Medicinal Chemistry - Volume 8, Issue 5, 2012

The Editorial Board wishes to dedicate this issue of Medicinal Chemistry to the Editor-in-Chief of the journal, Prof. Dr. Atta-ur-Rahman, FRS, on his 70th birthday. The Editorial Board acknowledges the tremendous achievements of Prof. Rahman in the fields of Organic Chemistry in general and on bioactive natural products in particular. Prof. Rahman’s honors include: the first scientist from the Muslim world to have won the prestigious UNESCO Science Prize (1999) in the 35 year old history of the Prize; elected as Fellow of Royal Society (London) in July 2006; conferred honorary doctorate degrees from many prestigious universities, including the University of Cambridge. On a national level his services are acknowledged in the form of four prestigious civil awards, including these highest national awards: Nishan-e-Imtiaz (2002), Hilal-e-Imtiaz (1998), Sitara-e-Imtiaz (1991) and Tamgha-e-Imtiaz (1983). At an academic level, Prof. Rahman has 856 publications in several fields of organic chemistry including 658 research publications, 21 patents, 114 books and 65 chapters in books published largely by major U.S. and European presses. He is currently the Editor-in-Chief of 12 scientific journals in fields ranging from Medicinal Chemistry to Pharmaceutical Drug Design. Seventy six students have completed their Ph.D. degrees under his supervision. He chairs the Network of Academies of Sciences of Islamic Countries (NASIC) and is the Vice-President (Central & South Asia) of the Academy of Sciences for the Developing World (TWAS) Council, and Foreign Fellow of Korean Academy of Sciences. Prof. Atta-ur-Rahman was the President of the Pakistan Academy of Sciences (2003-2006) and was again elected as the President of the Academy from 1st of January 2011. In particular, Prof. Rahman has made outstanding contribution to Medicinal Chemistry. The contributions of Prof. Rahman to the uplifting of science in Pakistan in his capacity as the Federal Minister for Science & Technology and later as Chairman Higher Education Commission were acknowledged by a high Cilvil Awards of the government of Austria and TWAS prize for institution building as well as by four editorials in Nature. The Editorial board wishes health and prosperity to Prof. Atta-ur-Rahman in the years to come.

A series of 1,3-oxathiolane-based nucleoside analogs 5-methyl substituted was synthesized and tested as potential antiviral agents. Structural characterization and C2-C4 / C2-C5 relative stereochemistry assignments were performed by NMR experiments. All tested isomers were found to be inactive and cytotoxic.

The synthesis of twenty seven novel pyrazole derivatives bearing aryl substituted groups at positions 1 and 3 of the pyrazole structural motif and various functional groups at position 4 is presented. The critical step for their synthesis is the TCT/DMF promoted cyclization of the corresponding hydrazine precursors, which provided the desired pyrazole skeleton. The anticancer properties of the novel pyrazole derivatives were evaluated in vitro against human prostate (DU145), melanoma (A2058) and breast cancer (MCF-7) cell lines. Among the compounds tested, pyrazole 5a and its methoxy derivatives 3d,e were assayed as the most potent, displaying selective activity against the MCF-7 cell line with IC50 values of 14, 10 and 12 μM respectively. Results herein indicate that the reported backbone represents a promising structural lead for further development as antitumor agents.

Despite numerous synthetic efforts and extensive SAR studies on paclitaxel analogs, little work has been devoted to derive SAR of the C-1 hydroxy group. Up to now, 1-deoxypaclitaxel has only been reported to be isolated from the Chinese yew, Taxus mairei (Taxaceae). However, the isolation from natural sources does not solve the availability problem due to the reported low yield of isolation. Also, only several analogues of this type have been reported. Thus, there is an urgent need for exploration of new synthetic methods on this structurally intriguing molecule and further SAR studies. In present work, we report the initial expedient semi-synthesis of 1-deoxypaclitaxel and its novel analogues with structural variations at C7 and C10 from 1-deoxybaccatin VI, as well as their cytotoxic activities against A 549 cell line.

Leflunomide is an immunomodulating drug that has been used clinically for the treatment of rheumatoid arthritis and other immune system disorders. As a continuation of our previous work, four novel analogues of leflunomide (6a, 6b, 7a and 7b) were synthesized; here, an imidazolyl group has replaced the isoxazolyl moiety, while the 4- trifluoromethylphenyl group has been retained. These analogues were synthesized and investigated in vitro for their immunomodulating activity by examining human lymphocyte proliferation and determining the cytokine interferon-γ concentrations in human lymphocyte cells. For this purpose, 5 x 104 human lymphocyte cells were incubated at 37°C in 5% CO2 with phytohemagglutinin and one of the analogues (concentrations ranging from 1 to 100 mM), negative controls or cyclosporine (0.1 mM). The compounds' effects on lymphocyte proliferation and interferon-γ (IFN-γ) production were determined using an MTT assay and an ELISA, respectively. All compounds were found to have significant effects on both lymphocyte proliferation and IFN-γ production in comparison to the negative control. However, the compounds' effects were weaker than those of the positive control. Some differences among compounds 6a, 6b, 7a and 7b were seen on lymphocyte proliferation and cytokine production. Compound 6a (R=CH3 containing a trifluoromethylaniline moiety) suppressed lymphocyte proliferation and IFN-γ production with a potency comparable to the positive control. Therefore, further studies to evaluate the compound's effects in clinical conditions are suggested.

All-trans-retinoic acid reverses malignant cell growth and induces cell differentiation and apoptosis. Poor aqueous solubility and uncertain bioavailability are the limiting factors for using all-trans-retinoic acid for tumor therapy. The objective of present study was to encapsulate the hydrophobic drug all-trans-retinoic acid in the polymer poly (lactide-coglycolide). The encapsulation was expected to improve the bioavailability and solubility of the drug. Oil in water single emulsion solvent evaporation technique used for the preparation efficiently encapsulated about 60% of the drug. The drug release profile showed a biphasic pattern with 70% of the drug being released in first 48 hrs and the residual drug showing a slow controlled release reaching up to 8 days. The particle size of 150-200 nm as determined with TEM was ideal for tumor targeting. All-trans-retinoic acid loaded nanoparticles were efficient to induce differentiation and blocked the proliferation of HL-60 cells invitro. These studies also revealed that the dosage of drug required for the therapeutic effects have been reduced efficiently. Our studies thereby demonstrate that Poly (lactide-co-glycolide) based nanoparticles may be efficient for parenteral administration of the drug.

This study critically examines the role of conceptual DFT descriptors and docking scores on a diverse set of 156 inhibitors of HIV proteases. Five QSAR models were developed on the basis of available experimental IC50 values (HIV-I and HIV-IIIB infected MT4 and CEMSS cells and HIV-I infected C8166 cells) and sixth QSAR model was generated by combining the inhibitors of all five models. B3LYP/6-31G(d) optimizations were carried out on all considered inhibitors, and the results are compared with more economic semi-empirical SCF AM1 results in order to find out the best and efficient way of descriptor calculations. Interestingly semi-empirical results appear to be satisfactory for this class of inhibitors. Selected QSAR models were validated by taking about 20% of inhibitors in the test sets. The effect of the number of descriptors on the R2 and R2 cv values was tested and three to four orthogonal descriptors based models were selected to be the optimum ones to avoid over correlation.

Two novel groups of hexapeptide inhibitors for NS3 serine protease of the hepatitis C virus (HCV) are designed. The hexapeptide is an amino acid sequence of NS5A/NS5B substrate (Glu-Asp-Val-Val-Cys-Cys). In the first group, the hexapeptide binds to a cellulose monomer at the positions 2, 3 or 6 while in the second group, the hexapeptide binds to a cellulose dimmer at the positions 2, 3, 6, 2', 3'or 6'. Molecular modeling semiemprical PM3 calculations are used to optimize the geometry and calculate the electronic properties of the suggested inhibitors compared to that of natural substrate. Computational results show that the second group has the maximum stability and reactivity indicating that it would be considered as a promising HCV NS3 protease inhibitor.

In order to discover compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 9 new indolyl glyoxamide derivatives (3a-i) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro. Among all the derivatives, especially compounds 3e and 3h showed the potent anti-HIV-1 activity with EC50 values of 6.83 and 4.35 μg/mL, and TI values of >27.15 and 49.45, respectively. It demonstrated that introduction of the substituent R3 as the halogen atom and the position of R3 were generally important to their activity.

Thiazolidinedione (TZD) derivatives are the novel class of oral antidiabetic drugs which are selective agonist for the nuclear PPAR γ that enhances the transcription of several insulin responsive genes but TZDs are known to cause weight gain, hepatotoxicity and fluid retention. So a new series of coumarin coupled thiazolidinedione derivatives and its bioisosters (oxazolidinedione and imidazolidinedione) were synthesized by Knoevenagel condensation of 4-((7-hydroxy- 2-oxo-2H-chromen-4-yl) methoxy) benzaldehyde with 2,4 thiazolidinedione and its bioisosteres. The structures of these compounds were established by means of FT IR, 1H-NMR, elemental analysis and mass spectroscopy. All the compounds were screened for antidiabetic activity in streptozotocin induced diabetic wistar male rats. Most of the compounds revealed significant antidiabetic activity when compared with the standard drug rosiglitazone. Compounds 5 & 6 containing oxazolidinedione ring system were found to be more active than compounds having thiazolidinedione and imidazolidinedione nucleus. Molecular docking was performed on 2 PRG protein by using the software Glide (Schrödinger, LLC, USA). The QikProp program was used to obtain the pharmacokinetic properties of analogues.

A series of metronidazole ester derivatives 1-34 has been synthesized with the aim of developing new leads with antiglycation activity. The in vitro evaluation of antiglycation potential of 1-34 showed that the ester derivatives 28, 16, and 3 have IC50 values 218.97 ± 2.5, 245.3 ± 5.1, and 278.6 ± 0.8 μM, respectively, comparable to the standard agent, rutin (IC50 = 294.5 ± 1.50 μM). The study identifies a new class of potent antiglycation agents. A structure-activity relationship has also been evaluated. All the compounds were characterized by using spectroscopic techniques, including 1H NMR, IR, and EI-MS.

In silico based QSAR and pharmacophore analyses of a series of piperidine derivatives were performed in order to investigate the structural features of the derivatives responsible for FTase inhibitory activity. The results derived from the QSAR analysis show that the FTase inhibitory activity mediated by the vdW surface area features such as partial charge (PEOE_VSA and Q_VSA) and v_surf (hydrophobic integy moment) of the molecules. The positive contribution of the partial charge descriptors such as Q_VSA_FPNEG and PEOE_VSA-4 reveal that the fractional negative charge on the vdW surface of the molecules and the aqueous solubility (LogS) of the molecules are important for the FTase inhibitory activity. While the hydrophobic integy moment reveals that a clear separation between the hydrophobic and the hydrophilic region in the molecules is important with electrostatic groups (fractional negative charge) for better activity. The pharmacophore analyses of the piperidine derivatives also show that the aromatic, acceptor and donor groups on the molecule favorable for the FTase inhibitory activity.

Eight aromatic amino acid derivatives (9a-9h) as gastrin-releasing peptide receptor (GRPR) antagonists were designed and synthesized. For the design, the tertiary structure of GRPR was predicted by blast searching in the premise of 1u19 protein as the template. Eight target compounds were docked into the binding pocket to investigate their possible binding interactions. Their anti-itch activities were tested by intrathecal injection using Kunming mice as experimental animals and chloroquine phosphate as a modeling medium. Compounds 9e and 9f significantly inhibited scratching behaviors. The anti-itch activities of these compounds decreased with the following sequence: 9e > 9f = 9d > 9b > 9g > 9a > 9h > 9c predicted by computer-aided drug design (CADD) and 9e > 9f > 9b > 9h > 9g > 9d > 9a > 9c evaluated by preliminary test. They were broadly in line with activity order pretested by CADD. It showed that the predicted tertiary structure of GRPR could be used for antipruritic drug design.

Indan derivatives, namely, 5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and 5-(5',6'-dichloroindan-1'-yl)- methyltetrazole (12b), were synthesized conveniently from 5,6-dichloroindan-1-carboxylic acid (9a) and 5,6- dichloroindan-1-acetic acid (9b), respectively, as potential analgesic and anti-inflammatory agents. The analgesic and anti-inflammatory properties of 9a, 9b, 12a and 12b were evaluated by the acetic acid induced writhing in Swiss albino mice and the carrageenan-induced rat paw edema models, respectively. Compounds 9a and 12a exhibited significant analgesic activity with the doses of 50 and 100 mg/kg body weight, comparable to that of the positive controls, phenylbutazone, indomethacin and aminopyrine. The anti-inflammatory potencies of 9a and 12a were also comparable to that of the positive control, phenylbutazone. Compounds 9b and 12b showed analgesic and anti-inflammatory activities, but were weaker than that of compounds 9a and 12a.

The influence of a number of usnic acid derivatives on auto(polyADP-ribosyl)ation catalyzed by PARP1 and DNA synthesis catalyzed by DNA polymerase β was studied. The derivatives of usnic acid containing aromatic substituents were shown to be moderate inhibitors of PARP1. The presence of both usnic acid tricyclic structure and aromatic substituent at any position of the molecule is a key factor for the inhibitory action. In the case of DNA polymerase β, no relationship between the structure and inhibitory properties has been found with the only exception. Derivatives with modified ring A showed mild activation of DNA synthesis catalyzed by DNA polymerase β.

In the present study, three dimensional quantitative structure activity relationship (3D QSAR) models using 3D Pharmacophore, CoMFA and CoMSIA approaches were developed for a series of phenyl alkyl ketone derivatives as PDE4 receptor antagonists. An ideal 3D QSAR pharmacophore model was developed and validated using external test set, Fischer's randomization method and decoy set screening. The top scoring four feature pharmacophore model, Hypo1, includes two hydrogen bond acceptors, two hydrophobic features. Amongst the developed models, Hypo1 has the maximum correlation coefficient (0.9658), cost difference (349.593), low RMS (1.41), and high goodness of fit. CoMFA and CoMSIA models were developed based on the alignment obtained using the pharmacophore (Hypo1), substructure alignment and by application of region focusing. The robustness of CoMFA and CoMSIA model was confirmed with the help of leave one out cross-validation method, while the predictive ability of models was tested using a test set. 3D-QSAR models with high squared correlation coefficient of up to 0.9720 for CoMFA and 0.9610 for CoMSIA were established. Robustness of the models is demonstrated by R2 cv values of up to 0.7582 and 0.8539 for CoMFA and CoMSIA, respectively. Predictive ability of the models is reflected by R2 pred values of 0.9630 and 0.9470 for CoMFA and CoMSIA respectively. Novel molecules were designed on the basis of results of 3D QSAR studies. Designed molecules were evaluated by Docking and Lipinski filters. Predicted activity of the designed molecules correlated well with the docking scores and the molecules also passed the Lipinski filters.

RTKs - Receptor Tyrosine Kinases are the key regulators for cellular function and any abnormalities in the signaling of such leads to cancer. Mutations that result in the constitutive activation of this receptor result in Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia. Pharmacophore mapping, a well-established method is used to build up 3D QSAR model from two classes of compounds viz. 2-acylaminothiophene-3- carboxamide derivatives and 4-amino-6- piperazin-1yl-pyrimidine-5-carbaldehyde oxime derivatives, which helps us to quantify the crucial structural requirements for designing newer potent inhibitors for FLT3. The derived model AADHR.939 (Pearson- R = 0.8912, q2 = 0.7471 and non-cross-validated r2 = 0.9154) shows that the ring feature is quite crucial for the FLT3 inhibitory activity. Moreover the model is showing 94% predicted activity, which makes an understanding that the model is capable of finding newer potent molecules from any database.

A series of novel Ligustrazinyl acylguanidines was designed, synthesized and evaluated for their protective effect on injured vascular endothelial cell (ECV-304). The preliminary results demonstrated that some compounds possessed more potent activities than that of Ligustrazine in stimulating replication of the injured endothelial cell. Among the active compounds, compounds 8b, 8f and 8l displayed remarkable antioxidative activity with low EC50 values of 0.097, 0.059 and 0.094 mM, respectively. Structure-activity relationships were briefly discussed.

As one of the main active component of protopanaxdiol type ginsenosides, ginsenoside Rb3 is rarely reported in the treatment of diabetes. The anti-diabetic activity of ginsenoside Rb3 was investigated in a model of alloxan-induced diabetic mice in the present study. The physiological parameter such as fasting blood glucose level, oral glucose tolerance, body weight, food intake and water intake were measured. Glucose consumption in C2C12 myotubes was also determined in order to investigate the molecular mechanism of ginsenoside Rb3 in anti-diabetes. The alloxan-induced diabetic mice were treated with ginsenoside Rb3 for 2 weeks at doses of 5 mg/kg, 15 mg/kg and 25 mg/kg. After 2 weeks treatment of ginsenoside Rb3, the fasting blood glucose levels of DG 15 and DG 25 were respectively reduced by 36.70% and 37.50% compared to control group. At a dose of 25 mg/kg, oral glucose tolerance was significantly improved compared to control group (P < 0.05). The AUC decreased by 34.47% (from 2442 ± 291 mmol·min/L to 1600 ± 109 mmol·min/L). Both food intake and water intake were remarkably lowered. The injury of pancreas tissues was repaired, which was observed by using HE staining and optic microscope. In vitro, at concentrations of 100 and 200 μM, ginsenoside Rb3 increased glucose consumption in C2C12 myotubes by 76.83% and 97.20%, respectively, as compared to the control group. However, the body weight of diabetic mice was not significantly altered. In conclusion, our results showed that ginsenoside Rb3 reduced fasting blood glucose level, food intake, water intake, improved oral glucose tolerance, and repaired injured pancreas tissues of alloxan-induced diabetic mice. Therefore, it was suggested that ginsenoside possesses the potential of the clinical use in preventing and treating diabetes.

In order to predict the antioxidant activity of 7 polycyclic lactams, a two dimensional quantitative-structure activity relationships (2D-QSAR) study based on a 5-descriptor model was performed. The synthetic compounds built from a condensed lactam scaffold were screened for their abilities to inhibit the autoxidation of pyrogallol, a superoxide anion radical-dependent process. The ketone 2 (8,9-dihydro-7H-benzo[de]pyrrolo[1,2-a]quinoline-7,10(7aH)-dione) exhibited the most potent antioxidant activity in vitro. The oxidation mechanism was proved by the isolation and characterization of alcohol 5 formed in the reaction of ketone 2 with dissolved oxygen in methanol.