the A549 cell line, which was two-fold, acted more active than ADM (adriamycin) and α, γ-Mangostin, and had the most potent anti-tumor activity (IC50=2.15 μM) for the MCF-7 cell line in all synthetic derivatives. α, γ-Mangostin and ADM showed potent anti-tumor activity (IC50=2.82 μM) for HepG2 cell line, and less potent anti-tumor activity in other cell lines compared with the compound LT-12. It was obtained by esterification of the C-3, C-7 phenolic-OH of the α-Mangostin with acetyl group resulted the potent anti-tumor acvitity, which indicated that the phenolic-OH of the Mangostins had a great impaction on the anti-tumor activity of Mangostins.

The spiro analogues of benzothiazolylchromenopyranopyridine, benzothiazolyl- chromenoquinoline, benzothiazolylpyranoquinoline, benzothiazolylchromenopyridopyrimidine and benzothiazolylpyranopyridopyrimidine have been synthesized by an efficient domino reaction using sulfamic acid as catalyst in aqueous medium and screened for their cytotoxic activity against tumor cell lines, namely human cancer cell lines of colon (sw620), breast (MCF-7), cervix (HeLa) and heptatoma (HepG2) using a sulforhodamine B (SRB) assay. The synthesized compounds have shown promising cytotoxic activity against MCF-7 (breast cancer) & HeLa (cervical cancer) cancer cell lines.

The different substituted polyphosphazene-linked azo prodrug of Methotrexate (9-12) and chitosan-linked azo prodrug of methotrexate (13) were synthesized and characterized by modern analytical techniques such as IR, 1H NMR, 31P NMR and GPC. The in-vitro stability study showed that all polymeric drug conjugates are stable in upper GIT (pH = 1.2) and small intestine (pH = 7.4). In-vitro drug release showed that polyphosphazene-linked azo prodrug of methotrexate (12) has maximum release (88.4%) in the presence of rat cecal content compared to chitosan linked azo prodrug of methotrexate (13). Therefore, the synthesized polyphosphazene linked azo based drug conjugates of methotrexate (9-12) are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects.

Studies of the neuroprotective activity of a series of monoterpene-derived compounds on the MPTP mice model showed that 4-[(3aR,7aS)-1,3,3a,4,5,7a-hexahydro-3,3,6-trimethylisobenzofuran-1-yl]-2-methoxyphenol 15 possessed a considerable neuroprotective activity. Compound 15 was synthesized by one-stage reaction of (+)-2-carene with vanillin. It has low acute toxicity and significantly decreased the development of catalepsy evoked by haloperidol in rats.

Herein, we present a validated predictive QSAR model to provide more insight into the relationship between the molecular properties of diketo acid and carboxamide derivatives as well as HIV-I integrase inhibition. A set of 40 diketo acid and carboxamide derivatives possessing integrase inhibitory activity was subjected to 2D-QSAR using Discovery studio V3.5. The QSAR results presented here were based on a genetic function algorithm (GFA) approach. Logarithmic inverse values of IC50 (μM) were taken as the dependent variables, and physicochemical parameters were taken as the independent variable. A suitable set of molecular descriptors was calculated using GFA approach (max 500 generations). Results showed that radius of gyration, Zagreb index, Wiener index and minimized energy are statistically significant with the correlation coefficient value of 0.820 and play an important role in HIV-1 integrase inhibition.

A series of 4-butyl-5-(4-alkoxyphenyl)-2H-1,2,4-triazole-3(4H)-ones (6a-6u) was designed and synthesized. The anticonvulsant effects and neurotoxicity of the compounds were evaluated with maximal electroshock test and rotarod test. Among the synthetic compounds, 4-butyl-5-(4-(2-fluorinebenzyl)phenyl)-2H-1,2,4-triazole-3 (4H)-one (6k) was the most potent with ED50 value of 27.4 mg/kg and protective index (PI = TD50/ED50) value of 12.0. Besides the anti-MES efficacy, the potency of compound 6k against seizures induced by pentylenetetrazole (PTZ), 3-mercaptopropionic acid (3- MP), and bicuculline (BIC) was also established, which suggested that the mechanisms of action including enhancing of GABAergic activity might be involved in its anticonvulsant activity.

The important aim of this research was to develop an appropriate model to predict relationships between three casual factors on the responses based on an artificial neural network (ANN). As model formulation, 28 types of gels were prepared. The weight ratio of GMO/water (w/w) and PEG 300/GMO (w/w), percentage of Olanzapine (OZ) were selected as input data. Entrapment efficacy, maximum percentage of release, particle size and viscosity were estimated as gel characterization. A set of gel characterization and input data were employed as tutorial data for ANN methodology by using neural network toolbox in Matlab. Different topologies have been performed in order to determine the single network with good performance and accuracy. Four training algorithms (Levenberg–Marquardt, Bayesian- Regularization, BFGS Quasi-Newton, and Gradient Descent) were applied to train ANNs containing different numbers of hidden layers with various nods. The ability to predict the responses of all the algorithms were in the order of: BR > LM >BFGS> GD.

Dopamine is an abundant neurotransmitter in the brain, and acts as a regulator of many physiological functions in the central nervous system, such as motor activity, cognition, and positive reinforcement, and in the periphery, as a modulator of cardiovascular function, among others. Dopamine receptors belong to a superfamily of G protein-coupled receptors, and to date five sequences in the human body have been reported with various isoforms each. Disturbances in the dopaminergic systems are associated with several diseases, such as, for example, Parkinson's disease and schizophrenia. Since the disturbances affecting the locomotor activity are related to dopamine D2 receptors. Quantitative structureactivity relationship analysis in four-dimensional (4D-QSAR) studies was applied on a series of 73 tetracyclic tetrahydrofuran derivatives containing a substituted cyclic amine side chain with binding affinity towards dopamine D2 receptors. The 4D-QSAR models were developed using 60 compounds, the training set, and externally validated using 13 compounds, the test set. We tested three different alignments, and the Model 3, generated from Equation 3, showed the best statistical results, the same being chosen to represent the data set. The model developed in this work shows descriptors with important pharmacophoric groups for inhibiting dopamine D2 receptors, suggesting structural changes for new inhibitors.

The DFT-B3LYP method, with the basis set 6-31G (d, p), was employed to calculate some quantum chemical descriptors of 33 biphenyl imidazole derivatives as bombesin receptor subtype-3 agonists. The descriptors were then employed to establish a quantitative structure activity relationship (QSAR) using combination of principal component analysis (PCA) and radial basis function neural network (RBF). The statistical results indicate that the correlation coefficient (R2) and cross validation using leave-one-out were 0.968 and 0.963, respectively. To validate the predictive power of the resulting model, external validation was carried out on the test set. The results show that the PCA-RBF model has not only favorable estimation stability but also good prediction power. Furthermore, it can be concluded that the agonist activity of studied compounds toward the bombesin receptor subtype-3 depends on the electronic distribution.

In this study, combination-principle was reported to improve the hepatoprotective activity of andrographolide. Ten andrographolide derivatives were synthesized and evaluated for in vivo hepatoprotective activity in CCl4-induced liver injury mice. The pharmacological results revealed that 6 derivatives exhibited significant hepatoprotective activity. The most promising compound 6b significantly improved liver enzymes (ALT and AST) activity as compared with andrographolide, with high potency to be a new lead.

Pyrazole scaffold containing compounds have been found to be as enzyme activator or inhibitor in the diabetic disease condition. The pyrazole containing compounds have been found to be activators in case such as glucokinase and as inhibitors in cases such as sodium glucose co-transporter-1, sodium-glucose co-transporter-2, dipeptidyl peptidase-4, glycogen synthase kinase-3beta, Glucagon-stimulated intracellular cAMP formation and 11β-HSD1. Pyrazole containing compounds can also act as competitive antagonist at cannabinoid-1 receptor while agonist at peroxisome proliferatoractivated receptor-α and γ. In present work, the most active pyrazole derivatives have been selected from reported literature along with methods utilized for detection of blood plasma glucose levels or urinary glucose levels as well as assays involving enzyme inhibition or activation at cellular level. The activity values of corresponding pyrazole compounds obtained from synthetic or structural activity relationship studies can be helpful for medicinal chemist to focus design of novel chemical entities containing pyrazole system as a part of antidiabetic drug substance.