Letters in Drug Design & Discovery - Volume 6, Issue 1, 2009

A novel library of eighteen 4-substituted-3-hydroxy-5-oxo-10-oxa-4-azatricyclo[5.2.1]dec-3-yl acetic acid ethyl esters was generated in high yield in two steps from norcantharidin, a known protein phosphatase 1 and 2A inhibitor that displays good anticancer activity. Interestingly these analogues are bereft of anticancer and protein phosphatase activity, but possess the attributes needed for medicinal agents and could be used as scaffolds in other targets.

Dependence can be induced and measured in vitro by using guinea-pig ileum. Tissues from untreated animals, after a brief exposure to opioids, show a strong naloxone-induced contracture indicating that the cellular mechanisms of dependence may occur very rapidly following occupation of receptors and that these mechanisms operate within the myenteric plexus. The characteristics of dependence development and the precipitation of withdrawal by naloxone in the guinea-pig ileum are very similar to those of acute dependence in experimental animals and man. Several observations indicate that brain serotoninergic system has been widely implicated in many of the pharmacological effects of opioids. Although the role of serotonin in the development of dependence has been previously reported the effects exerted by chronic treatment of p-Chlorophenylalanine (p-CPA), an inhibitor of tryptophan 5-hydroxylation which is the rate limiting step in the synthesis of serotonin, on the acute opiate withdrawal was investigated in vitro and whether p-CPA interferences on opiate withdrawal take place through μ and/or κ opioid receptors. Following a 4 min in vitro exposure to the opioid agonist (Morphine, DAGO or U50-488H), the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone (80% of contraction vs. acetylcholine control). By contrast, ilea from guinea-pigs treated for 6 days with p-CPA (10 mg/Kg/i.p.), following a 4 min in vitro exposure to the opioid agonist, did not show any contracture after the addition of naloxone (0% of contraction vs. acetylcholine control). The results of the present study confirm an important functional interaction between the serotoninergic system and opioid system.

Buprenorphine maintenance treatment has become a major intervention in the care and treatment of drug dependence in Europe. Still little is known about sexual behaviour and sexual dysfunction especially under buprenorphine or methadone maintenance treatment. Our study aimed to evaluate patterns of sexual behaviour and dysfunction prevalence within buprenorphine and methadone maintenance treatment. Significant differences between both groups could be observed regarding sexual excitation disturbances and ability to orgasm. 33.3% of the methadone-maintained group showed significantly higher sexual excitation disturbances (p = 0.006). Future studies of sexual dysfunction in opioid-treated persons should examine the potential benefits of dose reduction, androgen replacement, and choice of opioid.

GTP-bound mutant form H-Ras (Harvey-Ras) proteins are found in 30% of human tumors. Activation of H-Ras is due to point mutation at positions 12, 13, 59 and/or 61 codon. Mutant form of H-Ras proteins is continuously involved in signal transduction for cell growth and proliferation through interaction of downstream-regulated protein Raf. In this paper, we have reported the virtual screening of lead compounds for H-Ras P21 mutant protein from ChemBank and DrugBank databases using LigandFit and DrugBank-BLAST. The analysis resulted in 13 hits which were docked and scored to identify structurally active leads that make similar interaction to those of bound complex of H-Ras P21 mutant- Raf. This approach produced two different leads, 3-Aminopropanesulphonic acid (docked energy -3.014 kcal/mol) and Hydroxyurea (docked energy -0.009 kcal/mol) with finest Lipinski's rule-of-five. Their docked energy scores were better than the complex structure of H-Ras P21 mutant protein bound with Raf (1.18 kcal/mol). All the leads were docked into effector region forming interaction with ILE36, GLU37, ASP38 and SER39.

Two series of 2-substituted aryl, heteroaryl and alkyl, 4-substituted aryl 1,3-oxazole (2a-k) and thiazole (4a-k) molecular scaffolds containing divalent bioisosteres, viz., oxygen and sulphur were synthesized by condensing substituted amides and thioamides with substituted phenacyl bromide in absolute ethanol medium. The structure of newly synthesized compounds was characterized by analytical and spectral (IR, 1H-NMR, 13C-NMR and LC-MS) methods. The synthesized compounds were evaluated for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup plate and micro-titration methods, respectively. Preliminary pharmacological observations revealed that some of the substituents such as 2-alkyl and heteroaryl at second position, chloro and bromo at the fourth position of the aryl moiety and a divalent sulphur atom in the five-membered heterocyclic ring system influenced significantly the antibacterial activity when compared to its bioisostere counterpart 2-substituted aryl, heteroaryl and alkyl, 4-substituted aryl 1,3-oxazole systems.

Screening of a non-ionizable compound library and hit optimization studies has resulted in a series of compounds based on a 4-arylmethyl-3-(4-carboxyphenyl)-5-hydroxyisoxazole scaffold with GCP II inhibitory activity in the low micromolar range.

In this study we have prepared and characterized, in terms of structure and morphology, different cationic lipid- DNA complexes (lipoplexes). Condensation studies showing the ability of cationic lipids to condense DNA are presented. The effect of the presence of serum and the ligand transferrin (Tf) has also been evaluated. Studies of negative stain transmission electron microscopy (TEM), infrared spectroscopy (FTIR), differential thermal analysis (DTA) and X-ray diffractometry have shown stable complexes with different morphology and structural rearrangements.

The cytochrome-P450 (CYP) complex aromatase is the rate-limiting step in the production of endogenous estrogen. This synthesis can be controlled with aromatase inhibitor (AI). Different types of AIs are under extensive study for use in the treatment of advanced breast cancer in postmenopausal patients. In view of such significance, the present study explored the pharmacophores of benzofuran derivatives containing pyridine, imidazole and triazole substituents for inhibiting selective aromatase enzyme, CYP19 activity. Implementing classical QSAR (R2=0.858, Q2=0.737, s=0.349, R2 test=0.839) and space modeling (R2=0.908, Δ cost=179.138, rmsd=1.235, R2 test=0.867) approaches, it has been explored that molecular hydrophobicity, presence of suitable ring substituent and hydrogen bond acceptors are the crucial key features of the benzofuran scaffold for imparting CYP19 inhibitory activity. Moreover steric properties of the molecule have influence on the activity.

A series of substituted 3-phenyl-4-phenylvinyl benzopyranone derivatives (11a-e) was evaluated for their antiimplantation activity in mature female Sprague-Dawley rat model. Compounds were further evaluated for antiproliferative activity in human adenocarcenoma breast cancer cell line (MCF-7 cancer cell line). The tested compounds showed significant anti-proliferative activity with moderate anti-implantation activity. The inhibitory concentration (IC50) values of most active compounds 11 (c-e) are 8.43 μM, 7.97 μM and 7.91 μM respectively and comparable to that of tamoxifen (5.10 μM), a well known antiestrogen used for treatment of breast cancer.

A novel series of 4-chloro-3-arylmaleimide derivatives have been synthesized and evaluated for their cytotoxicity in vitro against human leukemia cell line and four human solid cancer cell lines. Most compounds showed high or mediate activity against the cancer cell lines when compared with bisindolylmaleimide. Among them, 4b is the most promising compound.

Previously, we designed and synthesized the 2,3,6,7-tetrahydro-1H-pyrrolo[1,2-a]indole-1,8(5H)-dione as a versatile structural platform to be functionalized to obtain potential DNA-interactive agents by intercalation and/or reversible enzyme inhibition. Herein, we report an alternative synthetic route for the preparation of this heterocyclic template as well as the synthesis of an its “two-armed” derivative. Also, a computational docking study to investigate the possible DNA-binding mode of well-known binders and title compound was performed.

The antimicrobial activity of ethanolic and aqueous extracts of a commercial green propolis and of 13 standard antibiotics was evaluated against Staphylococcus spp. strains isolated from milk of goats with mastitis. More than 95% of the isolates were sensitive to cephalothin and tetracycline, whereas only 28.9% were sensitive to streptomycin. All the isolates were susceptible to both ethanolic and aqueous extracts, but the former showed the higher antimicrobial activity. The larger mean diameter of the inhibition zone of coagulase-negative staphylococci (15.5 mm) was in fact obtained with the ethanolic extract. A Minimum Inhibitory Concentration of 50 μg/mL of both extracts was determined, which highlighted a promoting in vitro activity.

A variety of imidazolones 1-34 derivatives were synthesized and tested for their antibacterial effects against Escherichia coli, Bacillus subtilis, Shigella flexnari, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhi. Compound 18 found to be moderately active against S. flexnari, however, compounds 8, 11, 15, 21, 22, 25 showed to be moderate and compounds 31 and 34 exhibited good activities against P. aeruginosa. Compounds 7, 9, 12-14, 24-26, and 29 demonstrated good to excellent activity against S. typhi, while remaining compound did not show significant antibacterial activities. Compounds 7, 9, 12, 13, 14, 25, 26, 29 showed good activities against S. typhi. The antifungal activities of imidazolones were also determined against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, Candida glabrata and found that compounds showed varying degree of percentage inhibition.

The naturally-occurring alkaloid ibogaine, found in the West African shrub Tabernanthe iboga, possesses the ability to diminish self-administration of substances of abuse, such as cocaine, heroin and alcohol. The presence of the isoquinuclidine ring system in the structure of ibogaine became the lead for the design of a 16-member library of N-aryl isoquinuclidines, where pyridine, pyrimidine and quinoline ring systems were attached directly to the bicyclic nitrogen. A solution-phase method for their synthesis is described.

F-18 analog of 1-α-D-(5'-deoxy-5'-fluoro-(1S,2R,3S,4S) arabinofuranosyl)-2-nitroimidazole (FAZA) is a clinical PET tracer for diagnosing hypoxic tumors in cancer patients. Original synthesis of FAZA is lengthy, expensive and low yielding (∼12%). Current procedure is fast, economical, and affords FAZA (25%) in a single step, along with three useful synthons, 3, 4 and 5, to prepare other positional analogues of FAZA. Their chemical ratio depends on the solvent and reaction conditions.