Letters in Drug Design & Discovery - Volume 14, Issue 7, 2017

Background: An efficient synthesis of hitherto unreported 4-heteroarylpyridines was described via regioselective 1,3-dipolar cycloaddition reactions of 3-(dimethylamino)-1-(pyridin-4- yl)prop-2-en-1-one (2) with nitrilimines 4a-h to afford the corresponding pyrazole derivatives 6a-h. Hydrazinolysis of 6a-c,e-f yielded the respective pyrazolopyridazines 7a-f. The enaminone 2 reacts also with 6-aminothiouracil (8) to yielded thione 9. The reaction of 9 with hydrazonoyl chlorides 3 yielded products 13a-h. Pyridine analogs substituted in the 4-position with a pyridinones 18, 20, 22 or naphthofuran 24 were also synthesized. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses. Method: The newly synthesized products were evaluated for their antimicrobial activities. Results: The results revealed that compounds 18 and 24 have good activities compared with Cefepime reference drug. Moreover, the computational studies using MOE 2014.09 software are confirming the results in biological activity.

Introduction: Fourteen novel 8,8-dimethyl-8,9-dihydro-5H-chromeno[2,3-d]pyrimidin-6(7H)- one derivatives were rationally designed and synthesized successfully. The synthetic procedures adopted for the target molecules were achieved by facile protocols and the yields were good to excellent (> 80%). Method: All the synthesized compounds were characterized by 1H NMR, 13C NMR, HR-MS and FT-IR spectral analysis. All new compounds were evaluated for their in vitro antioxidant activity by using DPPH, ABTS, NO and H2O2 methods. Results: Among the novel derivatives, two of the synthesized compounds exhibited good antioxidant activities similar to ascorbic acid, in all the four tested methods.

Background: Three new series of coumarin derivatives 4a-e, 6a-d and 7a-d were synthesized and characterized by elemental analyses and spectral data including 2D NMR. All compounds 4a-e, 6a-d and 7a-d were evaluated for their in vitro antioxidant and anticancer activity against Hep-G2 hepatic cancer and MCF-7 breast cancer cell lines. Method: Compounds 4c, 4e, 6d and 7c showed higher antioxidant activity (IC50 = 78, 20, 90 and 46 μM, respectively) than the reference drug silymarin (IC50 = 76 μM). Results and Conclusion: However, the anticancer screening for the three series showed promising anticancer activity against hepatic Hep-G2 cancer cell line and compounds 4d, 4e, 6a and 6c (IC50 = 1890, 5327, 5715 and 10339 μM, respectively) have more potent cytotoxic activity than cisplatin (IC50 = 11898 μM). On the other hand, all compounds showed no anticancer activity against MCF-7 cell line except compound 6a with IC50 = 32441 μM in comparison with cisplatin (IC50 = 15030 μM).

Background: Tuberculosis is a worldwide public health threat, according to the World Health Organization, 10.8 million people acquired the infection and 1.8 million deaths occurred due to the disease in 2015. Currently, β-lactam derivatives have emerged as antituberculosis agents. Objective: β-lactam derivatives were synthesized and tested in vitro against M. tuberculosis (pan-susceptible and resistant strains) and macrophage cell line J77A.1. Methods: Three series of β-lactam derivatives were synthetized following the Staudinger reaction of an aromatic imine and an acid chloride. The antimycobacterial activity was carried out by the microplate Alamar blue assay and cytotoxicity was assessed by the trypan blue exclusion assay on macrophage cell line J774A.1. The software AutoDock Vina was used to perform molecular docking studies of the synthesized drugs on the active site of the crystal structures of β -lactamase and transpeptidase from M. tuberculosis. Results: 7 β-lactam derivatives were effective against M. tuberculosis, including resistant strains. β-5 was the most active compound against the five strains (MIC= 3.125-6.25 μg/mL) with low cytotoxicity. In silico analysis indicated the probable binding sites of the synthesized derivatives on β-lactamase and transpeptidase. Conclusion: β-lactam derivatives were effective on resistant M. tuberculosis strains with a low cytotoxicity; therefore these compounds could be used for development new antitubercular agents.

Background: Histone deacetylases (HDACs) emerged as important epigenetic regulators of gene expression. Method: In order to identify potential positron emission tomography (PET) tracers for imaging HDACs, we evaluated in vitro and in cellulo activities of some compounds that were reported as potent HDAC2-selective inhibitors. We observed marked differences between reported activity values and the values obtained in our assays for some of the compounds. To understand the structural basis of the activity of some of these inhibitors, we also performed molecular docking studies to understand their interaction patterns and binding modes with HDAC2. Results and Conclusion: We observed the low affinity compounds 4, 6 and 7 did not showed equal number of key π-π interactions and hydrogen bonding when compared to high affinity compounds, and could be the possible reason for poor inhibition as reflected in in vitro assays. These preliminary experimental and computational results will help to interpret the HDAC affinity values of these key compounds with caution.

Background: A 3D-QSAR study of histone deacetylase 6 (HDAC6) inhibitors including comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) was carried out. Method: Sixty-six compounds with their in vitro inhibitory activities (IC50 values) were first docked into a homology model of HDAC6 using the LibDock program and then used to generate the training and testing sets of compounds for both the CoMFA and CoMSIA studies. Results and Conclusion: The best CoMFA model produced a q2 of 0.637 and an r2 of 0.987, and the best CoMSIA model produced a q2 of 0.767 and an r2 of 0.987, indicating a high statistical significance as a predictive model. The models and related information may provide important insight into inhibitor–HDAC6 interactions and help in the design of novel potent HDAC inhibitors.

Background: Aflatoxin B1 (AFB1) is the most potent mycotoxin of A. parasiticus and is considered as a group I carcinogen for humans. AFB1 causes detrimental health effects on human and domestic animal. AFB1 is basically blamed for their acute toxicity that responsible for severe hepatic cancer and other metabolic disturbances. Polyketide synthase (PKS) enzyme lays the foundation of the biosynthesis of the carcinogenic secondary metabolite aflatoxin B1 in Aspergillus parasiticus. The PKS contains a product template (PT) domain that controls the specific aldol cyclization and aromatization of the polyketide precursor which further leads to aflatoxin B1 biosynthesis. Methodology: In his investigation we docked the different types of ligands that are interact with PT domain of PKS that restrict the aflatoxin biosynthesis. Result: The computational molecular level interaction has discovered that there is presence of inhibition of different compounds such as amentoflavone, 6,6-bigenkwanin, 5,7-dihydroxychromone, ferulic acid, gallic acid and vanillic acid, into the active site of the protein which competitively bind to its substrate binding residues. Successful inhibition would lead to the formulations that can be used to control aflatoxin contamination of agriculture crop yields and poisoning.

Background: Mesenchymal stem cells (MSCs) are spindle shaped and multipotent stromal cells which can differentiate into a variety of cell types. Human dental pulp stem cells (hDPSCs) display self-renewal and multi-lineage differentiation potential as well as possess immunomodulatory properties and potential clinical applications. Objective: Preliminary study demonstrated that MSCs have advantage in regenerative and immune treatments. However, the senescence and spontaneous differentiation of MSCs during long term in vitro culturing restrict the amount and quantity of cells for scientific research and clinical application. Thus, it is crucial the develop methods maintain the mesenchymal properties of MSCs during long-term culture. Such data on the senescence of hDPSCs have not been reported. Method: Here, we investigated the differentiation potential, culture-related phenotypes and senescence of hDPSCs. hDPSCs showed senescence properties after serially passaged implied by changed cell morphology, decreasing proliferation ability, increasing of SA-β-Gal positive cells, low levels of pluripotent and proliferative genes expression, and high levels of genes expression which related to senescence. We also investigated the effects of tranylpromine (TCP), a monoamine oxidase inhibitor to against DPSCs senescence. Results and Conclusion: Results demonstrated that low concentration of TCP not only significantly improved the proliferation ability and delayed the senescence of hDPSCs, but also increased the expression of pluripotent and proliferative genes, such as octamer-binding transcription factor 4 (OCT4), Nanog, (sex-determining region Y)-box (SOX2), telomerase reverse-transcriptase (TERT) and C-X-C chemokine receptor 4 (CXCR4). Whats more, low concentration of TCP can suppress the spontaneous differentiation of hDPSCs and the expression of senescence marker p53. Altogether, our study showed the characteristics of hDPSCs after long term culture in vitro and may provide an efficient approach to delay or even reverse the senescence of hDPSCs.

Background: In spite of increasing number of chemotherapeutic drugs, achieving chemotherapy drug with minimal side effects in cancer treatment is still a major challenge. Chemotherapy has an important role in the treatment of non- Hodgkin's lymphoma cancer. Chlorambucil (CBL) is a lipophilic DNA alkylating drug having been administrated in many cancers like leukemia but its use has been limited because of chemical instability, low permeability of the cells and high toxicity. Objective: The main aim of this study is improving in vitro anticancer activity of CBL through conjugating CBL with Poly (DL-lactide-co-glycolide) (PLGA). The characterization of physiochemical structure of PLGA-CBL conjugation was determined by different techniques such as dynamic light scattering (DLS), Scanning electron microscopy (SEM), Atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), and HNMR Spectrometry. Moreover, therapeutic effect of new PLGA-CBL conjugated was evaluated, after which, the cell viability was determined by MTT assay and the numbers of apoptotic/necrotic cells were calculated by flowcytometry using Annexin V/PIkit on a non- Hodgkin's lymphoma cell line. Results and Conclusion: The results of in vitro cytotoxicity showed significantly greater conjugated PLGA-CBL on the non-Hodgkin's lymphoma compared to CBL alone

Background: It has been reported that statins therapy can up-regulate PSCK9 expression, which might be associated with the “6% rule” of statins. Additionally, previous data indicated that the extended-release statin could greatly reduce the exposure of statin in circulation. However, whether extended-release statin has less effect on serum PCSK9 level is completely unknown. Methods: In this randomized, controlled, open-label, prospective study, 61 patients who had not receive any lipid-lowering drugs before were enrolled and assigned to the three groups: immediaterelease fluvastatin 40mg/d, immediate-release fluvastatin 80mg/d and extended-release fluvastatin 80mg/d. Serum PCSK9 levels were measured at baseline and day 3 after treatment. Results: Serum PCSK9 level was significantly higher on day 3 than that at baseline in all groups (all p=0.0000). Moreover, after 3 days, serum PCSK9 level was significantly higher in immediaterelease fluvastatin 80mg/d group than that in immediate-release fluvastatin 40mg/d group and extended-release fluvastatin 80mg/d group (p=0.011, p=0.007, respectively), while no difference was found between extended-release fluvastatin 80mg/d group and immediate-release fluvastatin 40mg/d group (p=1.000). However, data showed that there was no difference in lipid parameters among groups on day 3. Conclusion: The data firstly suggested that extended-release fluvastatin had lower impact on serum PCSK9 levels and might be an alternative strategy for attenuating statin-induced elevation on PCSK9.

Background: The glyoxalase enzyme system is a critical component in the detoxification of cellular metabolically generated alpha-ketoaldehydes, such as methylglyoxal. Inhibitors of these enzymes have been shown to have potential in the development of antimicrobial and antitumor agents. A number of glyoxalase I (Glo1) metalloenzymes have been identified and have been categorized as either Zn2+-activated or Ni2+-activated metalloenzymes. Method: In the current work, four Glo1 from both metal activation classes and also having different quaternary structures were screened against two prototypic hydroxamate-containing peptide inhibitors in order to provide preliminary information on inhibition characteristics for these diverse metalloenzymes. Conclusion: This information should prove useful in future inhibitor design initiatives to develop more potent and organism selective Glo1 inhibitors.

Background: Grape marc and the wine cakes are known for high content of catechins, which have been reported to have many beneficial effects for human health. The most important are the effects on cardiovascular system. Also some potential to combat the Alzheimer´s disease has been reported for catechins contained in a green or white tea. Objective: To extract polyphenols from the wine grape seeds and try to characterize basic targets, which play an important role in AD. Methods: Using HPLC method we have identified and assessed the content of various catechins in the wine cake and grape seeds extracts. Applying in vitro methodologies we have evaluated the potency of the extract to inhibit acetylcholinesterase and prolyl oligoesterase. We also assessed the effect on the cell viability (MTT test) and its antioxidant activity (DPPH test) Results and Conclusion: It was shown that Pinot Gris, Pinot Noir and Hibernal are the varieties containing most of the polyphenolic compounds. Catechin followed by epicatechin and epigallocatechin were the most abundant polyphenols in the cake extract. We also report the biological activity of the extract with regard to a potential to improve cognitive decline associated with neurodegenerative disease like the Alzheimer´s disease. Apart from the expected antioxidant activity, there is an interesting prolyl oligopeptidase affinity, which can be an added value for targeting the cognitive decline.