Synthesis of new bis(thiosemicarbazone) derivatives and DFT analysis of antioxidant characteristics in relation to HAT and SET reactions

A series of new bis(thiosemicarbazones) have been synthesized from terephthalaldehyde and various thiosemicarbazides. IR, ¹H NMR, ¹³C NMR spectroscopic methods, and elemental analysis were used to characterize the identification of the synthesized compounds. The in vitro antioxidant activity determinations were made using the 1,1-Diphenyl-2-Picryl Hydrazil (DPPH) method. The compounds exhibited very different inhibition activities with the change of groups attached to the bis(thiosemicarbazone) structure. The spectral and electronic properties of the compounds were investigated by DFT calculation. Intramolecular interactions were analyzed by QTAIM and IRI calculations. Intrinsic bond strength index values of the N–H bonds, Fukui indices and the local electron affinities of the compounds were calculated, and the relationships between the compounds and their antioxidant activity properties were investigated. The SET and HAT mechanisms in the reactions of the compounds with DPPH were affected by the concentration of the compounds, and the possible effects of the parameters supporting the dominant characteristics in these reactions were examined using theoretical data.     

Synthesis,spectroscopic studies,and antioxidant activities of novel thio/carbohydrazones and bis-isatin derivatives from terephthalaldehyde

New bis(isatins-thio/carbohydrazones) based on Schiff bases were prepared from terephthalaldehyde biscarbohydrazone and 5-substituted isatins in the presence of a drop of sulfuric acid under reflux in ethanol. Terephthalaldehyde bis(thio/carbohydrazone) was synthesized by the reaction of (thio)/carbohydrazide and terephthalaldehyde in the presence of a few drops of acetic acid under reflux in ethanol. The structures of these synthesized compounds were determined using IR, ¹H NMR, and ¹³C NMR spectroscopy and elemental analysis. The in vitro antioxidant activity of all the compounds was determined by the 1,1-diphenyl-2-picryl hydrazyl (DPPH.) free radical scavenging method. Compound 2 showed the best antioxidant activity.     

Anticancer Profile of Rhodanines: Structure–Activity Relationship (SAR) and Molecular Targets—A Review

The rhodanine core is a well-known privileged heterocycle in medicinal chemistry. The rhodanines, as subtypes of thiazolidin-4-ones, show a broad spectrum of biological activity, including anticancer properties. This review aims to analyze the anticancer features of the rhodanines described over the last decade in the scientific literature. The structure–activity relationship of rhodanine derivatives, as well as some of the molecular targets, were discussed. The information contained in this review could be of benefit to the design of new, effective small molecules with anticancer potential among rhodanine derivatives or their related heterocycles.     

Isolation,Chemical Characterization and Antioxidant Activity of Pectic Polysaccharides of Fireweed (Epilobium angustifolium L.)

The aim of this study was to isolate pectins with antioxidant activity from the leaves of Epilobium angustifolium L. Two pectins, EA-4.0 and EA-0.8, with galacturonic acid contents of 88 and 91% were isolated from the leaves of E. angustifolium L. by the treatment of plant raw materials with aqueous hydrochloric acid at pH 4.0 and 0.8, respectively. EA-4.0 and EA-0.8 were found to scavenge the DPPH radical in a concentration-dependent manner at 17–133 μg/mL, whereas commercial apple pectin scavenged at 0.5–2 mg/mL. The antioxidant activity of EA-4.0 was the highest and exceeded the activity of EA-0.8 and a commercial apple pectin by 2 and 39 times (IC₅₀—0.050, 0.109 and 1.961 mg/mL), respectively. Pectins EA-4.0 and EA-0.8 were found to possess superoxide radical scavenging activity, with IC₅₀s equal to 0.27 and 0.97 mg/mL, respectively. Correlation analysis of the composition and activity of 32 polysaccharide fractions obtained by enzyme hydrolysis and anionic exchange chromatography revealed that the antioxidant capacity of fireweed pectins is mainly due to phenolics and is partially associated with xylogalacturonan chains. The data obtained demonstrate that pectic polysaccharides appeared to be bioactive components of fireweed leaves with high antioxidant activity, which depend on pH at their extraction.     

Euphorbia Diterpenes: An Update of Isolation,Structure, Pharmacological Activities and Structure–Activity Relationship

Euphorbia species have a rich history of ethnomedicinal use and ethnopharmacological applications in drug discovery. This is due to the presence of a wide range of diterpenes exhibiting great structural diversity and pharmacological activities. As a result, Euphorbia diterpenes have remained the focus of drug discovery investigations from natural products. The current review documents over 350 diterpenes, isolated from Euphorbia species, their structures, classification, biosynthetic pathways, and their structure–activity relationships for the period covering 2013–2020. Among the isolated diterpenes, over 20 skeletal structures were identified. Lathyrane, jatrophane, ingenane, ingenol, and ingol were identified as the major diterpenes in most Euphorbia species. Most of the isolated diterpenes were evaluated for their cytotoxicity activities, multidrug resistance abilities, and inhibitory activities in vitro, and reported good activities with significant half-inhibitory concentration (IC₅₀) values ranging from 10–50 µM. The lathyranes, isopimaranes, and jatrophanes diterpenes were further found to show potent inhibition of P-glycoprotein, which is known to confer drug resistance abilities in cells leading to decreased cytotoxic effects. Structure–activity relationship (SAR) studies revealed the significance of a free hydroxyl group at position C-3 in enhancing the anticancer and anti-inflammatory activities and the negative effect it has in position C-2. Esterification of this functionality, in selected diterpenes, was found to enhance these activities. Thus, Euphorbia diterpenes offer a valuable source of lead compounds that could be investigated further as potential candidates for drug discovery.     

Synthesis and Anticancer Properties of New 3-Methylidene-1-sulfonyl-2,3-dihydroquinolin-4(1H)-ones

Quinolinones have been known for a long time as broad-spectrum synthetic antibiotics. More recently, the anticancer potential of this group of compounds has been investigated. Following this direction, we obtained a small library of 3-methylidene-1-sulfonyl-2,3-dihydroquinolin-4(1H)-ones with various substituents at positions 1, 2, 6, and 7 of the quinolinone ring system. The cytotoxic activity of the synthesized analogs was tested in the MTT assay on two cancer cell lines in order to determine the structure–activity relationship. All compounds produced high cytotoxic effects in MCF-7, and even higher in HL-60 cells. 2-Ethyl-3-methylidene-1-phenylsulfonyl-2,3-dihydroquinolin-4(1H)-one, which was over 5-fold more cytotoxic for HL-60 than for normal HUVEC cells, was selected for further tests. This analog was shown to inhibit proliferation and induce DNA damage and apoptosis in HL-60 cells.     

Synthesis,spectroscopic characterization,biological screening and in vitro cytotoxic studies of 4‐methyl‐3‐thiosemicarbazone derived Schiff bases and their Co (II), Ni (II), Cu (II) and Zn (II) complexes

A series of twenty compounds inclusive of bidentate Schiff bases derived from condensation of 4‐methyl‐3‐thiosemicarbazide with substituted derivatives of napthaldehyde/benzaldehyde/salicylaldehyde and their mononuclear Co (II), Ni (II), Cu (II) and Zn (II) complexes in molar ratio (1:1) were synthesized and characterized. The coordination behavior, modes of bonding and overall geometry of the compounds was known from the elemental analysis, spectral techniques (IR, UV–Vis, ¹H NMR, ¹³C NMR, ESR and ESI‐mass), magnetic moment measurements, molar conductance, thermal and powder XRD studies. The studies revealed octahedral geometry for all the complexes where ligands coordinated in a neutral bidentate manner (NS) via nitrogen atom of azomethine group and sulphur atom of thione group with the metal centre. In vitro biological effects of the compounds were tested against four bacterial species and two fungal strains. The results indicated that the metal complexes showed a marked enhancement in biocidal activity in comparable with the parent Schiff bases. In vitro anticancer activity against the malignant tumor cell lines; human alveolar adenocarcinoma epithelial cell line (A549), human breast adenocarcinoma cell line (MCF7), human prostate cancer cell line (DU145) and human normal lung cell line (MRC‐5) using MTT assay, exposed compound 16 as a leading member with lowest IC₅₀ value of 10.6 ± 0.14 μM against (A549) cell line.     

Design,Synthesis, and Bioassay of 2′-Modified Kanamycin A

Chemical modification of old drugs is an important way to obtain new ones, and it has been widely used in developing new aminoglycoside antibiotics. However, many of the previous modifying strategies seem arbitrary for their lack of support from structural biological detail. In this paper, based on the structural information of aminoglycoside and its drug target, we firstly analyzed the reason that some 2′-N-acetylated products of aminoglycosides caused by aminoglycoside-modifying enzyme AAC(2′) can partially retain activity, and then we designed, synthesized, and evaluated a series of 2′-modified kanamycin A derivatives. Bioassay results showed our modifying strategy was feasible. Our study provided valuable structure–activity relationship information, which would help researchers to develop new aminoglycoside antibiotics more effectively.     

The Biosynthesis Related Enzyme,Structure Diversity and Bioactivity Abundance of Indole-Diterpenes: A Review

Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure–activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure–activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.     

Nucleus-Independent Chemical Shift (NICS) as a Criterion for the Design of New Antifungal Benzofuranones

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL^–1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL^–1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.     

Organotin (IV) complexes derived from tridentate Schiff base ligands: Synthesis,spectroscopic analysis,antimicrobial and antioxidant activity

Organotin complexes of Schiff bases (derived from the condensation of hydrazides with salicylaldehyde derivatives) were prepared and their characterization was done using several spectroscopic techniques like FTIR, NMR (¹H, ¹³C, and ¹¹⁹Sn) and mass spectrometry. The spectroscopic data of the ligands and their corresponding complexes revealed that the Schiff bases chelated to the tin metal in a tridentate manner through –ONO atoms (oxygen atom of the hydroxyl group of the salicylaldehydic derivatives, the nitrogen atom of azomethine group, and the oxygen atom of enolic group present in the carboxylic acid hydrazides). Around tin atom pentacoordinated geometry was exhibited. The synthesized ligands and their complexes have been assessed for their biological potency (antibacterial, antifungal and antioxidant using Ciprofloxacin, Fluconazole and Ascorbic acid as reference compounds) and few of the compounds showed optimistic activity. The ligands having electron withdrawing group attached showed greater antimicrobial activity as compared to the other ligands. The complexes showed the better activity than the ligands. The general trend followed by the complexes was diphenyl ?> ?dibutyl ?> ?dimethyl substituted complexes. Compound 11 was the most active against microbes. The antioxidant activity increased with electron donating group. The phenyl substituted complexes showed better activity as compared to the dibutyl and dimethyl substituted complexes. Compound 20 was the best antioxidant.     

Synthesis and antimicrobial activity of new 2-((1-furan-2-yl)ethylidene)hydrazono)-4-phenylthiazol-3(2H)-amine derivatives and their schiff bases with 4-nitrobenzaldehyde

Abstract

A new series of 2-((1-furan-2-yl)ethylidene)hydrazono)-4-substitutedphenylthiazol-3(2H)-amines (2a–2o) and their Schiff bases (3a–3o) from 4-nitrobenzaldehyde were synthesized. The chemical structures of all the synthesized compounds were confirmed by their IR, ¹H-NMR, ¹³C-NMR spectroscopy and mass spectrometry. They were screened for their antimicrobial and antifungal activities. Additionally, in vitro cytotoxic acivity of the most active antifungal compound (3o) and ketoconazole was determined in NIH/3T3 cells by MTT assay. Compound 2i (4-{3-Amino-2-[(1-(furan-2-yl)ethylidene)hydrazono]-2,3-dihydrothiazol-4-yl}phenol) showed the greatest antifungal activity among the newly synthesized derivatives. Schiff bases (3c-3n) displayed an undeniable fungicidal action against Candida parapsilosis ATCC 22019 as intense as the reference ketoconazole. In addition, the most active Schiff base 3o (2-[(1-(Furan-2-yl)ethylidene)hydrazono]-N-(4-nitrobenzylidene)-4-(2,3,4-trichloro phenyl)thiazol-3(2H)-amine) showed the highest antifungal activity against both Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019, and was as potent as ketoconazole. Moreover, compound 3o was found to be non-cytotoxic against NIH/3T3 cells.     

Design,Synthesis and Biological Evaluation of N-phenylindole Derivatives as Pks13 Inhibitors againstMycobacterium tuberculosis

Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis (Mtb), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb. The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole N moieties. Thirty-six N-phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure–activity relationship (SAR) studies resulted in the discovery of the potent Compounds 45 and 58 against Mtb H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound 58 displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of Mtb and provides a novel scaffold for developing leading anti-TB compounds.     

An Insight into Antihyperlipidemic Effects of Polysaccharides from Natural Resources

Hyperlipidemia is a chronic metabolic disease caused by the abnormal metabolism of lipoproteins in the human body. Its main hazard is to accelerate systemic atherosclerosis, which causes cerebrovascular diseases such as coronary heart disease and thrombosis. At the same time, although the current hypolipidemic drugs have a certain therapeutic effect, they have side effects such as liver damage and digestive tract discomfort. Many kinds of polysaccharides from natural resources possess therapeutic effects on hyperlipidemia but still lack a comprehensive understanding. In this paper, the research progress of natural polysaccharides on reducing blood lipids in recent years is reviewed. The pharmacological mechanisms and targets of natural polysaccharides are mainly introduced. The relationship between structure and hypolipidemic activity is also discussed in detail. This review will help to understand the value of polysaccharides in lowering blood lipids and provide guidance for the development and clinical application of new hypolipidemic drugs.     

Synthesis and Antifungal Activity of Chimonanthus praecox Derivatives

To search for efficient agricultural antifungal lead compounds, 39 Chimonanthus praecox derivatives were designed, synthesized, and evaluated for their antifungal activities. The structures of target compounds were fully characterized by ¹H NMR, ¹³C NMR, and MS spectra. The preliminary bioassays revealed that some compounds exhibited excellent antifungal activities in vitro. For example, the minimum inhibitory concentration (MIC) of compound b15 against Phytophthora infestans was 1.95 µg mL⁻¹, and the minimum inhibitory concentration (MIC) of compound b17 against Sclerotinia sclerotiorum was 1.95 µg mL⁻¹. Therefore, compounds b15 and b17 were identified as the most promising candidates for further study.     

Polydentate Schiff-base ligands and their Cd(II) and Cu(II) metal complexes: synthesis,characterization, biological activity and electrochemical properties

Synthesis, characterization, microbiological activity and electrochemical properties of the Schiff-base ligands A¹–A⁵ and their Cd(II) and Cu(II) metal complexes are reported. The ligands and their complexes have been characterized by elemental analysis, FT–IR, UV–Vis, ¹H- and ¹³C-NMR, mass spectra, magnetic susceptibility and conductance measurements. In the complexes, all the ligands are bidentate, the oxygen in the ortho position and azomethine nitrogen atoms of the ligands coordinate to the metal ions. The keto-enol tautomeric forms of the Schiff-base ligands A¹–A⁵ have been investigated in polar and non-polar organic solvents. Antimicrobial activity of the ligands and metal complexes were tested using the disc diffusion method and the chosen strains include Bacillus megaterium and Candida tropicalis. The electrochemical properties of the ligands A¹–A⁵ and their Cu(II) metal complexes have been investigated at different scan rates (100–500?mV?s^?1) in DMSO.     

Structural Characteristics,Antioxidant and Hypoglycemic Activities of Polysaccharide from Siraitia grosvenorii

The structural characterization, the in vitro antioxidant activity, and the hypoglycemic activity of a polysaccharide (SGP-1-1) isolated from Siraitia grosvenorii (SG) were studied in this paper. SGP-1-1, whose molecular weight is 19.037 kDa, consisted of Gal:Man:Glc in the molar ratio of 1:2.56:4.90. According to the results of methylation analysis, GC–MS, and NMR, HSQC was interpreted as a glucomannan with a backbone composed of 4)-β-D-Glcp-(1→4)-, α-D-Glcp-(1→4)-, and 4)-Manp-(1 residues. α-1,6 linked an α-D-Galp branch, and α-1,6 linked an α-D-Glcp branch. The study indirectly showed that SGP-1-1 has good in vitro hypoglycemic and antioxidant activities and that these activities may be related to the fact that the SGP-1-1’s monosaccharide composition (a higher proportion of Gal and Man) is the glycosidic-bond type (α- and β-glycosidic bonds). SGP-1-1 could be used as a potential antioxidant and hypoglycemic candidate for functional and nutritional food applications.     

Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

Histone-modifying proteins have been identified as promising targets to treat several diseases including cancer and parasitic ailments. In silico methods have been incorporated within a variety of drug discovery programs to facilitate the identification and development of novel lead compounds. In this study, we explore the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni histone deacetylase (smHDAC) using molecular docking and binding free energy (BFE) calculations. The developed docking protocol was able to correctly reproduce the experimentally established binding modes of resolved smHDAC8–inhibitor complexes. However, as has been reported in former studies, the obtained docking scores weakly correlate with the experimentally determined activity of the studied inhibitors. Thus, the obtained docking poses were refined and rescored using the Amber software. From the computed protein–inhibitor BFE, different quantitative structure–activity relationship (QSAR) models could be developed and validated using several cross-validation techniques. Some of the generated QSAR models with good correlation could explain up to ~73% variance in activity within the studied training set molecules. The best performing models were subsequently tested on an external test set of newly designed and synthesized analogs. In vitro testing showed a good correlation between the predicted and experimentally observed IC₅₀ values. Thus, the generated models can be considered as interesting tools for the identification of novel smHDAC8 inhibitors.     

Synthesis,antimicrobial and cytotoxic activity of novel azetidine-2-one derivatives of 1H-benzimidazole

A series of 1-methyl-N-[(substituted-phenylmethylidene)-1H-benzimidazol-2-amines (4a–4g) were prepared via the formation of 1-methyl-1H-benzimidazol-2-amine (3), which was prepared by the cycloaddition of o-phenylenediamine (1) with cyanogen bromide in the presence of aqueous base followed by N-methylation with methyl iodide in the presence of anhydrous potassium carbonate in dry acetonitrile. Moreover, the four-membered β-lactam ring was introduced by the cycloaddition of 4a–4g and chloroacetyl chloride in the presence of triethylamine catalyst to give 3-chloro-1-(1-methyl-1H-benzimidazol-2-yl)-(4′-substituted)-phenylazetidin-2-one 5a–5g. A total of 14 compounds were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and Mass spectral technique, in addition they were evaluated for anti-bacterial and cytotoxic properties. Among the chemicals tested 4a, 4b, 5a, 5b, 5g exhibited good antibacterial activity and 5f, 5g shown good cytotoxic activity in vitro.     

Different Schiff Bases—Structure,Importance and Classification

Schiff bases are a vast group of compounds characterized by the presence of a double bond linking carbon and nitrogen atoms, the versatility of which is generated in the many ways to combine a variety of alkyl or aryl substituents. Compounds of this type are both found in nature and synthesized in the laboratory. For years, Schiff bases have been greatly inspiring to many chemists and biochemists. In this article, we attempt to present a new take on this group of compounds, underlining of the importance of various types of Schiff bases. Among the different types of compounds that can be classified as Schiff bases, we chose hydrazides, dihydrazides, hydrazones and mixed derivatives such as hydrazide–hydrazones. For these compounds, we presented the elements of their structure that allow them to be classified as Schiff bases. While hydrazones are typical examples of Schiff bases, including hydrazides among them may be surprising for some. In their case, this is possible due to the amide-iminol tautomerism. The carbon–nitrogen double bond present in the iminol tautomer is a typical element found in Schiff bases. In addition to the characteristics of the structure of these selected derivatives, and sometimes their classification, we presented selected literature items which, in our opinion, represent their importance in various fields well.