Letters in Drug Design & Discovery - Volume 11, Issue 2, 2014

1-Aroyl-3,5-dimethyl-1H-pyrazole derivatives (7-12) were synthesized from some hydrazides (1-6) with acetylacetone (2,4-pentanedione) by microwave irradiation. Their structures were elucidated by FT-IR and 1H-NMR spectral data and elemental analysis. Compound activities were evaluated against HCV NS5B and in cell based HCV reporters. Compound 8 was the most promising of this series in inhibiting intracellular NS5B activity and HCV RNA replication in reporter cells. The selected compounds 9, 10 and 12 by National Institue of Health were screened for their anticancer activity against 60 human tumor cell lines. Compound 9 (3-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-2',4'- difluorobiphenyl-4-ol) possessed significant activity against human immortalized myelogenous leukemia (K-562) exhibiting cell growth promotion 30.05%, with inhibition of 69.95% at 10-5M concentration. Compounds 3 and 9 were evaluated for cell viability and growth inhibition by K-562 cells of MTT assay, at different doses (10-6- 10-2M). Further, compound 9 exhibited anticancer activity against K-562 cells with IC50 value of 4 μM. Apoptosis levels of compound 9 were determined for three different concentrations (10-6, 10-5 and 10-3M) at two time points (24 and 48 h). Compound 9 induced apoptosis of K-562 cells, thus suggesting that compound 9 might be a potential chemopreventive agent for chronic myelogenous leukemia.

Novel simplified Aspirin derivatives were developed, characterized by using IR, 1H NMR, 11C NMR and elemental analysis techniques and evaluated for anticancer activity in human cell lines. The results revealed that most of the compounds exhibited inhibitory effects of growth of cancer cell lines in vitro against T-acute lymphoblastic leukemia cell lines Molt-4, chronic myclogenous leukemia cell lines K-562, acute myelocytic leukemia cells lines HL-60, human breast cancer cell lines MCF-7, human hepatic carcinoma cell lines HepG-2 and human lung cancer cell lines A-549. It was observed that some of these compounds exhibited significant anticancer activity particularly 5i which had stronger antileukemia activity with IC50 values ranging from 11.12 to 19.25 μmol·L-1 against 3 leukemia cells than control fluorouracil, so some of the compounds may constitute a novel class of anticancer medicines, which deserves further study.

Cancer and malaria are two major diseases, which have devastating effects on public health systems. In a quest of developing new anticancer and antimalarial agents, a series of 22 unsymmetrical C5-curcumionds was synthesized and evaluated for their anticancer activity against HeLa, KB, PC3 and DU145 cancer cell lines. Out of these, four compounds displayed potent activity in HeLa cancer cell line (IC50 ranging from 0.7 to 0.9 μM) than standard FDA-approved drug doxorubicin (IC50 = 1.7 μM). They also showed weak to moderate activity against other cancer cell lines. Unsymmetrical C5-curcumionids were also evaluated for their antimalarial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. Weak antimalarial activities were observed with some compounds without any toxicity towards the mammalian cell line at the highest tested concentration of 10 μM.

Divalent ligand provides a special approach for designing bioactive molecules. Aiming at searching for novel insecticidal divalent neonicotinoid insecticides, bis-phenylazoneonicotinoids were designed and synthesized here using nitromethylene analogue of imidacloprid, diazo unit and benzene system as pharmacophore, linker and spacer, respectively. The designed divalent compounds exhibited moderate insecticidal activity against cowpea aphids (Aphis craccivora).

In the effort of finding novel acetyl cholinesterase (AChE) inhibitors to improve the efficacy of Alzheimer’s disease (AD) treatment, series of substituted aryl-1´-methyldispiro[indan-2,2´ pyrrolidine-3´,2”-indan]-1,3,1”-trione and substituted 7´-aryl-5´,6´,7´,7a´-tetrahydrodispiro-[indane-2,5´-pyrrolo[1,2-c][1,3]thiazole-6´,2”-indan]-1,3,1”-trione analogues were synthesized using [3+2]-cycloaddition reactions. These newly synthesized pyrrolidine compounds were assayed for their biological activity using Ellman’s method. The structural elucidation of the compounds was performed by using 1H-NMR, 13C-NMR, ESI-MS spectra and elemental analyses. Eight out of twenty synthesized compounds showed more than 50% inhibition at concentration of 10 μM. Compound 2e, 2i and 3e were among the most active one, giving IC50 value as 3.3 µM for 2e, 3.7 μM for 2i and 5.5 μM for 3e, respectively. Lineweaver-Burk plot indicated that 2i inhibits AChE in a competitive manner. Molecular modelling study was performed to disclose the binding interaction of these compounds with the active site of AChE.

The objectives of this study were to gain insights into the structure-retention and structure-lipophilicity relationships of series of twenty antidepressants and to propose model for estimating their retention and lipophilicity. The lipophilicity of antidepressants has been determined by reversed-phase thin-layer chromatography using binary methanol– water mobile phases. The chemical structures of the antidepressants have been characterized by molecular descriptors which are calculated from the structure and related to the chromatographic retention parameters as well as chromatographically determinated lipophilicity parameters by multiple linear regression analysis. The obtained models were used for interpretation of the lipophilicity and retention behavior of the investigated compounds.

Creation of effective antidepressant drugs is the key problem of the modern neuropharmacology. Here, the effect of acute administration of a new potential psychotropic drug, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6- amine hydrochloride (TC-2153) (10 and 20 mg/kg), on depressive-like behavior in the forced swim test (FST), anxietylike behavior and locomotion in the open field (OFT) and in the elevated plus-maze (PMT) tests was compared with those of classic antidepressant drugs, fluoxetine (20 mg/kg) and imipramine (20 mg/kg). Experiments were performed on adult male mice of AKR.CBA-D13Mit76 recombinant strain. TC-2153 at the doses of 10 or 20 mg/kg as well as fluoxetine and imipramine significantly decreased immobility time in the FST. Both doses of TC-2153 did not alter mouse behavior in the OFT. At the same time, imipramine significantly reduced the distance travelled and the number of rearing bouts, while fluoxetine decreased the number of rearing bouts in the OFT. All drugs produced no effect on the time spent in the center of the OFT and in the open arms in the PMT. These results suggest that TC-2153 is a promising psychotropic drug with the antidepressant-like activity similar to imipramine or fluoxetine, but lacking any visible negative side effect (reduction of locomotion or exploratory behavior).

Formulation of controlled release acyclovir loaded chitosan nanoparticles was optimized based on the optimization technique using response surface method (RSM) and artificial neural network (ANN) simultaneously to develop a model to identify relationships between variables affecting drug nanoparticles. In this research, the goal was to create a representation of three irregular factors, i.e. concentration of acyclovir, concentration ratio of chitosan/ Tripolyphosphate (TPP) and pH on response variables. ANN was used to create a fit model of formulations via these four training algorithms including: Levenberg–Marquardt (LM), Gradient Descent (GD), Bayesian–Regularization (BR) and BFGS Quasi- Newton (BFG) were applied to train ANN containing a various hidden layer, applying the testable data as the training set. Criterion to stop training was the divergence of the RMSE (root mean squared error) between target and output values. Both methods including gradient descent and Levenberg-marquardt have showed similar results in the data formulation. Corresponding to batch back propagation (BBP)-ANN performance, a gain in pH of polymer solution reduced the size and polydispersity index (PdI) of nanoparticles. Moreover, decreases in the concentration ratio of chitosan/TPP consequently cause an increase in entrapment efficiency (%EE). The next aim of this research was to investigate the performance of predictive algorithms. For this reason each training algorithm in order to consider the accuracy of predictive ability was evaluated and the result was as follow: LM BFGs GD BR.

Development of potent, selective and orally bioactive dipeptidyl Peptidase IV inhibitors as antihyperglycemic agents is challenging task due to potential side effects are associated with them. It may result from other prolyldipeptidases of DPP-4 include DPP-2, DPP-8 and DPP-9. To resolve the selectivity issue in different DPP enzymes hologram quantitative structure-activity relationship studies were carried out on a series of potent and selective DPP-4 ligands. To measure selectivity between two kinds of enzyme selectivity data of DPP-4 over DPP-2, DPP-8 and DPP-9 were calculated and best HQSAR models were generated with significant correlation coefficients. The statistical results of the three models showed the best prediction and fitness for the selectivity activities. Docking studies were carried out on conformationally rigid 3-azabicyclo [3.1.0] hexane derivatives which suggested the substitution pattern on P1 and P2 fragment. The finally QSAR model, along with the information obtained from contribution maps and docking studies should be useful for the design of novel DPP-4 ligands having improved selectivity without side effects.

CuI facilitated the intramolecular cyclization of 8-alkynyl substituted 2,3-dihydroquinolin-4(1H)-ones leading to 5-subtituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones via intramolecular C-N bond forming reaction. Some of the synthesized compounds have shown encouraging inhibition of Sir 2 protein (a yeast homolog of mammalian SIRT1) when tested using a yeast cell based assay. A representative compound showed dose dependent inhibition of yeast Sir 2 (IC50 = 30.09 μM) and cell growth inhibition properties when tested against different cancer cell lines. It’s in silico interactions with sirtuins are presented.

The carboxamide derivatives of Febuxostat were synthesized via the reaction of Febuxostat with various amines through by Schotten-Baumann reaction. All the synthesized compounds have been evaluated for their in vitro Xanthine Oxidase inhibitory activity. The present study reveals that most of carboxamides were acting as better XO inhibitors and play an important role in decreasing uricacid levels. Almost all the compounds surprisingly showed nearly 30% higher XO inhibition activities than the standard Allopurinol. 3h, 3k and 3l stand as the best among the synthesized compounds.

In different RNA viruses, the nucleocapsid protein N (N protein) plays an important functional role by enwrapping the viral genomic RNA in an RNase-resistant form. Targeting this essential protein is one of the best methods to find novel Chandipura virus (CHPV) inhibitors. The model of N protein of CHPV showed that this protein bears an alpha helical type topology. Computational characterization of N protein of CHPV exhibited that it bears DNA/ RNA binding region. Among all of the computationally screened compounds by GOLD, Flex X and ligandfit (DSv2.5) programs, antiviral compounds such as nelfinavir, acyclovir, azidothymidine are having very high binding affinity towards N protein of CHPV.

Condensation of ketones 1a-b with deferent aldehydes 2a-e gives chalcones 3a-j. These chalcones on cyclization with hydrazine hydrate/ phenylhydrazine in the presence of glacial acetic acid give the corresponding pyrazolines 4a-t. The structures of new compounds have been established by extensive IR, NMR and X-ray crystallographic studies and were assayed for their antitubercular activity against M. tuberculosis H37Rv and INH resistant M. tuberculosis strains using agar dilution method. Among the both derivative compounds, 4-hydroxy-3-(5-(4- trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl-2H-chromen-2-one 4m produced the highest efficacy, exhibited >90% inhibition against MTB at a concentration of 4.94 μM and against INHR-MTB at 14.78 μM.

In soybean, a small hormone like peptide, leginsulin was found to bind Basic 7S Globulin (Bg7S) and stimulate its tyrosine kinase activity. The NMR-structure of leginsulin, along with crystal structure of Bg7S, was used to create a rigid docking model, followed by flexible refinement of the interaction complex. This study provides structural insights into the binding of leginsulin to Bg7S. The complex is stabilized predominantly by hydrophobic forces and hydrogen bonds. The cleft is lined to a large extent by the cysteine rich region of the α-subunit of chain D as well as the carboxylterminal region of α-subunit of chain A. The model is in agreement with the available experimental evidence for the hotspot regions of Bg7S and leginsulin. We also observed another similar site on the surface of Bg7S by virtue of its pseudo- 222 symmetry. We have further hypothesized that two leginsulin molecules may bind to Bg7S in its crystal structure or tetrameric form.

Alzheimer’s disease is a brain disease that slowly destroys memory and thinking skills, and eventually, the ability to carry out the simplest tasks. It begins slowly and gets worse over time. The main risk factor for Alzheimerμs disease is increased age. As a population ages, the frequency of Alzheimer's disease continues to increase. Currently, there is no cure. There are many compromises in the brain of an Alzheimer's patient. Essentially, three modifications occur: decrease of cholinergic impulse, increased toxic effects caused by ROS, and an inflammatory process in which amyloid plaque participates. This study is a mini-review of Alzheimer’s disease, and we report advances in the studies concerning enzymes, and substances or targets of these three processes. Our review was focused on a few biological pathways and involved in the pathophysiology of AD: cholinergic system; oxidative stress; beta-amyloid processing; insulin signaling. We analyzed a large body of evidence coming from biochemical studies and a series of compounds which act on these pathways as alternative treatments for the disease.