Medicinal Chemistry - Volume 11, Issue 2, 2015

Neuropharmacological relation of religious belief supports the role of dopaminergic activation as the leading neurochemical feature. However, vesicular monoamine transporter-2 (VMAT-2) has been shown to be responsible for removing of neurotransmitters such as dopamine that may secondarily lead to a neuroprotective activity by different neurodegeneration models. Moreover, there are interesting data showing that VMAT-2 may play an important role during religious belief and experience. In the light of these findings, we aimed to review the preclinical and clinical neuroprotective data of Vesicular monoamine transporter (VMAT-2) in different neurodegenerative and neuropsychiatric diseases. In respect of rapidly increasing evidences about the neurobiological and neuroimaging correlates of religious belief, we hypothesized that there is a link between belief and neuroprotection.

The interest of researchers for ligands of the endothelin receptors ETA and ETB is due to their extensive therapeutic potential. In particular, receptor antagonists are useful in a number of diseases such as pulmonary hypertension, acute myocardial infarction, congestive heart failure, renal failure, and atherosclerosis. In the context of our research program aimed to the development of new endothelin receptor ligands, in this paper we describe the synthesis and structure- activity relationships of a new series of 1,3,5-substituted pyrrole-2-carboxylic acid derivatives 27-40 possessing the structural features for ET receptors binding. New synthesized compounds were tested on ETA and ETB receptors stably expressed in CHO cells and some of them showed interesting affinity and selectivity towards ETA receptors.

Synthesis, characterization and investigation of antifungal and antibacterial activities of fourteen 2,4- disubstituted 1,3-selenazoles is presented. Their structures were determined using 1H and 13C NMR, FAB MS and HRMS analyses. Among the derivatives, compounds 5, 6, 8, 9, 12, 13 and 15 had very strong activity against reference strains of C. albicans ATCC 10231 and C. parapsilosis ATCC 22019 with MIC = 0.24-7.81 µg/ml. The compounds 5, 6, 8, 13 and 15 showed also very strong activity against clinical isolates belonging to non-albicans Candida spp. strains, i.e. C. krusei, C. inconspicua, C. famata, C. lusitaniae, C. sake, C. parapsilosis, C. dubliniensis with MIC = 0.24-7.81 µg/ml. The activity of several of these was similar to the activity of most commonly used antifungal agents fluconazole. The compounds 9 and 16 indicate also very strong antibacterial activity against S. epidermidis and M. luteus with MIC = 1.95-3.91 µg/ml. Additionally, the compound 11 is strong active against M. luteus with MIC = 3.91 µg/ml.

A series of 4-methyl-7-O-substituted coumarins (3-12) was synthesized and evaluated for in vitro antimicrobial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), four Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Proteus vulgaris) and three fungal strains (Candida albicans, Cryptococcus terreus and Saccharomyces cerevisiae) by two-fold serial dilution technique. The results of bioactive assay showed that some of the synthesized coumarins displayed comparable or even better antibacterial and antifungal activities against tested strains in comparison with reference drugs erythromycin, novobiocin and amphotericin B. Compound 9 showed potent antimicrobial activities against seven of the nine microbial strains examined in this study with MIC values ranging between 1.09 and 25 µg/mL and was the most active compound of the series. The present work also describes the effect of substituent on bioactivity.

NorA is a member of the Major Facilitator Superfamily (MFS) drug efflux pumps that have been shown to mediate antibiotic resistance in Staphylococcus aureus (SA). In this study, QSAR analysis, virtual screening and molecular docking were implemented in an effort to discover novel SA NorA efflux pump inhibitors. Originally, a set of 47 structurally diverse compounds compiled from the literature was used to develop linear QSAR models and another set of 15 different compounds were chosen for extra validation. The final model which was estimated by statistical values for the full data set (n = 45, Q2 = 0.80, RMSE = 0.20) and for the external test set (n = 15, R2 = 0.60, |res|max = 0.75, |res|min = 0.02) was applied on the collection of 182 flavonoides and the traditional Chinese medicine (TCM) database to screen for novel NorA inhibitors. Finally, 33 lead compounds that met the Lipinski's rules of five/three and had good predicted pIC50 values from in silico screening process were employed to analyze the binding ability by docking studies on NorA homology model in place of its unavailable crystal structures at two active sites, the central channel and the Walker B.

Inhibition of photosynthetic electron transport (PET) in spinach chloroplasts by sixty-one ring-substituted N-benzylsalicylamides was investigated. The inhibitory potency of the compounds expressed by IC50 value varied from 2.0 to 425.3 μmol/L. Several evaluated compounds can be considered as effective PET inhibitors; these include N-(3,4- dichlorobenzyl)-2-hydroxy-5-nitrobenzamide (IC50 = 2.0 μmol/L), 3,5-dibromo-N-(3,4-dichlorobenzyl)-2-hydroxybenzamide (IC50 = 2.3 μmol/L) and 3,5-dibromo-N-(4-chlorobenzyl)-2-hydroxybenzamide (IC50 = 2.6 μmol/L) with activity comparable with that of the standard Diuron (IC50 = 1.9 μmol/L). The PET inhibiting activity increased approximately linearly with increasing lipophilicity of the compounds as well as with the increasing sum of Hammett σ constants of the substituents on the acyl fragment (R1 = H, 5-OCH3, 5-CH3, 5-Cl, 5-Br, 5-NO2, 4-OCH3, 4-Cl, 3,5-Cl and 3,5-Br) and the benzylamide fragment (R2 = H, 4-OCH3, 4-CH3, 4-F, 4-Cl and 3,4-Cl). Based on the evaluated structure-PET inhibiting activity relationships (QSAR) it was confirmed that the inhibitory activity of the compounds depends on lipophilicity (log P or distributive parameters π 1 and π2of individual substituents) and electronic properties of the substituents on the acyl (σ1) and the benzylamide fragments (σ2), the contribution of σ1 being more significant than that of σ2.

Thirty-nine caudatin analogs were designed and synthesized. Their anti-hepatitis B virus (HBV) activities were evaluated in vitro. Among them, twenty-three compounds showed much better anti-HBV activity than caudatin, and eleven compounds significantly inhibited the HBV DNA replication with IC50 values < 10 μM. Interestingly, three compounds (22, 28, 29) exhibited excellent activity against the secretion of HBsAg (IC50 = 63.02 μM, 52.81 μM, 56.08 μM), HBeAg (IC50 = 204.80 μM, 173.51 μM, 70.39 μM), along with HBV DNA replication (IC50 = 24.55 μM, 5.69 μM, 8.23 μM) with lower cytotoxicity. The structure-activity relationships (SARs) of these caudatin analogs were also discussed.

A series of aromatic diketone derivatives were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated to determine their ability to inhibit the strand transfer process of HIV-1 integrase. The results indicate that (Z)-1-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-3-hydroxy-3-(substituted)phenylprop-2-en-1-one (5a-5d) can moderately inhibit HIV-1 integrase. The cyclization and condensation products (6a-6c and 7e-7f) of compounds 5a-5d show poor inhibitory activity against HIV-1 integrase. The molecular docking results indicate that the different types of compounds act on HIV-1 integrase in different ways, and these results can explain the differences in the inhibitory activities.

A new series of 1-{(5-substituted-alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl}-2-(piperidin-1-ylmethyl)-1Hbenzimidazoles (5a-5r) was synthesized and screened for their inhibitory activity against COX (1 and 2). In vivo antiinflammatory activity of potent compounds was done by carrageenan-induced rat paw edema model. In vitro anticancer activity of synthesized compounds was also performed at the National Cancer Institute (NCI) against NCI 60 cell lines panel. Out of the 18 compounds screened, 5h, 5i, 5j and 5l were found to be potent COX-2 inhibitors in the range of IC50 0.06-0.81 μM. In vivo anti-inflammatory screening results revealed that the compounds 5h and 5j manifested profound percent protection of 72.8 and 75.0%, respectively. Compound 5f exhibited moderate cytotoxicity with 58.79% growth inhibition against SNB-75 (CNS Cancer) cell lines and moderate activity against COX-2 (IC50 = 8.0 μM).

N-(α-Alkyloxime-3-phenylpropionyl) proline was designed and synthesized as an acylating agent to modify the 6-OH of 1-O-acetylbritannilactone. Eight intermediates and eight target compounds were obtained. The structures of sixteen novel compounds were characterized by 1HNMR, IR and HRMS. The activities against HL-60 and Bel-7402 cell lines were tested, the IC50 values of compound IVg were 2.7 μM and 4.3 μM, respectively.

Herein we report an efficient, simple and green synthesis of novel types of α-hydroxyphosphonates bearing a nitrile group, from the reaction of γ-ketonitriles with dialkyl phosphites in the presence of magnesium oxide as solid support, under solvent-free conditions. All the title compounds were screened for their antioxidant activity by 1,1-diphenyl-2- picrylhydrazyl (DPPH), hydroxyl radical, reducing power and ferrous ion chelating (FIC) methods and they showed significant antioxidant activity.