Medicinal Chemistry - Volume 9, Issue 8, 2013

The aim of this article is to get an overview of the metabolism of quinoxaline 1,4-di-N-oxides (QdNOs) used in food animals. The derivatives of QdNOs (carbadox, olaquindox, mequindox, quinocetone, and cyadox) are the potent synthetic antimicrobial agents that are used for improving the feed efficiency and controlling dysentery in food-producing animals. Studies have demonstrated that the toxicity of QdNOs is closely associated with the production of their metabolism, especially with the production of their reduced metabolites. To the best of our knowledge, no one has systematically compiled the metabolism data of QdNOs. Therefore, the metabolism of QdNOs in animals has been discussed in the review for the first time. These drugs undergo extensive metabolism prior to excretion. N-oxide group reduction is the major metabolic pathway of QdNOs. Moreover, the N1- and N4-oxide reductions of QdNOs by different reducing mechanisms are also described. Obvious differences in metabolic pathways for QdNOs were observed owing to the differences on the side chain of these drugs. Therefore, understanding the metabolic pathways of QdNOs in animals will provide the guides for further studies of metabolism and toxicology of these drugs, and will also provide abundant information for the food safety assessment.

Embelin is a natural product, inhibitor of XIAP (X-chromosome-linked Inhibitor of APoptosis) with strong proapoptotic properties on cancer cells. In order to clarify the role of two OH groups on benzoquinone core, we have prepared by hemisynthesis close analogs of embelin, where these OH groups have been replaced in a systematic manner by OMe and OAc groups. Proapoptotic activities of six embelin derivatives have been studied as single agent, or in combination with TRAIL, and their abilities to interact with XIAP have been evaluated by Surface Plasmon Biacore. Our results show that these new embelin analogs have good proapoptotic properties against selected cancer cells, often higher than the natural product itself. Further, this activity is not directly mediated by XIAP. Altogether these preliminary results demonstrate that for active embelin analogs, the two OH groups are not absolutely required for anticancer activity, opening new possibilities for the design of proapoptotic derivatives in these series.

A series of novel analogues of 1,3-diarylprop-2-en-1-one (3a-m) were synthesized and evaluated for their inhibitory activity of FOX P3 gene expression and apoptosis in CD4+T cells that had been isolated from the spleen of 8 to 10 weeks old mice. The structure-activity relationship (SAR) of the R1 and R2 modification was studied to identify a candidate with the maximum potency. Of these compounds, 3d showed the highest inhibitory activity of FOX P3 gene expression and apoptosis (66.5 % inhibition at 10 μM). To the best of the authors’ knowledge this is the first report of 1,3- diarylprop-2-en-1-ones as regulators of FOX P3 gene expression.

Multivariate adaptive regression splines (MARSplines) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon software. The structures of the compounds were firstly pre-optimized with the MM+ mechanics and semi-empirical AM1 method procedure included in the HyperChem and resulting geometrical structures were studied with the use of Dragon software, and several molecular descriptors of acridinones were calculated and used as predictor (independent) variables in the MARS model building. Principal component analysis (PCA) was used to select the training and test sets. The optimal MARS model uses 28 basis functions to describe acridinones' antitumor activity and characterized high correlation between predicted antitumor activity and that one from biological experiments for the data used in the training and testing sets of acridinones with correlation coefficients on the level of 0.9477 and 0.9660, respectively. Generally, results showed that MARS model provided powerful capacity of prediction of antitumor activity of acridinone derivatives. Moreover, a physicochemical explanation of the descriptors selected by MARSplines analysis is also given, and indicated that molecular parameters describing 3-D properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity.

Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza® (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing research to find novel small molecules to target these important enzymes, we synthesized a series of benzothiazole-containing analogues of SAHA and found several compounds with very potent anticancer cytotoxicity. In this study, three more compounds of this type, including N1-(6- chlorobenzo[d]thiazol-2-yl)-N8-hydroxyoctanediamide (3a), N1-[6-(trifluoromethyl)benzo[d]thiazol-2-yl]-N8-hydroxyoctanediamide (3b) and N1-(thiazol-2-yl)-N8-hydroxyoctanediamide (6) were synthesized and evaluated for HDAC inhibition and cytotoxic activities. All three compounds showed very potent HDAC inhibitory effects. Docking revealed that both two compounds 3a, 3b showed higher affinities towards HDAC8 compared to SAHA. In vitro, compound 3a exhibited cytotoxicity equipotent to SAHA against five human cancer cell lines. In term of in vivo activity, compound 3a demonstrated equivalent efficacy to SAHA in mouse xenograft model.

To improve the anti-tumor effects of gallic acid and mangiferin, a gallic acid-mangiferin hybrid molecule (GAMA) was synthesized from gallic acid with mangiferin in the presence of ionic liquid ChC1(choline chloride)·2SnC12. Chemical and spectroscopic methods, such as 1H and 13C NMR spectroscopy, and HR-ESIMS were used for the structure identification of GA-MA. Using the cell counting kit-8 (CCK-8) assay, the in vitro anti-tumor effects were compared between GA-MA, gallic acid and mangiferin on human hepatoma HepG2, human nasopharyngeal carcinoma CNE, human lung cancer NCI-H460, human ovarian cancer SK-OV-3, and human cervical cancer Hela cells. The results showed that the half inhibitory concentration (IC50) of GA-MA on HepG2, CNE, NCI-H460, SK-OV-3, and Hela cells was significantly lower than that of gallic acid or mangiferin. This showed that GA-MA has a better in vitro anti-tumor effect than gallic acid and mangi-ferin.

Synthesis and evaluation of cytotoxicity of a series of heterocyclic compounds derived from 1, 4-bis-(5- [hydrazinocarbonylmethylthio]-4-phenyl-1,2,4-triazol-3-yl) butane (1a-b) are described. The triazolo-triazoles (9-15) and thiadiazoles (16-18) were prepared from respective thiosemicarbazide intermediates (2-8). The Schiff bases (19-24) were prepared from (1a, b) by reacting with different carboxaldehydes in acetic acid medium. All the synthesized compounds were characterized by IR, NMR and Mass spectral studies. The compounds were evaluated for in vitro cytotoxicity potential using the standard MTT assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29 and Breast Cancer MDA MB-231. The DNA damage activity of the compound 24 was evaluated by alkaline comet assay.

For the prediction of anticancer activity of glycyrrhetinic acid (GA-1) analogs against the human lung cancer cell line (A-549), a QSAR model was developed by forward stepwise multiple linear regression methodology. The regression coefficient (r2) and prediction accuracy (rCV2) of the QSAR model were taken 0.94 and 0.82, respectively in terms of correlation. The QSAR study indicates that the dipole moments, size of smallest ring, amine counts, hydroxyl and nitro functional groups are correlated well with cytotoxic activity. The docking studies showed high binding affinity of the predicted active compounds against the lung cancer target EGFR. These active glycyrrhetinic acid derivatives were then semi-synthesized, characterized and in-vitro tested for anticancer activity. The experimental results were in agreement with the predicted values and the ethyl oxalyl derivative of GA-1 (GA-3) showed equal cytotoxic activity to that of standard anticancer drug paclitaxel.

We report herein the results of antifungal activity of fifteen 1,2,3-triazoles against Candida albicans, Candida krusei, Candida parapsilosis, Candida kefyr, Candida tropicalis, Candida dubliniensis, Tricophyton rubrum, Microporum canis and Aspergillus niger. All of the 1,2,3-triazoles were prepared from 1,3-dipolar cyclizations between aryl azides and alkynes catalyzed by Cu(I), and several of the compounds exhibited antifungal activity with low cytotoxicity. The results demonstrated the potential and importance of developing new 1,2,3-triazoles compounds with antifungal activity.

A series of novel isoxazole and pyrazoline derivatives has been synthesized and evaluated for their effects on the chemiluminescence and chemotactic activity of human phagocytes. Their effects on the chemotactic migration of isolated polymorphonuclear leukocytes (PMNs) and on the release of reactive oxygen species (ROS) during respiratory burst of human whole blood and PMNs were carried out using the Boyden chamber technique and luminol-based chemiluminescence assay, respectively. Of the compounds tested, compounds 8, 9, 11 and 12 exhibited higher inhibitory activity on the release of ROS (with IC50 values ranging from 5.6 to 8.4 μM) than acetylsalicylic acid (IC50 = 9.5 μM). These compounds also showed strong inhibitory activity on the migration of PMNs with compound 8 exhibiting an IC50 value lower than that of ibuprofen. The results suggest that some of these isoxazole and pyrazoline derivatives have ability to modulate the innate immune response of phagocytes at different steps, indicating their potential as a source of new immunomodulatory agents.

A novel series of thienopyrimidine derivatives bearing various substituents or linked to various heterocyclic moieties through atoms spacers were prepared starting from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6- carboxamide potassium salt 3. Twelve out of the prepared compounds were selected and evaluated for their antiinflammatory activity using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays using diclofenac sodium as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. In addition, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. The results revealed that compounds 5a, 13, 14b, 15a, 16a and 16b had high anti-inflammatory effect comparable to diclofenac sodium, whereas compounds 5a, 14a, 15a and 16a revealed pronounced analgesic activity that is equal or higher than that of the reference. All of the tested compounds revealed high GI safety profile and were well tolerated by the experimental animals with high safety margin (ALD50 > 3.0g/Kg).

A series of novel pyrazole carboxylic acid derivatives was designed and synthesized, and their antagonism effect on endothelin (ET)-1-induced contraction in the rat thoracic aortic ring was screened. The radio receptor assay was used to examine the potency of the compounds on ET receptor. Some target compounds demonstrated significant inhibitory activity, especially 7m, which showed a potent inhibition percentage higher than the contrast compound BQ123. Further assays on the binding and selectivity for ET showed that 7m had highly potent binding activity on ETA at the nanomole level, and the ratio of ETA/ETB was 36. Therefore, we inferred that 7m was a non-selective antagonist of ETA and ETB and had potential for further development in cardiovascular diseases.

In the present study, Poly (D,L-lactide-co-glycolide) microspheres (PLGA MSs) were prepared for delivering a novel oligopeptide derived from rhBMP-2 (Peptide-24). Hydroxypropyl-β-cyclodextrin (HP-β-CD) and Bovine serum albumin (BSA) were used as stabilizers for retaining bioactivity of the oligopeptide. The morphology, diameter, drugloading rates and encapsulation rates of the PLGA MSs were detected and compared. The PLGA MSs were incubated for 3 and 30 days respectively to obtain the release supernatant containing Peptide-24. The structure and bioactivity of released Peptide-24 from PLGA MSs were evaluated through physicochemical detections and cell culture. The structure integrity of the Peptide-24 was confirmed by Far-UV circular dichroism and matrix-assisted laser desorption/ionization time-of-flight Mass Spectrometer (MALDI-TOF-MS) analysis. The interaction between PLGA matrix and loaded Peptide- 24 was verified through Raman. The results showed that the diameter of PLGA MSs was from 8.62 to 15.34 μm, the loading rate was 0.7-0.8%, and the encapsulation rate was 69.3-85.3%. The released Peptide-24 from PLGA MSs was proved to retain original bioactivity by the cellular activity and alkaline phosphatase (ALP) test. HP-β-CD is a kind of excellent stabilizer for retaining the bioactivity of Peptide-24 in PLGA MSs.

A series of 5-halogenomethylsulfonylbenzimidazole and benzotriazole derivatives was synthesized as potential antibacterial agents. A new method of synthesis of benzimidazoles was developed. The antimicrobial activities of these compounds were tested against a series of reference and clinical strains. The reference strains include Gram-positive bacteria (S. aureus, S. epidermidis, B. subtilis, B. cereus, E. hirae, M. luteus) and Gram-negative rods (E. coli, P. vulgaris, P. aeruginosa, B. bronchiseptica). The clinical strains include six methicillin-resistant (MRSA) and two methicillin-sensitive (MSSA) S. aureus strains, one methicillin-resistant S. epidermidis, three E. faecalis and two E. faecium strains. Compound with trifluoromethyl- substituent at C-2 position (4) displayed significant antibacterial activities comparable with nitrofurantoin against four strains, and higher against Micrococcus luteus. MIC values for clinical Staphylococci strains (MRSA) were 12.5-25 μg/mL; for Enterococcus strains these values were 50-100 μg/mL. MIC values for reference and clinical strains of Staphylococcus and Enterococcus group were similar, respectively.