New benzothieno[3,2-d]-1,2,3-triazines with antiproliferative activity: Synthesis,spectroscopic studies,and biological activity

New benzothieno[3,2-d]-1,2,3-triazines, together with precursors triazenylbenzo[b]thiophenes, were designed, synthesized and screened as anticancer agents. The structural features of these compounds prompted us to investigate their DNA binding capability through UV–vis absorption titrations, circular dichroism, and viscometry, pointing out the occurrence of groove-binding. The derivative 3-(4-methoxy-phenyl)benzothieno[3,2-d]-1,2,3-triazin-4(3H)-one showed the highest antiproliferative effect against HeLa cells and was also tested in cell cycle perturbation experiments. The obtained results assessed for the first time the anticancer activity of benzothieno[3,2-d]-1,2,3-triazine nucleus, and we related it to its DNA-binding properties.     

Isolation of Natural Naphthoquinones from <Emphasis Type="Italic">Juglans regia</Emphasis> and In Vitro Antioxidant and Cytotoxic Studies of Naphthoquinones and the Synthetic Naphthofuran Derivatives

The naphthoquinones and their derivatives containing hydroxyl group exhibit wide range of pharmacological activities, such as antioxidant, antibacterial, antiviral, anticancer, antimalarial, and antifungal activities. In particular, the antioxidant and anticancer behaviors of these compounds continue to draw attention of researchers. In the present communication, three natural naphthoquinones—juglone, lawsone, and plumbagin—isolated from the chloroform extract of nutshells of Juglans regia Linn. and two 1,4-naphthoquinone derivatives—ethyl-5-hydroxynaphtho[ 1,2-b]furan-3-carboxylate and diethylnaphtho[1,2-b:4,3-b′]difuran-3,4-dicarboxylate—and three 5-hydroxy- 1,4-naphthoquinone derivatives—diethyl-7-hydroxynaphtho[1,2-b:4,3-b']difuran-3,4-dicarboxylate,4-ethoxycarbonyl- 7-hydroxynaphtho[1,2-b:4,3-b']difuran-3-carboxylic acid, and 7-hydroxynaphtho[1,2-b:4,3-b']difuran-3,4- dicarboxylic acid were synthesized and examined for their in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) bioassays. In addition, the cytotoxicity test using human hepatocellular liver carcinoma cell line (HepG2) was carried out for all the compounds. The 5-hydroxy-1,4-naphthoquinone derivatives displayed almost equivalent scavenging activity in DPPH assay and higher activity in ABTS assay relative to ascorbic acid. On the other hand, naphthoquinones Juglone and Plumbagin showed lesser antioxidant activity, but higher cytotoxic activity than naphthofurans except for diethyl naphtho[1,2-b:4,3-b′]difuran-3,4-dicarboxylate, which showed excellent cytotoxic activity.     

Synthesis of novel bis(pyrimido[5,4-c]quinoline-2,4(1H,3H)-dione) and its derivatives: Evaluation of their antioxidant properties

One pot cyclocondensation reaction of barbituric/thiobarbituric acid with aromatic aldehydes and p-phenylenediamine/2,6-diaminopyridine by refluxing in glacial acetic acid afforded novel bis(pyrimido[5,4-c]quinoline-2,4(1H,3H)-diones)/pyrido bis(pyrimido[5,4-c]quinoline-2,4(1H,3H)-diones. All the synthesized compounds were screened for their antioxidant activities using FRAP and DPPH methods. Compounds with chloro substituents showed relatively good antioxidant properties.     

Antioxidant activity and phenolic profile of pistachio (Pistacia vera L., variety Bronte) seeds and skins

Pistachio (Pistacia vera L.; Anacardiaceae) is native of aride zones of Central and West Asia and distributed throughout the Mediterranean basin. In Italy, a pistachio cultivar of high quality is typical of Bronte (Sicily), an area around the Etna volcano, where the lava land and climate allow the production of a nut with intense green colour and aromatic taste, very appreciated in international markets. Pistachio nuts are a rich source of phenolic compounds, and have recently been ranked among the first 50 food products highest in antioxidant potential. Pistachio nuts are often used after removing the skin, which thus represents a significant by-product of pistachio industrial processing. The present study was carried out to better characterize the phenolic composition and the antioxidant activity of Bronte pistachios, with the particular aim to evaluate the differences between pistachio seeds and skins. The total content of phenolic compounds in pistachios was shown to be significantly higher in skins than in seeds. By HPLC analysis, gallic acid, catechin, eriodictyol-7-O-glucoside, naringenin-7-O-neohesperidoside, quercetin-3-O-rutinoside and eriodictyol were found both in pistachio seeds than in skins; furthermore, genistein-7-O-glucoside, genistein, daidzein and apigenin appeared to be present only in pistachio seeds, while epicatechin, quercetin, naringenin, luteolin, kaempferol, cyanidin-3-O-galactoside and cyanidin-3-O-glucoside are contained only in pistachio skins. The antioxidant activity of pistachio seeds and skins were determined by means of four different assays (DPPH assay, Folin-Ciocalteau colorimetric method and TEAC assay, SOD-mimetic assay). As expected on the basis of the chemical analyses, pistachio skins have shown to possess a better activity with respect to seeds in all tests. The excellent antioxidant activity of pistachio skins can be explained by its higher content of antioxidant phenolic compounds. By HPLC-TLC analysis, gallic acid, catechin, cyanidin-3-O-galactoside, eriodictyol-7-O-glucoside and epicatechin appeared to be responsible for the antioxidant activity of pistachio skin, together with other unidentified compounds. In conclusion, our work has contributed to clarify some particular characteristics of Bronte pistachios and the specific antioxidant power of pistachio skins. Introduction of pistachios in daily diet may be of undoubted utility to protect human health and well-being against cancer, inflammatory diseases, cardiovascular pathologies and, more generally, pathological conditions related to free radical overproduction. On the other hand, pistachio skins could be successfully employed in food, cosmetic and pharmaceutical industry.     

Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine

A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5 μg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA.     

Triazolopyridazine derivatives: Synthesis,cytotoxic evaluation,c-Met kinase activity and molecular docking

Novel series of some triazolo[4,3-b]pyridazine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated for their cytotoxic activity at 10⁻⁵ M concentration towards 60 cancer cell lines according to USA NCI protocol. Most of the synthesized compounds showed good activity against SR (leukemia) cell panel. The most active compounds, 2f and 4a were subjected for further evaluation at a five dose level screening and their efficacy for c-Met kinase inhibition was determined in vitro. Binding mode of these derivatives was explored via molecular docking.     

Synthesis and Characterization of Novel Thiazolo[3,2‐a]pyrimidine Derivatives and Evaluation of Antioxidant and Cytotoxic Activities

A series of novel thiazolo[3,2‐a]pyrimidines were synthesized and characterized by FT‐IR, ¹H, ¹³C‐NMR and mass techniques. Their antioxidant activities were investigated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical scavenging assay and the results showed that all the synthesized compounds exhibit good antioxidant activity. In addition, it was found that any substituent on the aromatic ring of the products plays an important role in their antioxidant activity. In vitro cytotoxicity of compounds 4a – 4j was investigated using MTT cell viability assay. Among these compounds, 6‐ethyl 2,3‐dimethyl 5‐(4‐chlorophenyl)‐7‐methyl‐2,3‐dihydro‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐2,3,6‐tricarboxylate ( 4e ) bearing a chlorine substituent displayed the highest cytotoxic effect (IC₅₀=6.26±0.6 μm ) in comparison with doxorubicin (IC₅₀=0.68±0.1 μm ) as a standard after 72 h. Therefore, it is assumed that these compounds could be used as effective antioxidant and cytotoxic agents.     

Chemical Composition and Bioactivities of Quercus canariensis Flour Acorns Extracts Growing in Tunisia

The current study was conducted to investigate the chemical composition of Quercus canariensis flour acorns extracts as well as its biological activities in regards to the growing area using spectrophotometric and chromatographic techniques. The phenolic profile was composed of 19 compounds identified through HPLC-DAD analysis. Coumarin was the most abundant compound quantified in BniMtir, Nefza and ElGhorra and gallic (12.58–20.52 %), syringic (4.70–7.64 %) and trans-ferulic (2.28–2.94 %) acids were the abundant phenolic acids while kaempferol was the major flavonoid compounds quantified only in Quercus canariensis growing in BniMtir. On the other hand, Ain Snoussi acorn extract was characterized by its high content in luteolin-7-O-glucoside (58.46 %). The in-vitro antioxidant activities of the studied extracts were investigated and the results showed that Nefza ethanolic extract's has the highest activities. A bactericidal effect against Staphylococcus aureus was observed only by Elghorra population. On the other hand, Ain Snoussi acorn extract was efficient to inhibit growth of pathogenic bacteria, mentioned the highest activity against Escherichia coli. These results is the first study highlighted that zeen oak acorns are an excellent source of natural antioxidants and antibacterial compounds related to their lysozyme activity which could be exploited in the pharmaceutical and food sectors.     

Synthesis and structure-activity relationships of novel camphecene analogues as anti-influenza agents

A chemical library was constructed based on the scaffold of camphecene (2-(E)-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol). The modifications included introduction of mono-and bicyclic heterocyclic moieties in place of the terminal hydroxyl group of camphecene. All compounds were tested for cytotoxicity and anti-viral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells. Among 15 tested compounds 11 demonstrated a selectivity index (SI) higher than 10 and IC₅₀ values in the micromolar range. The antiviral activity and toxicity were shown to strongly depend on the nature of the heterocyclic substituent. Compounds 2 and 14 demonstrated the highest virus-inhibiting activity with SIs of 106 and 183, and bearing pyrrolidine and piperidine moieties, correspondingly. Compound 14 was shown to interfere with viral reproduction at early stages of the viral life cycle (0–2 h post-infection). Taken together, our data suggest potential of camphecene derivatives in particular and camphor-based imine derivatives in general as effective anti-influenza compounds.     

Design,synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine and quinazoline derivatives as potent antitumor agents

Four series of novel thieno[3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC₅₀ values of 1.78 μM, 1.02 μM, 1.98 μM, 0.41 μM and 0.22 μM against HT-29, MDA-MB-231, U87MG, PC-3 and HCT-116 cell lines respectively. Inhibition of enzymatic assays showed that PI3Kα was very likely to be one of the drug targets of 14 with the IC₅₀ value of 0.20 μM. According to the results of antitumor activity, the SARs were summarized, which indicated that thieno[3,2-d]pyrimidine and semicarbazone are optimal fragments. In addition, compounds with hydroxyl group at the 4-position on the terminal phenyl ring were more active. Annexin-V and propidium iodide (PI) double staining confirmed that the most active cytotoxic compound 14 can induce cell apoptosis in HCT-116 cells. Moreover, the influence of 14 on the cell cycle distribution was assessed on the HCT-116 cell line, exhibiting a cell cycle arrest at the G2/M phase. Furthermore, molecular docking analysis was also performed to determine possible binding modes between PI3Kα and the target compound. These results will guide us to further refine the structure of the thieno[3,2-d]pyrimidine and quinazoline derivatives to achieve optimal antitumor activity.     

Stereoselective synthesis of enantiopure N-substituted pyrrolidin-2,5-dione derivatives by 1,3-dipolar cycloaddition and assessment of their in vitro antioxidant and antibacterial activities

1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.     

Variation of chemical composition and antioxidant activity of essential oils of Mentha x rotundifolia (L.) Huds. (Lamiaceae) collected from different bioclimatic areas of Tunisia

The variation of the essential oils composition of 10 Tunisian Mentha x rotundifolia (L.) Huds. Populations and their antioxidant activity were assessed. Essential oils showed high percentages of oxygenated monoterpenes and sesquiterpene hydrocarbons. Rotundifolone, p-menthane-1,2,3-triol, β-caryophyllene and germacrene D were identified as main compounds at the species level. A variation in the essential oil composition was observed according to the populations and ecological factors. The populations 7, 8, 9 and 10 from the upper semi-arid bioclimatic zone and situated at high altitudes, exhibited the highest amount of rotundifolone. The populations 1, 2, 3, 4 and 5 from the lower humid showed a rotundifolone/β-caryophyllene/germacrene D chemotype. The population 6, situated at the lowest altitude, was characterized by the highest amount of p-menthane-1,2,3-triol. The level of antioxidant activity of the populations was linked to their chemical composition difference. The highest scavenging activity and the best ability to reduce ferric ions were recorded for the population 10. The most important capacity to inhibit β-carotene bleaching was revealed for the population 8. For all populations, the antioxidant activities were substantial but lower than antioxidant standards used (Trolox and BHT).The populations (7, 8, 9 and 10) from the upper semi-arid showed the best yields of essential oils and the highest contents of rotundifolone. Chemotypes within these populations could be selected for improvement programs.     

Synthesis and bioevaluation of some new isoniazid derivatives

The aim of the study was to synthesize some new compounds with potential anti-tuberculosis activity, containing isoniazid and α,β-unsaturated thiocinnamamide-like thioamides as precursors. The obtained derivatives were evaluated regarding their biological activity (antioxidant and antibacterial), as well as their influence on the eukaryotic cell cycle. The results suggested that the newly obtained derivatives of isoniazid exhibited different biological activities, depending on their structure; thus, the most active compound in terms of anti-oxidant and anti-Mycobacterium tuberculosis effects proved to be the isonicotinic acid N′-(1-amino-1-mercapto-3-phenyl-propen-1-yl)-hydrazide. This compound also increased the expression of NAT1 and NAT2 genes, which are implicated in the metabolism of the isoniazid, demonstrating that it could be rapidly metabolized, and thus well tolerated. The largest spectrum of antibacterial activity (excluding M. tuberculosis) was noticed for the isonicotinic acid N′-[1-amino-1-mercapto-3-(p-chloro-phenyl)-propen-1-yl]-hydrazide, which was also the most cytotoxic, especially at high concentrations, although not significantly affecting the cellular cycle phases. The obtained results showed that the new derivatives could represent potential candidates for the treatment of M. tuberculosis infections, but further research is needed in order to improve their pharmacological properties, by increasing their antimicrobial activity and reducing the risk of side-effects.     

Exploration of antimicrobial and antioxidant potential of newly synthesized 2,3-disubstituted quinazoline-4(3H)-ones

A series of 2-(chloromethyl)-3-(4-methyl-6-oxo-5-[(E)-phenyldiazenyl]-2-thioxo-5,6-dihydropyrimidine-1(2H)-yl)quinazoline-4(3H)-ones 9a-j was synthesized by treating 2-(chloroacetyl)amino benzoic acid with 3-amino-6-methyl-5-[(E)-phenyldiazenyl]-2-thioxo-2,5-dihydropyrimidine-4(3H)-one 8a-j and was screened for in vitro antibacterial activities against a representative panel of Gram-positive and Gram-negative bacteria. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of IR, ¹H NMR, Mass and elemental analysis data. All the synthesized compounds elicited the potent inhibitory action against all the tested bacterial stains. Furthermore, in order to explore the antioxidant potential of newly synthesized compounds, the free radical scavenging activity measurement were performed by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay method. It is revealed from the antioxidant screening results that the compounds 9c and f manifested profound antioxidant potential.     

Tautomeric and non-tautomeric N-substituted 2-iminobenzimidazolines as new lead compounds for the design of anti-influenza drugs: An in vitro study

A series of 1,3-disubstituted 2-iminobenzimidazolines as well as a number of their tautomeric analogs were synthesized. The synthesized compounds were tested for their cytotoxicity against MDCK cells and for inhibiting activity against influenza virus A/California/07/09 (H1N1)pdm09. Based on the results obtained, 50% cytotoxic concentration (CC₅₀), 50% inhibiting concentration (IC₅₀) and selectivity index (SI) were calculated for each compound. It was found that some of synthesized benzimidazole derivatives (7 of 22, 32%) possess strong virus-inhibiting activity against pandemic influenza virus (IC₅₀’s in low micromolar range) with quite moderate cytotoxicity (CC₅₀ in the range of thousands micromoles). Due to their high selectivity (highest SI’s = 50–83) these compounds are of significant interest for further in vivo experiments as well as for further structural optimization and drug development.     

Green chemoselective synthesis of thiazolo[3,2-a]pyridine derivatives and evaluation of their antioxidant and cytotoxic activities

The green chemoselective synthesis of thiazolo[3,2-a]pyridine derivatives was achieved in water via microwave-assisted three-component reactions of malononitrile, aromatic aldehydes and 2-mercaptoacetic acid with molar ratios of 2:1:1.5 and 2:2.2:1, respectively. These compounds were subject to the experiments of antioxidant activity and cytotoxicity to carcinoma HCT-116 cells and mice lymphocytes. Nearly all of the tested compounds possessed potent capacities for scavenging free radicals. In addition, most of these compounds showed cytotoxicity to HCT-116 cells and mice lymphocytes with no selectivity. Of these, only thiazolo[3,2-a]pyridine derivative 5d suggested selective cytotoxicity to tumor cell line HCT-116 cells.     

Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2

A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carried out by formaldehyde and secondary amines (diethylamine, pyrrolidine, morpholine, and homopiperazine). All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among 21 tested compounds, six derivatives demonstrated a selectivity index (SI) higher than 10, and their IC₅₀ values ranged from 0.19 to 5.0 μM. Moreover, two derivatives exhibited potent anti-SARS-CoV-2 infection activity. The antiviral activity and toxicity strongly depended on the nature of the diterpene core and heterocyclic substituent. Compounds 12 and 21 bearing pyrrolidine moieties demonstrated the highest virus-inhibiting activity with SIs of 128.6 and 146.8, respectively, and appeared to be most effective when added at the time points 0–10 and 1–10 h of the viral life cycle. Molecular docking and dynamics modeling were adopted to investigate the binding mode of compound 12 into the binding pocket of influenza A virus M2 protein. Compound 9 with a pyrrolidine group at C20 of 17-formylabietic acid was a promising anti-SARS-CoV-2 agent with an EC₅₀ of 10.97 µM and a good SI value > 18.2. Collectively, our data suggested the potency of diterpenic Mannich bases as effective anti-influenza and anti-COVID-19 compounds.     

Secondary metabolites,phytochemical characterization and antioxidant activities of different extracts of Sideritis congesta P.H. Davis et Hub.-Mor.

Sideritis congesta, an endemic plant to Turkey, is extensively consumed as energizing herbal tea and used as a remedy in folk medicine. This study was designed to comparatively evaluate the phytochemical composition and antioxidant potentials of different extracts (methanol, infusion) and fractions (chloroform, ethyl acetate, and remaining water) of S. congesta. Antioxidant potentials of the samples were evaluated by DPPH radical scavenging, FRAP, CUPRAC, and total antioxidant capacity tests. Total phenolic, phenolic acid, and flavonoid contents were also evaluated spectrophotometrically. Moreover, presence of twenty-two phenolic metabolites were affirmed by using LC-MS/MS in MRM scan mode and then the quantification of verbascoside, martynoside, and leucoseptoside A was performed by using HPTLC densitometry. EtOAc fraction contained the highest phenolic content and the antioxidant activity, as well as the highest verbascoside and martynoside contents followed by R-H₂O fraction. Phytochemical studies on R-H₂O fraction, yielded seven compounds, including a phenylethanoid glycoside, verbascoside (1), two flavonoids, stachyspinoside (2), isoscutellarein 7-O-(6‴-O-acetyl)-β-allopyranosyl-(1 → 2)-β-glucopyranoside (3), a phenolic acid chlorogenic acid (4), an iridoid glycoside ajugoside (5), and a monoterpenoid glucoside mixture betulalbuside A (6) and 1-hydroxylinaloyl 6-O-β-D-glucopyranoside (7). The molecular structures of the isolated compounds were determined by NMR and MS experiments. This is the first phytochemical study on the polar constituent of S. congesta and the first report of the isolation of compounds 2, 6 and 7 from the genus Sideritis L.     

Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives

Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC₅₀ values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.     

Evaluation and optimization of antioxidant potentiality of Chaetomium madrasense AUMC 9376

Antioxidants have recently become the topic of interest as radical scavengers, which inhibit lipid peroxidation and other free radical mediated processes. Chaetomium madrasense AUMC 9376 was isolated from Cairo soil and evaluated for antioxidant activity by various assays, such as DPPH, reducing power, scavenging activity by ferrous ion, nitric oxide (NO) and total phenolic content. Different physical and chemical conditions of the production medium were optimized for enhancement of antioxidant activity. The results revealed that incubation for 15 days at 25 °C and pH 6 was the most favorable for antioxidant activity. Moreover, both glucose and sodium nitrate were the proper carbon and nitrogen sources, respectively for the highest antioxidant activity. The extraction of the broth culture filtrate with different solvents revealed that ethyl acetate extract possesses the highest antioxidant activity. The obtained results suggest that the experimental fungus has the potentiality as a source of strong natural and safe antioxidants safe for application in the food and cosmetics industries.