Natural Products as Potential Lead Compounds for Drug Discovery Against SARS-CoV-2

For the past 2 years,the coronavirus responsible for the COVID-19 infection has become a world pandemic,ruining the lives and economies of several nations in the world.This has scaled up research on the virus and the resulting infection with the goal of developing new vaccines and therapies.Natural products are known to be a rich source of lead compounds for drug discovery,including against infectious diseases caused by microbes(viruses,bacteria and fungi).In this review article,we conducted a literature survey aimed at identifying natural products with inhibitory concentrations against the coronaviruses or their target proteins,which lie below 10μM.This led to the identification of 42 compounds belonging to the alkaloid,flavonoid,terpenoid,phenolic,xanthone and saponin classes.The cut off concentration of 10μM was to limit the study to the most potent chemical entities,which could be developed into therapies against the viral infection to make a contribution towards limiting the spread of the disease.

A comprehensive review on natural phenolic compounds as alternatives to in-feed antibiotics

Intensive livestock and poultry farming in China largely relied on the use of in-feed antibiotics until July 2020.The consequences of antibiotic overuse in animal feed include accumulation in animal products and the development of bacterial antibiotic resistance,both of which threaten food safety and human health.China has now completely banned the circulation of commercial feed containing growth-promoting drug additives(except Chinese herbal medicine).Therefore,alternatives to in-feed antibiotics in animal production are greatly needed.Natural phenolic compounds(NPCs)exist widely in plants and are non-toxic,nonpolluting,highly reproducible,and leave little residue.Many natural flavonoids,phenolic acids,lignans,and stilbenes have polyphenol chemical structures and exhibit great potential as alternatives to antibiotics.In this review we delineate the characteristics of plant-derived NPCs and summarize their current applications as alternatives to in-feed antibiotics,aiming to provide new strategies for antibiotic-free feeding and promote the development of more sustainable animal husbandry practices.

Growth and Application of Chalcogenides of Lead and Related Compounds

Large grain, low-dislocation, high-quality single crystals of various Pb-salt compounds have been grown reproducibly by the Horizontal Unseeded Vapor Growth (HUVG) technique. The Tunable Diode Lasers with better performance have been made with such crystals. The annealing feature, dislocations and diffusion in the crystals have also been investigated.

Differences in PLP-dependent cysteinyl processing lead to diverse S-functionalization of lincosamide antibiotics

Subject Code:B02With the support of the National Natural Science Foundation of China and the Chinese Academy of Sciences,the research team led by Prof.Liu Wen(刘文)at the State Key Laboratory of Bioorganic and Natural Products Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,uncovered the final biosynthetic pathway toward the distinct S-functionalization in lincosamide

Marine soft corals as source of lead compounds for anti-inflammatories

Marine soft corals are known to produce a wide array of secondary metabolites,particularly diterpenoids and steroids,and often characterized by uncommon structural features and potent bioactivities.The remarkable abundance and diversity of bioactive small molecule which have been isolated from soft corals have made these organisms an important source of new drug candidates for human diseases,particularly for their anti-inflammatory activity.In this paper,the authors reported anti-inflammatory marine natural products isolated from diverse species of soft corals determined in vitro by their inhibition of lipopolysaccharide-induced expression of inducible NO synthase and cyclooxygenase-2 in murine macrophage cells(RAW 264.7).

Effects of Lead on pH and Temperature-Dependent Substrate-Activation Kinetics of ATPase System and its Protection by Thiol Compounds in Rat Brain

Lead (Pb) inhibited the activities of Na+ -K+ ATPase (IC50= 2.0×10^(-6) M), K + -Para-Nitrophenyl phosphatase (PNPPase) (IC50= 3.5×10^(-6) M) and [3H]-ouabain binding (IC50 = 4.0×10^(-5) M) in rat brain P2 fraction. A variable temperature or pH significantly elevated the inhibition of Na+-K+ ATPase by Pb in buffered acidic, neutral and alkaline pH ranges. Noncompetitive inhibition with respect to activation of Na+ -K+ ATPase by ATP was indicated by a variation in Vmax values with no significant changes in Km values at any temperature studied. In the presence of Pb, for Na+ -K+ ATPase at pH 6.5 and 8.5, Vmax was decreased with an increase in Km values suggesting a mixed type of inhibition. Sulfhydryl agents such as dithiothreitol (DTT) and cvsteine (Cyst), but not glutathione (GSH) offered varied levels of protection against Pb-inhibition of Na + -K+ ATPase at pH 7.5 and 8.5. The present data suggest that inhibition of Na+ -K+ ATPase by Pb is both temperature and pH-dependent. These results also indicate that Pb inhibited Na + -K + ATPase by interfering with phosphorylation of enzyme molecule and dephosphorylation of the enzyme-phosphoryl complex and exerted an effect similar to that of SH-blocking agents.

Solderability and intermetallic compounds formation of Sn-9Zn-xAg lead-free solders wetted on Cu substrate

The eutectic Sn-9Zn alloy was doped with Ag （0 wt.%-1 wt.%） to form Sn-9Zn-xAg lead-free solder alloys. The effect of the addition of Ag on the microstructure and solderability of this alloy was investigated and intermetallic compounds （IMCs） formed at the solder/Cu interface were also examined in this study. The results show that, due to the addition of Ag, the microstructure of the solder changes. When the quantity of Ag is lower than 0.3 wt.%, the needle-like Zn-rich phase decreases gradually. However, when the quantity of Ag is 0.5 wt.%-1 wt.%, Ag-Zn intermetallic compounds appear in the solder. In particular, adding 0.3 wt.% Ag improves the wetting behavior due to the better oxidation resistance of the Sn-9Zn solder. The addition of an excessive amount of Ag will deteriorate the wetting property because the gluti- nosity and fluidity of Sn-9Zn-（0.5, 1）Ag solder decrease. The results also indicate that the addition of Ag to the Sn-Zn solder leads to the precipitation of ε-AgZn3 from the liquid solder on preformed interracial intermetallics （CusZn8）. The peripheral AgZn3, nodular on the Cu5Zn8 IMCs layer, is likely to be generated by a peritectic reaction L ＋ γ-Ag5Zns→AgZn3 and the following crystallization of AgZn3.

Interactions of naturally occurring compounds with antimicrobials

Antibiotics are among the most often used medications in human healthcare and agriculture.Overusing these substances can lead to complications such as increasing antibiotic resistance in bacteria or a toxic effect when administering large amounts.To solve these problems,new solutions in antibacterial therapy are needed.The use of natural products in medicine has been known for centuries.Some of them have antibacterial activity,hence the idea to combine their activity with commercial antibiotics to reduce the latter's use.This review presents collected information on natural compounds(terpenes,alkaloids,flavonoids,tannins,sulfoxides,and mycotoxins),of which various drug interactions have been observed.Many of the indicated compounds show synergistic or additive interactions with antibiotics,which suggests their potential for use in antibacterial therapy,reducing the toxicity of the antibiotics used and the risk of further development of bacterial resistance.Unfortunately,there are also compounds which interact antagonistically,potentially hindering the therapy of bacterial infection.Depending on its mechanism of action,each compound can behave differently in combination with different antibiotics and when acting against various bacterial strains.

Alkaline leaching of metal melting industry wastes and separation of zinc and lead in the leach solution

In this work, a thorough examinations on the extractability of zinc and lead present in the steelmaking dusts using alkaline leaching process and the effectiveness of the zinc and lead separation in the resultant leaching solutions using sulfide precipitation method were made. It was found that only about 53% of zinc and over 70% of the lead could be leached out of the dusts, while the other 47% of zinc and 30% of lead were left in the leaching residues. The zinc and lead in the resultant leaching solution can be effectively and selectively separated. When the weight ratio of sodium sulfide (M.W. = 222-240) to Pb was kept at 1.8, the lead in the solution could be precipitated out quantitatively while all the zinc was remained in the solution. The zinc left in the solution can be further recovered by the addition of extra sodium sulfide with a weight ratio of sodium sulfide to the zinc over 2.6. The resultant filtrate can be recycled to the leaching of dust in the next leaching process.

Formation of Bulk Intermetallic Compound AgaSn in Slowly-Cooled Lead-Free Sn-4.0 wt pct Ag Solders

Sn-Ag alloy system has been regarded as one of the most promising lead-free solder to substitute conventional Sn- Pb eutectic solder. But the formation of bulk Ag3Sn intermetallic compounds （IMCs） during reflow and post heat treatment significantly influences the performance of the solder joints. With an effort to clarify its microstructural evolution as a function of slow cooling rates, the fraction of bulk IMCs within the slowly solidified Sn-4.0 wt pct Ag solder was investigated by standard metallographic and compared with that detected by thermal analysis. It was found that the bulk IMCs fraction determined by thermal analysis corresponds quite well with the microstructure observation results. In accordance with the conventional solidification theory, the lower the applied cooling rate, the fewer the amount of bulk Ag3Sn IMCs formed in Sn-4.0 wt pct Ag alloy. In addition, Vickers hardness measurement results indicated that the relative coarse eutectic Ag3Sn IMCs distributing in the lamellar eutectic structure favored the improvement of the mechanical performance.

Solvothermal Synthesis,Crystal Structure and Luminescent Property of a Two-dimensional Lead(Ⅱ) Compound：[Pb(bmzbc)2]n

A two-dimensional coordination polymer, [Pb（bmzbc）2]n（1）（Hbmzbc =4-benzimidazole-1-yl-benzoic acid）, has been synthesized by the solvothermal reaction of Pb（NO3）2 with Hbmzbc at 120 ℃ in ethanol solvent. Compound 1 has been characterized by single-crystal X-ray diffraction, powder X-ray diffraction, thermogravimetry analysis, and IR spectrum. Compound 1 crystallizes in the orthorhombic system, space group Pccn, with a = 12.5801（7）, b = 20.0795（11）, c = 9.1830（6） ？, V = 2319.6（2） A^3, Z = 4, C（28）H（18）N4O4Pb, Mr = 681.65, Dc = 1.952 g/cm^3, μ = 7.319 mm^-1, F（000） = 1312, the final R = 0.0336 and wR = 0.0965 for 1699 observed reflection with I 〉 2σ（I）. In 1, the bmzbc^– ligands bridge the Pb（Ⅱ） ions to generate a 2-D sheet with（4, 4） topology. The complex exhibits turquoise photoluminescent emission with a maximum at 480 nm upon excitation at 300 nm.

Effects of Ga,Al,Ag,and Ce multi-additions on the wetting characteristics of Sn-9Zn lead-free solder

An orthogonal method was used to evaluate the effects of Ga, Al, Ag, and Ce multi-additions on the wetting characteristics of Sn-9Zn lead-free solders by wetting balance method. The results show that the optimal loading of Ga, Al, Ag, and Ce was 0.2 wt.%, 0.002 wt.%, 0.25 wt.%, and 0.15 wt.%, respectively. Intermetallic compounds （IMCs） formed at the interface between Sn-9Zn-0.2Ga-0.002Al-0.25Ag- 0.15Ce solder and Cu substrate were investigated by scanning electron microscope （SEM） and energy dispersive spectroscopy （EDS） analysis. The SEM images illustrate that the IMCs can be divided into two portions from the substrate side to the solder side： a planar CusZns layer and an additional continuous scallop-like AgZn3 layer. The EDS analysis also shows that Ga segregates in the solder abutting upon the interface. X-ray photoelectron spectroscopy （XPS） and Auger electron spectroscopy （AES） of the surface components of Sn-9Zn-0.2Ga-0.002Al- 0.25Ag-0.15Ce solder indicate that Al aggregates at the surface in the form of Al203 protective fdm, which prevents the further oxidation of the solder surface. On the other hand, Ce aggregates at the subsurface, which may reduce the surface tension of the solder and improve the wettability in consequence.

Effects of cooling rates on microstructure and microhardness of lead-free Sn-3.5%Ag solders

The microstructure and microhardness of Sn-3.5%Ag solders were explored in the cooling rate ranging from 0.08 to 104 K/s. Under rapid cooling condition, the strong kinetic undercooling effect leads to the actual solidification process starting at the temperature lower than the equilibrium eutectic point, and the actual metastable eutectic point shifts to the higher Ag concentration. Hence, the higher the applied cooling rate is, the more the volume fraction of primary β-Sn crystal forms. At the same time, the separation of primary β-Sn crystal favors restraining the formation of bulk Ag3Sn intermetallic compounds (IMCs) in solder due to the mismatch crystalline orientation relationship, those Ag3Sn phase separating through the eutectic reaction could hardly cling to the primary β-Sn crystal and grow up. Additionally, the Vickers hardness test shows that fine β-Sn and spherical Ag3Sn phase in the rapidly solidified alloy strongly improves the microhardness of the Sn-3.5%Ag solder.

Effects of rapid solidification on the microstructure and microhardness of a lead-free Sn-3.5Ag solder

A lead-free Sn-3.5Ag solder was prepared by rapid solidification technology. The high solidification rate, obtained by rapid cooling, promotes nucleation, and suppresses the growth of Ag3Sn intermetallic compounds （IMCs） in Ag-rich zone, yielding fine Ag3Sn nanoparticulates with spherical morphology in the matrix of the solder. The large amount of tough homogeneously-dispersed IMCs helps to improve the surface area per unit volume and obstructs the dislocation lines passing through the solder, which fits with the dispersion-strengthening theory. Hence, the rapidly-solidified Sn-3.5Ag solder exhibits a higher rnicrohardness when compared with a slowly-solidified Sn-3.5Ag solder.

Synthesis and Crystal Structure of Salicylyl-4-phenyl Thiosemicarbazide Lead with a Two-dimensional Network

A two-dimensional lead complex, [Pb（C14N3O2H12S）（NO3）]n·nH2O, was prepared by the reaction of salicylyl-4-phenyl thiosemicarbazide and lead nitrate. The compound （C14H13N4O6PbS, Mr = 572.53） crystallizes in the monoclinic space group P21/c with a = 11.2984（2）, b = 15.6628（7）, c = 11.1118（2）A,β= 113.564（2）°, V = 1802.43（10）A3, Dc= 2.110 g/cm3, Z = 4,μt（MoKα） = 9.515 mm-1, F（000） = 1084, the final R = 0.0394 and wR = 0.0701 for 2552 observed reflections with I 〉 2σ（I）. The Pb（Ⅱ） ion displays a distorted octahedron in which the hypothesized stereochemically active lone pair occupies the apex. The compound exhibits a two-dimensional network structure formed by the zigzag one-dimensional chains joined by two μ-O of two nitrate groups in overlapping. A large ring exists in the two-dimensional layers. The TGA of the title compound has been studied.

<i>In Silico</i>Pharmacological Analysis of a Potent Anti-Hepatoma Compound of Mushroom Origin and Emerging Role as an Adjuvant Drug Lead

Mushrooms are well-known to possess a continuum of anticancer metabolites that are vital in the development of anticancer adjuvant drug leads based on natural products. Owing to the fact that conventional cancer therapeutic methods were failed to lessen mortality caused by cancer to the estimated level with occurrence of adverse side effects, anticancer agents isolated from natural mushroom sources unarguably make an experimental research area worth mass focus today. The current study was targeted on in vitro cytotoxicity and in silico predictive pharmacological analysis of a flavonoid compound isolated from Fulvifomes fastuosus mushroom. Targeted compound was isolated from the mushroom using different chromatographic methods and identified by NMR spectrometry and mass spectrometry. Cytotoxicity experiments were carried out using MTT assay and apoptotic cells were identified by ethidium bromide/acridine orange staining. The SwissADME tool, BOILED-Egg construction model and Swiss target protein prediction software have been used to perform in silico predictive pharmacological analysis. The isolated compound has been identified as 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione by spectrometric methods. The result of MTT assay showed that 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has potent anticancer activity for hepatoma against Hep-G2 cell line (IC50 = 20.8 μg/ml) being less toxic to normal CC-1 epithelial cells (IC50 = 167.00 μM). The cells treated with compound ex-hibited apoptotic features such as cellular shrinkage, nuclear fragmentation and condensed cytoplasm. In summary, 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has shown potent anticancer properties against hepatoma with less cytotoxicity effect on normal cells. Furthermore, in silico study has revealed that properties of 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione may contribute to making a high absorption and clearance of the test compound as not interfering with the therapeutic failure of the compound. The properties of 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo-[3,2-c]pyran-3,2'-furan]-3',4-dione were compatible with well-known anticancer drug lapatinib. In conclusion, 2-(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]-5'-methylspiro[2H-furo[3,2-c]pyran-3,2'-furan]-3',4-dione has a high tendency to act as a good anticancer adjuvant drug in the treatment of hepatoma.

<i>In-Silico</i>Identification of Anticancer Compounds;Ligand-Based Pharmacophore Approach against EGFR Involved in Breast Cancer

Objective: Breast cancer is a public health challenge on a global scale that is caused by environmental or genetic factors. Breast cancer is affecting both males and females, but there is still a lack of effective drugs with improved potency and admissibility against breast cancer as many of the breast cancer drugs have severe side effects. Methods: The docking approach has been used to find a new compound for breast cancer with more efficacy and tolerance and with lesser side effects. A ligand-based pharmacophore approach has been generated for 39 anticancer compounds with significance for the development of new drugs. Result: Through docking, the approach found new lead compounds for breast cancer. The proposed pharmacophore model in this study contains two HBAs and one HYD, one hydrophobic domain and two Aromatic rings and the estimated distance range is minimum to maximum of derived pharmacophore features. Conclusion: Based on this research, it is proposed that these two lead compounds may be able to be used against EGFR in breast cancer. New compounds can be identified based on common features in the Pharmacophore model. 3D pharmacophore triangle could be used for further studies because this pharmacophore has better merging and in the future for more studies can suggest the same distance range of pharmacophore features as this pharmacophore.

Characteristics of Laser Reflow Bumping of Sn3.5Ag and Sn3.5Ag0.5Cu Lead-Free Solder Balls

ead-free Sn3.5Ag and Sn3.5Ag0.5Cu solder balls were reflowed by laser to form solder bumps. Shear test was performed on the solder bumps, and SEM/EDX （scanning electron microscopy/energy dispersive X-ray spectrometer） was used to analyze the formation of intermetallic compounds （IMCs） at interface region. A finite element modeling on the temperature gradient and distribution at the interface of solder bump during laser reflow process was conducted to elucidate the mechanism of the IMCs growth direction. The results show that the parameters window for laser reflow bumping of Sn3.5Ag0.5Cu was wider than that of Sn3.5Ag. The shear strength of Sn3.5Ag0.5Cu solder bump was comparable to that of Sn3.5Ag solder bump, and was not affected obviously by laser power and irradiation time when appropriate parameters were used. Both laser power and heating time had a significant effect on the formation of IMCs. A continuous AuSn4 intermetallic compound layer and some needle-like AuSn4 were observed at the interface of solder and Au/Ni/Cu metallization layer when the laser power is small. The formation of needle-like AuSn4 was due to temperature gradient at the interface, and the direction of temperature gradient was the preferred growth direction of AuSn4. With increasing the laser power and heating time, the needle-like AuSn4 IMCs dissolved into the bulk solder, and precipitated out once again during solidification along the grain boundary of the solder bump.

Effect of a Trace of Bi and Ni on the Microstructure and Wetting Properties of Sn-Zn-Cu Lead-Free Solder

The microstructure and melting behavior of Sn-9Zn-2Cu （SZC） lead-free solder with 3 wt pct Bi and various amount of Ni additions were studied. The wetting properties and the interracial reaction of Sn-Zn-Cu with Cu substrate were also examined. The results indicated that the addition of 3 wt pct Bi could decrease the melting point of the solder and Ni would refine the microstructure and the rod-shape Cu5Zn8 phase changed into square-shape （Cu, Ni）5Zn8 phase. The addition of Bi, Ni greatly improved the wettability of SZC solder. In addition, the interracial phase of the solders/Cu joint was typical planar Cu5Zn8 in SZC-3Bi-INi alloy.

Identification of Rare Earth Phase in the Deformed High Lead-Brasses

Deformed high lead-brasses have excellent machining characteristics and good mechanical and physicalproperties.They are widely used in mechanical,clock-watch and pen-making field.Especially,they are suit-able for deep-hole machining.Because of their worse hot-working characteristics,there exists trouble inproduction process.It is reported that the rare earth metals could improve the hot-rolling property,but themechanism is still unclear.