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Background: In recent years, the number of people infected with the hepatitis C virus (HCV) is increasing rapidly. This has become a major threat to global health, therefore, new anti- HCV drugs are urgently needed. HCV NS5B polymerase is an RNA-dependent RNA polymerase (RdRp), which plays an important role in virus replication, and can effectively prevent the replication of HCV sub-genomic RNA in daughter cells. It is considered a very promising HCV therapeutic target for the design of anti-HCV drugs. Methods: In order to explore the relationship between the structure of benzimidazole derivative and its inhibitory activity on NS5B polymerase, holographic quantitative structure-activity relationship (HQSAR) and Topomer comparative molecular field analysis (CoMFA) were used to establish benzimidazole QSAR model of derivative inhibitors. Results: The results show that for the Topomer CoMFA model, the cross-validation coefficient q2 value is 0.883, and the non-cross-validation coefficient r2 value is 0.975. The model is reasonable, reliable, and has a good predictive ability. For the HQSAR model, the cross-validated q2 value is 0.922, and the uncross-validated r2 value is 0.971, indicating that the model data fit well and has a high predictive ability. Through the analysis of the contour map and color code diagram, 40 new benzimidazole inhibitor molecules were designed, and all of them have higher activity than template molecules, and the new molecules have significant interaction sites with protein 3SKE. Conclusion: The 3D-QSAR model established by Topomer CoMFA and HQSAR has good prediction results and the statistical verification is valid. The newly designed molecules and docking results provide theoretical guidance for the synthesis of new NS5B polymerase inhibitors and for the identification of key residues that the inhibitors bind to NS5B, which helps to better understand their inhibitory mechanism. These findings are helpful for the development of new anti-HCV drugs.

Herein, an efficient and scalable synthesis of 2,4-diaryl substituted chromene [43-b] pyridine derivatives, using a multicomponent reaction strategy by microwave irradiation of 4-amino 2-oxo- 2H-chromene, aromatic aldehydes, and substituted anilines is described. This synthetic strategy was found to be very useful as it follows environment benign protocol. Also it gives a good outcome in terms of yield and requires a shorter reaction time.

Supplementary Material 1

Background: Malaria is one of the most important infectious diseases in the world. The most severe form of malaria in humans is caused by Plasmodium falciparum. Malaria is a worldwide health problem, with 214 million new cases in 2015 and 438,000 deaths, most of which are in Africa. Therefore, there is an urgent need for novel, low-toxic, more specific inhibitors to find new antimalarial agents. A promising target for antimalarial drug design is falcipain-2, a cysteine protease from P. falciparum that has received considerable attention due to its key role in the life cycle of the parasite. Materials and Methods: Three-dimensional quantitative structure-activity relationship (3D-QSAR) models of 39 peptidyl vinyl sulfone cysteine protease inhibitors was constructed using Topomer CoMFA. Topomer Search was employed to virtually screen lead-like compounds in the ZINC database. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between peptidyl vinyl sulfone cysteine protease inhibitors and active site residues. Results: The non-cross correlation coefficient (r2), the interaction validation coefficient (q2) and the external validation (r2 pred) were 0.902, 0.685 and 0.763, respectively. The results showed that the model not only had good estimation stability but also good prediction capability. 22 new molecules were obtained, whose predicted activity is higher than the template molecules. The results showed that the Topomer Search technology can be effectively applied to screen and design new peptidyl vinyl sulfone cysteine protease inhibitors. Molecular docking showed extensive interactions between peptidyl vinyl sulfone cysteine protease inhibitors and residues of LYS24, ASP21, LYS59, and ASP17 in the active site. Conclusion: : 39 peptidyl vinyl sulfone cysteine protease inhibitors were used in the 3D-QSAR study. Topomer CoMFA 3D-QSAR method was used to build the model, and the model was well predicted and statistically validated. The design of potent new inhibitors of cysteine protease can get useful insights from these results.

Background: A series of new zerumbone hydrazones 5a-f and 9a-f have been synthesized in via an in situ procedure in high yields. The structure of synthesized compounds has been confirmed using 1H, 13C NMR and HR-MS. The bioassay result showed that several compounds exhibited cytotoxic effects against three human cancer cell lines, including HepG-2, SK-LU-1, and MCF-7. Compound 9a showed the best cytotoxic effect against HepG-2, SK-LU-1, and MCF-7 with IC50 values of 8.20, 6.66, and 9.35 μM, respectively. Objective: This study aims at developing new zerumbone hydrazones as anticancer agents based on zerumbone, a natural compound wildly growing in Vietnam. Methods: A series of new zerumbone hydrazones was designed, synthesized, and evaluated for cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7, and SKLu-1, using the MTT method. Results: The bioassay result showed that several compounds exhibited cytotoxic effects against three human cancer cell lines, including HepG-2, SK-LU-1, and MCF-7. Especially, compound 9a displayed the best cytotoxic effect against HepG-2, SK-LU-1, and MCF-7 with IC50 values of 8.20, 6.66, and 9.35 μM, respectively. Conclusion: The research results suggest that some compounds could be considered as leads for the future design of zerumbone hydrazones in which bio-isosteric replacements in theortho position of the phenyl ring could be performed to improve the cytotoxic activity.

Background: In recent years, cancer has become the main cause of death and it is a serious threat to human health, so the development of new, selective and safe anticancer drugs is still the focus of medical research. Matrix metalloproteinases-2 (MMP-2) has been determined to play an important role in the regulation of tumor angiogenesis, which is closely related to the development of the tumor. Therefore, MMP-2 is considered as a promising target for tumor therapy. In this study, Tomper comparative molecular field analysis (Topomer CoMFA) and molecular docking were used to investigate the important role of sulfonamide hydroxamate derivatives, an inhibitor of MMP-2, in the inhibition of angiogenesis. Methods: Quantitative structure active relationship (QSAR) models of 35 sulfonamide hydroxamate derivatives with inhibitory MMPs were developed. The quantitative structure-activity relationship (QSAR) model was built by using Topomer comparative molecular field analysis (Topomer CoMFA) technique. Results and Conclusion: The results show that the cross-validated q2 value of the Topomer CoMFA model is 0.881 and the non-cross-validated r2 value is 0.967. The results show that the model is reasonable and reliable, and has good prediction ability. Molecular docking studies were used to find the actual conformations of chemicals in active sites of cancer protease, as well as the binding mode pattern to the binding site in MMP-2. The information provided by the 3D-QSAR model and molecular docking may lead to a better understanding of the structural requirements of 35 sulfonamide hydroxamate derivatives and help to design potential anti-cancer protease inhibitor molecules. Conclusion: Thirty-five analogs were used in the 3D-QSAR study. Topomer CoMFA 3D-QSAR method was used to build the model, and the model was well predicted and statistically validated. The results of 3D-QSAR and molecular docking analysis provide theoretical guidance for the synthesis of new MMP-2 inhibitors.

In this paper, the internal flow field of the equalizing flow regulating valve under the specified working conditions is simulated by CFD method, and its hydraulic and noise characteristics are studied. The results show that the full opening flow rate of the regulating valve reaches 120t/h under the pressure difference of 0.1MPa; when the mass flow rate of the outlet reaches 120t/h and 90t/h respectively under the pressure difference of 1.8MPa and 1.2MPa, the VDMA formula is adopted. The maximum sound pressure level is 86.83dB.