Combinatorial Chemistry & High Throughput Screening - Volume 23, Issue 1, 2020

Aims and Objective: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common chronic kidney disease that leads to End-Stage Renal Disease (ESRD). The key target of this therapy is to prevent the progression of kidney failure. Tolvaptan could slow kidney cyst growth and are proven highly effective. The aims of this analysis are to perform a systematic review, estimate and evaluate the efficacy and safety of tolvaptan in ADPKD patients. Materials and Methods: Randomized controlled trials of tolvaptan in ADPKD were identified in PubMed, Ovid, Web of Science and the Cochrane Library electronic database. The changes observed in kidney function, treatment efficiency and the incidence of adverse events between the tolvaptan and placebo groups were compared. Data were analyzed by the RevMan software. Results: Eight trials, including 7 double-blinded randomised controlled trials and 1 quasi RCT involving 1,536 patients were extracted. Significant differences in the annual rate of change in the total kidney volume TKV at any stages of CKD (MD = -3.32, 95%CI =-4.57,-2.07, I2 =70%) and the glomerular filtration rate (MD = 1.4, 95%CI = 0.83,1.97, I2 =0%) were observed between the tolvaptan group and the placebo group. Subgroup analysis of patients in different CKD stages also showed the same conclusion. There was an increase in the urine osmolality, and 24-hour urine volume in patients receiving tolvaptan. Tolvaptan reduced the rate of serious hypertension and kidney pain events in ADPKD patients. At higher doses, it increased the rate of adverse events (liver injuries, thirst, pollakiuria, and nocturia). There was no significant risk of bias in the included studies. Conclusion: Tolvaptan has a beneficial effect on ADPKD, but is associated with an increase in adverse events at high doses when compared with the placebo. Further RCTs on tolvaptan may be required to support this conclusion.

Objective: The primary objective of this study was to compare oxidative DNA damage markers, apoptosis markers and changes in miRNA levels in patients diagnosed with cancer and treated through chemotherapy. Our secondary objective was also to evaluate tumor responses that can be determined after post-chemotherapy clinical evaluations by physical examinations, laboratory results and radiological imagings, and to compare the clinical results to oxidative stress and apoptosis markers and micro RNA levels. Materials and Methods: To do that we designed a prospective observational cross-sectional study. A total of 34 cancer patients and 27 healthy controls were included in the study from the Harran University School of Medicine Department of Oncology. Newly diagnosed chemotherapy or radiotherapy naive patients without any chronic diseases were included into the study. Patients with a poor performance status (ECOG 2 and 3) and patients who did not meet the inclusion criteria were excluded. The cancer patients received chemotherapy according to their scheduled periods. Blood samples were taken from the patients before the first chemotherapy course and before the second chemotherapy round. Patients were called for toxicity control on the 10th day after the chemotherapy. Pre-chemotherapy, post-chemotherapy and control group miR-29a expression levels, change in apoptosis markers and oxidative DNA damage markers were obtained and compared. We studied 8-hydroxy 2-deoxyguanosine, total oxidant status, total anti-oxidant status, and oxidative status index for oxidative stress markers. We studied M30 and M65 as apoptosis markers. Clinical results of efficiency of the chemotherapy was acquired and compared to biochemical markers based on chemotherapy results. Chemotherapy toxicities were recorded. Results: As a result, we found oxidative DNA damage markers and apoptosis markers were high in the cancer group, demonstrating that oxidative DNA damage and apoptosis might play a direct or indirect role in cancer etiology. However, there were subtle differences between pre-chemotherapy and post-chemotherapy levels. Mir-29a expressions were lower in cancer patients as compared to controls. However, the expression levels were not significantly change in pre- and postchemotherapy status. Moreover, we found no relationship between clinical status of patients (progression and regression) and studied biochemical markers. Conclusion: Thus, checking for DNA damage markers and taking precautions to lower the levels of these markers in individuals with cancer risk may be helpful in preventing cancer.

Aims and Objective: Effective components and the mechanism of action of Zhichan powder for the treatment of Parkinson's disease were researched at a systematic level. Materials and Methods: Screening of active components in Zhichan powder for the treatment of Parkinson's disease was conducted using the Traditional Chinese Medicine Systems Pharmacology database, and a medicine-target-disease network was established with computational network pharmacology. Results: By using network pharmacology methods, we identified 18 major active components in Zhichan powder through screening, indicating a connection between chemical components of this Traditional Chinese Medicine and Parkinson’s disease-related targets. Conclusion: The medicine-target-disease system of Zhichan powder established by network pharmacology permitted visualization of clustering and differences among chemical components in this prescription, as well as the complex mechanism of molecular activities among those effective components, relevant targets, pathways, and the disease. Thus, our results provide a new perspective and method for revealing the mechanism of action of Traditional Chinese Medicine prescriptions.

Background: Human Immunodeficiency Virus 1 (HIV-1) is a lentivirus, which causes various HIV-associated infections. The HIV-1 core dissociation is essential for viral cDNA synthesis and phosphorylation of HIV-1 capsid protein (HIV-1 CA) plays an important role in it. Objective: The aim of this study was to explicate the role of three phosphoserine sites i.e. Ser109, Ser149 and Ser178 in the structural stability of HIV-1 CA, and it’s binding with GS-CA1, a novel potent inhibitor. Methods: Eight complexes were analyzed and Molecular Dynamics (MD) simulations were performed to observe the stability of HIV-1 CA in the presence and absence of phosphorylation of serine residues at four different temperatures i.e. 300K, 325K, 340K and 350K, along with molecular docking and DFT analysis. Results: The structures showed maximum stability in the presence of phosphorylated serine residue. However, GS-CA1 docked most strongly with the native structure of HIV-1 CA i.e. binding affinity was -8.5 kcal/mol (Ki = 0.579 μM). Conclusion: These results suggest that the phosphorylation of these three serine residues weakens the binding of GS-CA1 with CA and casts derogatory effect on inhibition potential of this inhibitor, but it supports the stability of HIV-1 CA structure that can enhance regulation and replication of HIV-1 in host cells.

Aims and Objective: Ionic liquids are a suitable medium for stabilization and preparation of catalytic systems. Materials and Methods: The two-dimensional (2D) ZnO/Fe3O4 nanocomposites were synthesized using ionic liquid [OMIM]Br as a stabilizer and soft template. The nanocomposites were characterized via FTIR, XRD, VSM and SEM analysis. Result: The catalytic activity of these composites was evaluated using a multicomponent reaction of primary amines, acetylacetone, and 2-bromoacetophenone. Conclusion: 2D ZnO/Fe3O4 as a recyclable and green catalyst showed excellent catalytic performance for the preparation of poly-substituted pyrroles.

Background: Tuberculosis (Mycobacterium tuberculosis) is an infectious bacterial disease with the highest levels of mortality worldwide, presenting numerous cases of resistance. In silico studies, which elaborate chemical and biological models in computational tools and make it possible to interpret molecular characteristics, are among the methods used in the search for new drugs. Objective: In this perspective, our aim was to use QSAR and molecular modeling to propose possible pharmacophores from benzothiazinone derivatives. Methods: In this study, a set of 69 benzothiazinone derivatives, together with computational tools such as molecular descriptor analysis in chemometrics, metabolic prediction, and molecular coupling to 4 proteins: DprE1, InhA, PS, and DHFR important for the bacillus were investigated. Results: The chemometric model computed in the Volsurf+ program presented good predictive values for both amphiphilicity and molecular volume. These are essential for biological activity. Metabolites from the cytochrome isoforms CYP3A4 and 2D6 interactions revealed coupling divergences which, noting that the metabolites did not present changes to the QSAR proposed pharmacophore structures, may be due to the reaction medium and existing differences in the benzothiazinone structures. Similarly, molecular docking with the four TB enzymes presented good interactions for the more active compounds. The fragments found using QSAR (being essential for biological activity) also presented as being essential for ligand-protein site interactions. Conclusion: From the benzothiazinone derivative series evaluated, compound 11026134 presented the best profile in all study analyses, noting that the trifluoromethyl, nitro group, and piperazine fragment with aliphatic hydrocarbon groups are likely pharmacophores for the benzothiazinones studied.

Aims and Objective: An efficient and practical procedure for the synthesis of heterocyclic compounds such as quinazolines, quinoxalines and bis(indolyl)methanes was developed using 3,5-bis(trifluoromethyl) phenyl ammonium hexafluorophosphate (BFPHP) as a novel organocatalyst. Materials and Methods: All of the obtained products are known compounds and identified by IR, 1HNMR, 13CNMR and melting points. Result: Various products were obtained in good to excellent yields under reaction conditions. Conclusion: The BFPHP organocatalyst demonstrates a novel class of non-asymmetric organocatalysts, which has gained much attention in green chemistry.