Synthesis and evaluation of some new 5-(hetaryl)thiazoles as potential antimicrobial agents

In continuing our efforts to find new effective antimicrobial agents for overcoming the problem of microbial resistance, a new series of functionalized 5-hetarylthiazoles have been designed and synthesized starting from readily accessible 1-(2-allylamino-4-methylthiazol-5-yl)ethanone (3). The structures of newly synthesized compounds were confirmed by elemental analyses, spectral data, and chemical transformations. The synthesized compounds were evaluated in vitro for their antimicrobial activity against some human pathogenic bacterial and fungal strains. The compounds 7, 18, and 24 exhibited higher antibacterial activity with minimum inhibitory concentration (MIC) values ranging from (0.03–0.06?µg/mL) than ampicillin (MIC, 0.12?µg/mL) against Streptococcus pneumoniae. Whereas compounds 4, 22, and 24 revealed higher antifungal potency than amphotericin B against Aspergillus fumigatus. The structure and antimicrobial activity relationship was also discussed.     

Gadolinium(III)-loaded nanoparticulate zeolites as potential high-field MRI contrast agents: relationship between structure and relaxivity

The effects of dealumination, pore size, and calcination on the efficiency (as expressed in the relaxivity) of Gd3+-loaded zeolites for potential application as magnetic resonance imaging (MRI) contrast agents were studied. Partial dealumination of zeolites NaY or NaA by treatment with (NH4)2SiF6 or diluted HCl resulted in materials that, upon loading with Gd3+, had a much higher relaxivity than the corresponding non-dealuminated materials. Analysis of the 1H NMR dispersion profiles of the various zeolites showed that this can be mainly ascribed to an increase of the amount of water inside the zeolite cavities as a result of the destruction of walls between cavities. However, the average residence time of water inside the Gd3+-loaded cavities did not change significantly, which suggests that the windows of the Gd3+-loaded cavities are not affected by the dealumination. Upon calcination, the Gd3+ ions moved to the small sodalite cavities and became less accessible for water, resulting in a decrease in relaxivity. The important role of diffusion for the relaxivity was demonstrated by a comparison of the relaxivity of Gd3+-loaded zeolite NaY and NaA samples. NaA had much lower relaxivities due to the smaller pore sizes. The transversal relaxivities of the Gd3+-doped zeolites are comparable in magnitude to the longitudinal ones at low magnetic fields (<60 MHz). However at higher fields, the transversal relaxivities steeply increased, whereas the longitudinal relaxivities decreased as field strength increased. Therefore, these materials have potential as T1 MRI contrast agents at low field, and as T2 agents at higher fields.     

Synthesis and biological evaluation of novel (99m)Tc-labelled bisphosphonates as superior bone imaging agents

A series of novel zoledronic acid (ZL) derivatives 1-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid (MIPrDP), 1-hydroxy-4-(2-methyl-1H-imidazol-1-yl)butane-1,1-diyldiphosphonic acid (MIBDP), and 1-hydroxy-5-(2-methyl-1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (MIPeDP) were prepared and successfully labeled with (99m)Tc in high labeling yields. The in vitro stability and in vivo biodistribution of (99m)Tc-MIPrDP, (99m)Tc-MIBDP and (99m)Tc-MIPeDP were investigated and compared. The biodistribution studies indicate that the radiotracer (99m)Tc-MIPrDP has highly selective uptake in the skeletal system and rapid clearance from soft tissues. The present findings indicate that (99m)Tc-MIPrDP holds great potential for use in bone imaging.     

Synthesis and evaluation of a series of 99mTc-labelled zoledronic acid derivatives as potential bone seeking agents

Developing novel superior bone-seeking radiopharmaceuticals for the detection of malignant bone lesions could further improve the diagnostic value of routine bone scanning. A series of radiolabeled diphosphonates (^99mTc-EIPrDP, ^99mTc-EIBDP and ^99mTc-EIPeDP) have been designed and synthesized successfully in high chemical yields and radiochemical purity. The in vitro and in vivo biological properties were systematically investigated and compared. The biodistribution in mice shows that ^99mTc-EIPrDP has higher bone uptake (13.3 ± 1.23) than those of ^99mTc-EIBDP and ^99mTc-EIPeDP (11.7 ± 0.28 and 8.69 ± 0.04 %ID/g) at 1–2 h post injection. It also has the highest uptake ratio of bone to muscle, spleen and heart, respectively, and faster blood clearance in early times. The present study indicates that ^99mTc-EIPrDP holds great promise as a bone imaging agent.     

Synthesis and biological evaluation of novel oxophenylarcyriaflavins as potential anticancer agents

We report the synthesis and biological evaluation of new oxophenylarcyriaflavins designed as potential anticancer agents. An efficient synthesis involving palladium-catalyzed Suzuki and Stille reactions is presented, without any indolic protective group. The central ring closure of the scaffold was performed through an electrophilic reaction on the position C-2 of the indole ring. The use of indole and 5-benzyloxyindole, along with substituted phenyl rings, generated three different scaffolds, which were successively exploited to modulate the structure. The cytotoxicity of the newly designed compounds on four cancer cell lines and activities against three kinases (CDK1, CDK5 and GSK3) were evaluated. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range, and induced important cell cycle perturbations, with a G2/M arrest. Some compounds revealed DNA binding properties and were found to inhibit topoisomerase-mediated DNA relaxation of supercoiled DNA, but these properties are not mandatory for a cytotoxic action. A novel lead compound () has been identified and warrants further investigations.     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

Synthesis and in vitro studies of Gd-DTPA derivatives as new potential MRI contrast agents

A new type of dendritic molecules, Gd-DTPA derivatives, which work as a functionalized ligand coordinating gadolinium(III) ion at the center of their frameworks with different terminal moieties on the molecular surfaces, was readily synthesized with high yield. The structures were established by ¹H, ¹³C NMR, and mass spectral studies. In vitro studies showed them to have enhanced r₁ value in albumin medium and good potentiality as MRI contrast agent.     

Hydroxy double salts intercalated with Mn(II) complexes as potential contrast agents

A series of Mn(II) aminophosphonate complexes were successfully synthesized and intercalated into the hydroxy double salt [Zn₅(OH)₈]Cl₂·yH₂O. Complex incorporation led to an increase in the interlayer spacing from 7.8 to 10–12 Å. Infrared spectroscopy showed the presence of the characteristic vibration peaks of the Mn(II) complexes in the intercalates' spectra, indicating successful incorporation. The complex-loaded composites had somewhat lower proton relaxivities than the pure complexes. Nevertheless, these intercalates may have use as MRI contrast agents for patients with poor kidney function, where traditional Gd(III)-based contrast agents cause severe renal failure.     

Synthesis of multimeric MR contrast agents for cellular imaging

We have prepared a series of molecular multimeric MR contrast agents for cell labeling that are easy to synthesize, relatively low molecular weight, and biocompatible. The relaxivities of the agents range from 17 to 85 mM(-1) s(-1). Cellular uptake is concentration dependent and viability is excellent. MR images of cell pellets reveal a marked increase in observed signal intensity.     

Synthesis and biological evaluation of new pyrrolopyrazinone compounds as potential antitumor agents

A series of pyrrolo[1,2-a]pyrazinone compounds(5a-9f) were synthesized,and their cytotoxic activity against SKOV-3,A549.HeLa cells in vitro were evaluated by the MTT method.Some of the compounds showed potential antitumor activity against three tumor cell lines.Among them,compounds 9c and 9d showed the most potent cytotoxic activity.The preliminary mechanism of action was discussed.     

Synthesis and biological evaluation of novel acenaphthene derivatives as potential antitumor agents

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by 1H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.     

Synthesis and preliminary cytotoxic evaluation of substituted indoles as potential anticancer agents

A variety of indole derivatives were designed,synthesized and preliminarily evaluated for their in vitro cytotoxic activity in the A431 and H460 cell lines.All the compounds examined conferred unusual potency in a tumor cell cytotoxicity assay.The findings showed the indole derivatives would be a promising candidate for the development of new anticancer agents.     

Synthesis of a tricyclic tetraazatriacetic ligand for gadolinium(III) as potential contrast agent for MRI

A tricyclic tetraazatriacetic compound, which is a rigidified derivative of PCTA12 ligand with a cyclohexylene bridge replacing an ethylene one, was prepared. Two synthetic routes have been investigated, both of them implying a common functionalized triamine intermediate. Whatever the route, four synthetic steps were necessary to obtain the target tricyclic ligand. The more effective one (Route B) led to the desired compound in 19% overall yield from the triamine intermediate. The corresponding gadolinium complex of 1/1 stoichiometry was then prepared in order to evaluate it as potential contrast agent for MRI.     

Synthesis and evaluation of novel ascorbyl cinnamates as potential anti-oxidant and antimicrobial agents

Research on Chemical Intermediates - An efficient preparation procedure has been proposed for the synthesis of 5,6-di-O-cinnamyl-l-ascorbic acid ester (5,6-CA–AA) and 2-O-cinnamyl-l-ascorbic...     

Synthesis and functional evaluation of chiral dendrimer-triamine-coordinated Gd complexes as highly sensitive MRI contrast agents

Novel chiral dendrimer-triamine-coordinated Gd complexes were synthesized and shown to have longitudinal relaxivity (r1) 3 times higher than that of clinically used Gd-DTPA. The pharmacokinetic differences between optical isomers were estimated from the affinity of 2-(R) and 2-(S) with bovine serum albumin (BSA), respectively, by a quartz crystal microbalance (QCM) measurement. As a result, the association constant K_a of 2-(S) was about 4 times higher than that of 2-(R), which means that 2-(S) is retained in the vascular retention for a longer time after administration. This result was also supported by T1-weighted MR images of mice before and after the intravenous injection of 2-(R) and 2-(S), as well as the time-course of the signal intensities (SI) at the blood vessels and quantification of Gd³⁺ concentration in the blood and urine.     

Synthesis of 3'-beta-carbamoylmethylcytidine (CAMC) and its derivatives as potential antitumor agents

3'-beta-Carbamoylmethylcytidine (CAMC) and its derivatives were synthesized using an intramolecular Reformatsky-type reaction promoted by SmI2 as the key step. In vitro tumor cell growth inhibitory activity was evaluated and CAMC was found to exhibit potent cytotoxicity against various human tumor cell lines. From a structure-activity relationship study it was postulated that the cytotoxic mechanism of action of CAMC did not require phosphorylation at the 5'-hydroxyl group. This study provides a novel strategy for the development of a new type of antitumor nucleoside.     

Synthesis and biological evaluation of some novel thiadiazole-benzofuran hybrids as potential antitumor agents

Two series of novel 1,3,4-thiadiazole-benzofuran and 1,3,4-thiadiazole-furochromene derivatives were synthesized through heterocyclization of alkyl 2-(1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)hydrazine-1-carbodithioate 3a–f and 2-(1-(5-methoxy-8-methyl-2,6-dioxo-2,6-dihydropyrano[3,2-g]chromen-3-yl)ethylidene)hydrazinecarbothioamide 9a,b with various hydrazonoyl halides, respectively. The structure of the newly synthesized products was elucidated through elemental analysis, spectral data and alternative routes whenever possible. Ten new compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF-7) cell lines in comparison with reference doxorubicin using MTT assay. The results showed that some new compounds have promising anticancer activity.     

The synthesis and evaluation of trimeric X-ray contrast agents

Novel trimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the aim of improving the already good safety profile of such agents. While the aim of low osmolality was achieved, the viscosity of the trimeric agents was found to be generally higher than current dimeric agents in clinical use.     

Synthesis of bis(2-chloroethyl)amino-1,8-naphthyridines for evaluation as anticancer agents

Some 1,8-naphthyridine nitrogen mustards have been synthesized for studies of their antitumor potentialities. All the tested intermediate and target compounds are devoid of antitumor properties.     

Synthesis of DTPA analogues derived from piperidine and azepane: potential contrast enhancement agents for magnetic resonance imaging.

Two DTPA derivatives (PIP-DTPA and AZEP-DTPA) as potential contrast enhancement agents in MRI are synthesized. The T1 and T2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the contrast agent, Gd(DTPA) which is in clinical use. The serum stability of the (153)Gd-labeled complexes is assessed by measuring the release of (153)Gd from the ligands. The radiolabeled Gd chelates are found to be kinetically stable in human serum for up to at least 14 days without any measurable loss of radioactivity.