Antioxidant Studies of Thiazole Ring Bearing Chalcone Derivatives

Oxidative stress is one of the common problems seen in a variety of diseases. Chalcones and in particular heteroaryl chalcones had reported with promising antioxidant activities. Hence, in the present work, we reported the antioxidant activity of twenty thiazole ring bearing chalcone derivatives (1-20). Among the tested compounds, compounds 17, 19 and 20 containing 2-pyridinyl, 3-pyridinyl and 2-thiazolyl scaffolds showed superior antioxidant activity than the standard with their IC50 values 4±1µg/mL, 3±1 µg/mL and 5±1 µg/mL respectively. The compound 19 is an interesting lead for the development of newer antioxidant agents.

FrpA is the outer membrane piscibactin transporter in Vibrio anguillarum: structural elements in synthetic piscibactin analogues required for transport

Piscibactin (Pcb) is a labile siderophore widespread among Vibrionaceae. Its production is a major virulence factor of some fish pathogens such as Photobacterium damselae subsp. piscicida and Vibrio anguillarum. Although FrpA was previously suggested as the putative outer membrane transporter (OMT) for ferri-piscibactin, its role in piscibactin uptake was never demonstrated. In this work, we generated mutants of V. anguillarum defective in FrpA and analyzed their ability to use piscibactin as iron source. The results showed that inactivation of frpA completely disables piscibactin utilization, and the original phenotype could be restored by gene complementation, confirming that FrpA is the OMT that mediates ferri-Pcb uptake. Additionally, the ability of several Pcb thiazole analogues, with different configurations at positions 9, 10, and 13, to be internalized through FrpA, was evaluated measuring their ability to promote growth under iron deficiency of several indicator strains. The results showed that while those analogues with a thiazole ring maintain almost the same activity as Pcb, the maintenance of the hydroxyl group present in natural piscibactin configuration at position C-13 is crucial for Fe3+ chelation and, in consequence, for the recognition of the ferri-siderophore by the cognate OMT. All these findings allowed us to propose a Pcb analogue as a good candidate to vectorize antimicrobial compounds, through the Trojan horse strategy, to develop novel compounds against bacterial fish diseases. Graphical abstract

Design and Synthesis of a Highly Simplified Pateamine Analogue

<p>Pateamine (1) is a natural product from the marine sponge Mycale hentscheli that exhibits potent anticancer properties, and has potential as an antiviral agent, and in preventing the muscle wasting disorder cachexia. This biological activity of pateamine is due to its ability to inhibit the eukaryotic initiation factor eIF4A, which leads to the formation of stress granules, the inhibition of protein synthesis, and ultimately cell death. Unfortunately, pateamine is obtained in very small amounts from Mycale hentscheli; thus, it is necessary to synthesise pateamine and novel structural analogues in the laboratory. Previously a separate binding and scaffolding domain of pateamine was proposed, which led to the synthesis of a simplified des-methyl des- amino analogue that reduced the number of synthetic steps compared to pateamine while retaining its biological activity. This was followed by the synthesis of a simplified triazole- containing analogue 9 6 ; unfortunately, this exhibited substantially reduced bioactivity compared to pateamine, and it is therefore necessary to determine if the reduction in bioactivity was due to the replacement of the thiazole ring with a triazole ring, or due to the removal of key methyl groups of pateamine. Thus, the thiazole-containing analogue of 96 is deemed to be an important synthetic target. In this Master’s project a highly simplified side chain-free analogue 130 was synthesised, which laid the groundwork for future synthesis of a thiazole-containing analogue of 96. The synthesis of 130 was achieved through a convergent synthesis with one commercially available and two prepared fragments. Particular attention was paid to the development of an efficient thiazole formation methodology, as well as optimising fragment synthesis and coupling reactions. Determination of the binding of analogue 130 with eIF4A using a competitive bioactivity assay in the presence of pateamine was then undertaken, which showed that either 130 does not bind to eIF4A or that it binds non-covalently and is then displaced by pateamine.</p>

Design and Synthesis of a Highly Simplified Pateamine Analogue

<p>Pateamine (1) is a natural product from the marine sponge Mycale hentscheli that exhibits potent anticancer properties, and has potential as an antiviral agent, and in preventing the muscle wasting disorder cachexia. This biological activity of pateamine is due to its ability to inhibit the eukaryotic initiation factor eIF4A, which leads to the formation of stress granules, the inhibition of protein synthesis, and ultimately cell death. Unfortunately, pateamine is obtained in very small amounts from Mycale hentscheli; thus, it is necessary to synthesise pateamine and novel structural analogues in the laboratory. Previously a separate binding and scaffolding domain of pateamine was proposed, which led to the synthesis of a simplified des-methyl des- amino analogue that reduced the number of synthetic steps compared to pateamine while retaining its biological activity. This was followed by the synthesis of a simplified triazole- containing analogue 9 6 ; unfortunately, this exhibited substantially reduced bioactivity compared to pateamine, and it is therefore necessary to determine if the reduction in bioactivity was due to the replacement of the thiazole ring with a triazole ring, or due to the removal of key methyl groups of pateamine. Thus, the thiazole-containing analogue of 96 is deemed to be an important synthetic target. In this Master’s project a highly simplified side chain-free analogue 130 was synthesised, which laid the groundwork for future synthesis of a thiazole-containing analogue of 96. The synthesis of 130 was achieved through a convergent synthesis with one commercially available and two prepared fragments. Particular attention was paid to the development of an efficient thiazole formation methodology, as well as optimising fragment synthesis and coupling reactions. Determination of the binding of analogue 130 with eIF4A using a competitive bioactivity assay in the presence of pateamine was then undertaken, which showed that either 130 does not bind to eIF4A or that it binds non-covalently and is then displaced by pateamine.</p>

Efficient Synthesis of Novel N-[4-Methyl-3-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)thiazol-2(3H)-ylidene]benzamide Hybrid Ring System as Potential Antibacterial Agents

Background: Heterocyclic compounds display versatile biological applications, so the aim of this paper was to prepare biologically important heterocycles with enhanced bacterial resistance and to evaluate for their various structural features that are responsible for their biological properties. Objective: The objective was to synthesize bacterial resistance compounds with enhanced antibacterial properties. Method: Ester moiety containing thiazole ring was converted into its hydrazide derivatives. These heterocyclic derivatives were cyclized into another ring oxadiazole; hence a hybrid ring system of two biologically active rings was prepared. Result: All the synthesized compounds were characterized by spectroscopic techniques and were screened for their antibacterial potential; they possess significant antibacterial activities. Conclusion: New hybrid heterocyclic ring systems were synthesized by cyclization of hydrazide derivatives by adopting two step strategy in good yields. All the synthesized compounds were evaluated for their antioxidant activities; they showed moderate to significant activities. QSAR and Molecular docking studies were performed to determine the mode of interaction. Experimental and computational data is in accordance with the determined antibacterial activities.

Pharmacological Evaluation of Novel 1,2,4-triazine Derivatives Containing Thiazole Ring Against Hepatocellular Carcinoma

Background: New 6-hydroxy-5-(p-hydroxybenzylidene)-3-phenyl-2-[(5-p-chlorophenyl)-1,3-thiazol-2-yl]-1, 2, 4-triazine derivatives containing a thiazole ring were synthesised as potential antitumor agents. Methods: Cytotoxicity of compounds (3) and (4) were evaluated in human hepatocellular carcinoma (HCC) cell lines (HepG2); compound (3) showed more cytotoxicity (IC50=9.0μg/ml) than compound (4) (IC50=18.40μg/ml) using doxorubicin as standard. The degree of toxicity of compound (3) was assessed by the LD50 with its anticancer performance by suppressing tumor angiogenesis against diethyl nitrosamine (DENA) induced hepatocellular carcinoma (HCC) in male rat model. Results : Carcinogenic rats showed a significant increase in markers of angiogenesis, tumour growth, and liver function tests and malondialdehyde level coupled by reduced hepatic glutathione level and caspase-3 activity. The distribution of compound (3) to animals after the development of HCC improved biochemical alterations from a DENA chemical carcinogen that is confirmed by hepatic histopathology. Conclusion: Compound 3 perhaps utilized as a strong applicant for newly therapeutic protocols against hepatocarcinogenesis by controlling tumor angiogenesis and renovating the activity of hepatic marker enzymes in addition reversing the oxidant-antioxidant imbalance in corporation with amelioration of histopathology. While the trial supports the use of compound 3 for improved HCC outcome and the toxicity and side effect should be considered.

Complex of Ca(II) with Ceftriaxone: Synthesis, Structure, Spectral and Antibacterial Properties

The calcium complex of ceftriaxone was synthesized and characterized by elemental, atomic-emission analysis, TGA, IR spectroscopy and density functional theory calculations. The luminescence and antibacterial properties of the ceftriaxone disodium and calcium complex were investigated. Ca(II) complex was obtained in a crystalline form, cell parameters of the compound were determined. Ceftriaxone was coordinated to the calcium ion by the oxygen of the triazine cycle in the 6th position, the nitrogen of the amine group of the thiazole ring, and the oxygens of the lactam carbonyl and carboxylate groups. The complex of Ca(II) with ceftriaxone was screened for antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, and the results were compared with the activity of ceftriaxone disodium salt

STUDY OF THE BIOLOGICAL PROPERTIES OF SEMI- AND THIOSEMICARBAZONES OF CARBONYL DERIVATIVES OF 4-BUTANOLIDES

Based on carbonyl derivatives of 4-substituted-4-butanolides, the appropriate semi- and thiosemicarbazones have been synthesized. It has been found that some representatives of thiosemicarbazones have pronounced algicidal activity against filamentous green alga Cladophora and blue-green alga (cyanobacterium) Synechocystis and some of the semi- and thiosemicarbazones exhibit moderate antitumor activity. The assessment of the antitumor activity of the compounds was carried out using strains of syngeneic and allogeneic tumor systems as test-objects: lymphocytic leukemia P-388, Lewis lung carcinoma, B16 melanoma and Ehrlich’s ascites tumor. It has also been established that some representatives of thiosemi­carbazones exhibit antimutagenic properties. It has been reliably proven that with the formation of a thiazole ring, all properties disappear and a new property in the series of thiazololactones is revealed – antibacterial․

Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis, Molecular Docking and In Vitro Studies

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing’s syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.

Novel Triarylamine-Based Hole Transport Materials: Synthesis, Characterization and Computational Investigation

Three novel triarylamine-based electron-rich chromophores were synthesized and fully characterized. Compound 1 and Compound 2 were designed with electron-rich triphenylamine skeleton bearing two and four decyloxy groups namely, 3,4-bis(decyloxy)-N,N-diphenylaniline and N-(3,4-bis(decyloxy)phenyl)-3,4-bis(decyloxy)-N-phenylaniline, respectively. The well-known electron-rich phenothiazine was introduced to diphenylamine moiety through a thiazole ring to form N,N-bis(3,4-bis(decyloxy)phenyl)-5-(10H-phenothiazin-2-yl)thiazol−2-amine (Compound 3). These three novel compounds were fully characterized and their UV–vis absorption indicated their transparency as a favorable property for hole transport materials (HTMs) suitable for perovskite solar cells. Cyclic voltammetry measurements revealed that the HOMO energy levels were in the range 5.00–5.16 eV for all compounds, indicating their suitability with the HOMO energy level of the perovskite photosensitizer. Density functional theory (DFT) and time-dependent DFT (TD-DFT) have been used to investigate the possibility of the synthesized compounds to be utilized as HTMs for perovskite solar cells (PSCs). The computational investigation revealed that the hole mobility of Compound 1 was 1.08 × 10–2 cm2 V−1 s−1, and the substitution with two additional dialkoxy groups on the second phenyl ring as represented by Compound 2 significantly boosted the hole mobility to reach the value 4.21 × 10–2 cm2V−1 s−1. On the other hand, Compound 3, in which the third phenyl group was replaced by a thiazole-based phenothiazine, the value of hole mobility decreased to reach 5.93 × 10–5 cm2 V−1 s−1. The overall results indicate that these three novel compounds could be promising HTMs for perovskite solar cells.