Letters in Drug Design & Discovery - Volume 4, Issue 2, 2007

The proteasome is a multicatalytic proteinase complex that is responsible for protein turnover through the ubiquitin-proteasome pathway. Bortezomib is the first drug to act as a proteasome inhibitor, and has yielded impressive anticancer effects in phase III trials in multiple myeloma. Its role in other hematological malignancies is being evaluated. Proteasome inhibition, therefore, represents a novel mechanism for anticancer therapy.

The synthesis, pharmacological properties and delivery characteristics in simulated aqueous gastric fluid of a series of symmetrical nitrogenated C2-substituted pyrrolo[2,3-f]quinolines are described. The cytotoxicity of the target molecules (5a-h) was evaluated in the human non-small lung cancer cell line NSCLCN16- L16 in vitro. One compound (5e) showed sufficient activity (IC50 = 26.4 μM) and satisfactory release characteristics from solid pharmaceutical formulations.

We rationally designed and synthesized a novel cationic polymer with intrinsic endosomolytic properties based on a semi-peptide monomer bridged by disulfide bonds. This polymer was shown to associate with DNA and to form polyplexes with gene transfection activity without addition of chloroquine, a known endosomolytic agent.

HIV-1 integrase (IN) inhibition of a novel series of quinoline derivatives was investigated. The compounds were designed on the basis of quinoline molecular scaffolds that attempt to mimic the basic naphtyridine motif of the L-870810 HIV-1 IN inhibitor. It appeared that the IN inhibition of the novel compounds was limited by the electroacceptor substitution within quinoline. Although the compounds studied here indicate structural similarity to L-870810, they are much less efficient than this compound. This can be explained by differences in conformations and apparent magnesium complexing ability in the naphtyridine and quinoline based amides.

Alzheimer's disease (AD) is a major neurodegenerative disease that affects mainly people over 65 years of age. The main therapeutic approach to AD is based on the use of acetylcholinesterase (AChE) inhibitors. Recent studies have shown that butyrylcholinesterase (BuChE) can also be considered an attractive target for the development of novel drugs for AD therapy. The design of new potent and selective BuChE inhibitors is of great importance in drug discovery. 2D quantitative structure-activity relationship studies were conducted on a series of potent inhibitors of human BuChE using classical and hologram QSAR (HQSAR) approaches. A training set of 40 compounds was employed to derive the models. Classical QSAR models showed moderate correlation (r2 = 0.836, q2 = 0.750), with no substantial predictive power for untested compounds. On the other hand, the best HQSAR model (r2 = 0.928, q2 = 0.723) was used to predict the potency of 10 test set compounds, and the predicted values were in good agreement with the experimental results, showing the potential of this model for new untested compounds.

A series of 9-anilinoacridines (1-15) and acridinyl hydrazides (16-29) with structural variations at C-9 were synthesized using an improved method, and their urease enzyme inhibitory activity was evaluated. These compounds showed varying degrees of urease inhibitory activity ranging between 19.05-135.01 μM. Out of twenty-nine compounds, eight of them (3, 4, 9, 11, 13,15, 17 and 24) were found to have a good urease inhibitory potential with IC50 values of 52.11, 64.00, 56.17, 19.05, 46.32, 101.35, 35.01, and 43.56 μM, respectively, if compared to thiourea (IC50 = 21.01 μM), used as standard.

3D-QSAR methodologies represent a useful, widespread tool in drug discovery and optimisation. Here we introduce an alternative QSAR tool for model generation: the non-linear Response Surface Analysis, that finds at present great application in Design of Experiment for optimizing drug production processes. Binding affinity estimation of human A3 adenosine receptor antagonists is considered as key study.

Phosphodiesterases are clinical targets for congestive heart failure, erectile dysfunction and inflammation. Intake of carotenoids decreases the risk of cardiovascular and inflammatory diseases. Therefore, phosphodiesterase binding of the carotenoid derivative disodium disuccinate astaxanthin (Cardax) was investigated using molecular modeling methods. Cardax was predicted to bind to PDE5A at the catalytic site.

Five compounds -1, 2, 3, 4, and 5 were placed into tissue culture similarly to isoniazid at concentrations ranging from 0.03125 mg/mL to 2.00 mg/mL, with Mycobacterium tuberculosis. Compounds 1 and 5 showed substantial growth inhibition at the lowest concentration of 0.03125 mg/mL, whereas compounds 2, 3, and 4 demonstrated similar effects starting at 0.0625 mg/mL. Compounds 2 and 3 showed polar surface area of 55.12 A2, suitable for penetrating the blood-brain barrier. Hierarchical cluster analysis, principal coordinates analysis, and principal components analysis were utilized to analyze numerical values of properties for all drugs and showed that isoniazid is highly similar to compounds 2 and 3, with compound 1 distinct from all other drugs, with compounds 4 and 5 having high similarity. This comparison was confirmed by by principal coordinates analysis and principal components analysis. Multiple regression analysis produced an equation that accurately predicts formula weight for similar drugs utilizing molar refractivity, molar volume, parachor, and polar surface area. Compounds 1, 2, 3, and isoniazid showed no violations of the Rule of 5, which indicates properties that enhance drug absorbance. Compounds 2, 3, 4, and 5 were synthesized by utilizing microwave methodology.

Sixteen 2-cyclohexenone and 6-(ethoxycarbonyl)-2-cyclohexenone analogs of combretastatin-A4 (CA-4, 1) were synthesized, and their ability to inhibit the growth of two murine cancer cell lines (B16 melanoma and L1210 leukemia) was determined using an MTT assay. One of the cyclohexenone analogs, 8, which contains the same substituents as CA-4 (1) is the most potent (IC50 = 0.91 μM, L1210). Exposure of A- 10 aortic cells to cyclohexenone 8 and its ester congener 7 produced significant reduction in cellular microtubules, with EC50 values of 27 and 37 μM, respectively. Molecular modeling studies indicate that analog 8 adopts a twisted conformation, similar to CA-4, suggesting that conformation and structure are crucial for activity. These compounds are worthy of further investigation as potential tubulin inhibitors in the quest for novel anti-cancer agents.

A series of C-2 and C-6 substituted pyridines was synthesized and evaluated in vitro against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus mutans and Candida albicans. Most of compounds exhibited a wide range of modest in vitro activity against the tested microorganisms.

The leishmanicidal and trypanocidal activities of chlorinated 1,7- and 1,8-naphthyridines were evaluated against cultured of L. amazonensis promastigote and T. cruzi epimastigote forms. Active compounds were also tested against blood trypomastigotes and their toxicity to Vero cells. Among the compounds evaluated 10 was the most active against L. amazonensis promastigotes and T. cruzi epimastigotes, IC50= 8.6 μM and IC50 =20.4 μM, respectively.

Oxidative stress is responsible for myocardial injury occurring after ischemia and reperfusion (IR) and has been shown to be modulated by the Haptoglobin (Hp) genotype. In this manuscript we demonstrate that the antioxidant BXT -51072, a glutathione peroxidase synthetic mimic, provides protection against IR injury in a Hp genotype dependent fashion.