Letters in Drug Design & Discovery - Volume 9, Issue 10, 2012

A series of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles is synthesized by Fisher or Bischler method, followed by alkylation with an appropriate alkyl or aryl halide. Two compounds exhibit non-competitive antagonism towards GluK1 and six – towards GluK2 receptor. The values of IC50 are in micromolar range. The investigated compounds belong to the most active GluK1 non-competitive inhibitors and are the first known negative allosteric modulators of GluK2 receptor. The observed pattern of activity is rationalized by molecular modelling, in particular by construction of the pharmacophore model.

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 are critical regulators of angiogenesis. The blockage of VEGFR-2 signaling by small molecule inhibitors has been shown to inhibit angiogenesis and tumor progression. The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of benzoquinone derivatives reported for VEGFR-2 inhibition. A five point pharmacophore model was developed with an excellent correlation coefficient value (r2 = 0.9395) along with good statistical significance as shown by the high Fisher ratio (F = 63.8). The model also exhibited good predictive power confirmed by the high value of the cross validated correlation coefficient (q2 = 0. 6228). The QSAR model suggests that hydrophobic character is crucial for the VEGFR-2 inhibitory activity, exhibited by these compounds and inclusion of hydrophobic substituent will enhance the VEGFR-2 inhibition. In addition to the hydrophobic character, H-bond donating groups and electron withdrawing groups positively contribute to the VEGFR-2 inhibition. Further, the pharmacophoric model was validated by ROC curve analysis and was employed for virtual screening to identify six potential VEGFR-2 inhibitors. The findings of this study provide a set of guidelines for designing compounds with better VEGFR-2 inhibitory potency.

Diabetes mellitus, a chronic condition caused by defects in insulin secretion, or action, or both, is a group of metabolic disorders whose complications can contribute significantly to ill health, disability, poor quality of life and premature death. From the three main types of diabetes, Type 2 is by far the most common, accounting for about 90% of cases worldwide. Studies on the role of protein tyrosine phosphatase 1B (PTP1B) have clearly shown that it serves as a key negative regulator of insulin signaling and is involved in the insulin resistance associated with Type 2 diabetes. In the present study, a QSAR modeling work was carried out on a series of 1, 2-naphthoquinone derivatives. The inhibitory activity of such compounds was investigated by two types of QSAR methods: multiple linear regression and non-linear neural networks. This strategy afforded QSAR models with good overall accuracy and predictivity on external data, showing it to be a simple, precise and credible tool to predict and screen 1,2-naphoquinone derivatives with high inhibitory activity.

Selected adamantanyl purines and pyrimidines 1-10 were synthesized. These compounds were evaluated for cytotoxic activity against NCI-60 DTP human tumor cell line screen. N9-(3'-Adamantan-1-yl)-4'-hydroxy(benzyl)-2- amino-6-chloropurine, 3 and N9-[(3'-(Adamantan-1-yl)-4'-(2'',3'',4''-trifluorobenzyloxy)]benzyl-2-amino-6-chloropurine, 6 elicited significant cytotoxic activity with GI50 values in the 1–10 μM range for selected human tumor cell lines. While other compounds elicited moderate activity with GI50 values in the 10–20 μM range for most human tumor cell lines.

In obtaining some new cytotoxic and chemopreventive agents with potent antiproliferative activity against cancer cells, a series of new β-isatin aldehyde-N,N'-thiocarbohydrazone, bis-β-isatin thiocarbohydrazones, bis-β-isatin carbohydrazones, N,2-bis(thiophen-2-ylmethylidene) thiocarbohydrazone and N,2-bis(thiophen-2-ylmethylidene) carbohydrazone derivatives was synthesized by microwave oriented reaction and evaluated for their in vitro cytotoxic activity. The newly synthesized compounds were characterized based on spectral (FT-IR, NMR, MS) analyses. The inhibitory effects of synthesized compounds on the proliferation of murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) were assayed by using MTT assay. The compounds were also tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-Otetradecanoylphorbol- 13-acetate (TPA). In vitro evaluation of these schiff bases revealed mild to moderate cytotoxic activity in a dose dependent manner. The results of the in vitro inhibitory activities of synthetic compounds against EBVEA activation with IC50 ranges from 485-535 (mol ratio/32pmol/TPA). Chlorine group containing derivatives did not show increased inhibitory activity against tumor promoter TPA induction. Sulphur containing derivatives also did not show a high inhibitory potency in this system.

Novel 3,5-disubstituted 1,2,4-oxadiazoles 4a-4j were prepared from commercially available chlorosalicylaldehyde and screened for their cytotoxicity properties using brine shrimp (Artemia salina) bioassay and compared with the standard podophyllotoxin. The oxadiazoles 4a, 4c, 4e and 4h exhibited cytotoxicity activity in the series.

Fourteen novel compounds were obtained and their chemical structures were established by 1H-NMR and IR spectra as well as elemental analyses. As one of the most important factors determining the changes of activity of respective fluorophenyl and iodophenyl derivatives, one should consider the volume of halogen substituent and its influence on the lipophilicity of the entire molecule.

The aim of this work was to synthesize a series of compounds to study their antimycobacterial potential. Eight compounds were found to be most active with minimum inhibitory concentration of less than 6μM and were more active than Isoniazid (INH) against Mycobacterium tuberculosis H37Rv (MTB). Compounds with electron withdrawing group substituted on the aryl ring were showing better activity. Among the fifteen newly synthesized compounds, compound 6- methyl-4-(4-nitrophenyl)-2-oxo-N-(pyridin-2-yl)-1,2,3,4tetrahydropyrimidine-5-carboxamide (B) was found to be the most active agent against MTB and INH resistant Mycobacterium tuberculosis (INHR-MTB) with minimum inhibitory concentration of <0.35 μM.

With the ultimate purpose of finding out the structural features that are relevant for MAO inhibitory activity and selectivity towards MAO-B isoform, a series of compounds encompassing a β-nitrostyrene moiety was designed and the in vitro inhibitory activity was evaluated. In the present work, we report the synthesis and the pharmacological evaluation of a series of functionalized derivatives of β-methyl-β-nitrostyrene with distinct substitution patterns in the phenyl ring, namely hydroxyl, methoxy, benzyloxy and methylenedioxy. All the studied compounds were substituted in meta and para positions of the phenyl ring related to the nitrovinyl side chain. The synthesized compounds were evaluated towards both human MAO isoforms, displaying some of them activities in the low micromolar range. Particularly compound 6 (a methylenedioxy derivative) exhibits high potency and selectivity towards MAO-B.

The series of 3,4–dihydropyrimidin–2-ones (DHPMs) were synthesized using recyclable silica supported RhCl3 as heterogeneous catalyst and evaluated for anti-neuroinfammatory effect in microglia cells. Among the DHPMs tested, compounds 4g, 4j and 4v strongly inhibited LPS-induced nitric oxide (NO) production with IC50 value of 67.32, 46.01 and 41.31 μM in the microglia cells. Also, compounds 4g, 4j and 4v significantly inhibited the enzyme activity of inducible NO synthase (iNOS) without changes of iNOS protein expression and NO scavenging activity. This result suggests that compounds 4g, 4j and 4v showed the anti-neuroinflammatory effect by suppressing iNOS enzyme activity.

Hydroxysafflor Yellow A (HSYA) is one of the most important active ingredients of Carthamus tinctorius L, and has long been widely used in the treatment of cardiovascular diseases in China. The purpose of this study was to evaluate the role of HSYA in protecting the kidney against ischemia/reperfusion injury (IRI). Male Wistar albino rats (200-250 g) were unilaterally nephrectomized and subjected to 45-min renal ischaemia and 24-h reperfusion. HSYA (1, 3 and 10 mg/kg, i.v.) or normal saline was administered 15 min prior to ischemia. At the end of the reperfusion period, rats were decapitated and kidney samples were taken for histological examination or determination of malondialdehyde (MDA), glutathione (GSH) and myeloperoxidase (MPO) activity. Blood urea nitrogen (BUN) and creatinine (Cr) levels were measured for the evaluation of renal function. Lactate dehydrogenase (LDH) and TNF-α levels were determined to evaluate generalized tissue damage. The results showed that BUN, Cr, LDH and TNF-α levels, and MDA and MPO activities in the renal tissue increased significantly after IRI (P<0.01) while the GSH content in the renal tissue decreased significantly (P<0.05 or P<0.01). Compared with saline-treated I/R group, BUN, Cr, LDH and TNF-α levels, MDA and MPO activities in HSYA-pretreated group decreased significantly in a dose-dependent manner (P< 0.05 or P< 0.01). The mean histological score in saline-treated I/R group increased markedly compared with that in sham-operated control group (P<0.05), and decreased in HSYA (3 and 10 mg/kg, i.v.) group compared with that in saline-treated I/R group (P<0.05). The results of the present study suggest that HSYA pretreatment may prevent IRI-induced oxidative injury from occurring in the renal tissue of rats.