High pressure assisted synthetic approach for novel 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline derivatives and their assessment as anticancer agents.

A novel, expedient and effective methodology for the synthesis of distinctly substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline systems has been developed with a new synthetic platform. This process includes ammonium acetate-mediated cyclocondensation reactions of 3-oxo-2-arylhydrazonopropanals with benzosuberone and tetralone precursors, respectively, using the high-pressure Q-tube reactor, which has been found to be superior to both conventional heating and microwave irradiation. The novel protocol benefits from its high atom efficiency, economy, ease of workup, broad substrate scope and is also applicable to gram-scale synthesis. To identify and confirm the newly synthesized targeted compounds, the X-ray single-crystal as well as all possible spectroscopic methods were utilized. The cytotoxicity of the newly synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j and 5,6-dihydrobenzo-[h]quinolines derivatives 6a-e were preliminary examined toward three cell lines of human cancer; lung cancer (A549), breast cancer (MCF-7) and colon cancer (HCT-116), by applying the MTT colorimetric assay. The achieved results reflected the promising profile of the prepared compounds in this study against cancer cells and have shown that members from the synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j exhibited promising cytotoxicity's against MCF-7, and A549 cancer cells respectively, while the HCT-116 (colon) cancer cells were inhibited by certain examples of 5,6-dihydrobenzo[h]quinoline derivatives 6c,d. These promising results could serve as a good primary base for further research into the design of anticancer drugs.

Synthesis of Five and Six-Membered Heterocycles Using Activated Nitriles for Industrial Applications.

The aim of this study is a synthesis of new bioactive heterocyclic compounds incorporated fatty chain for use in different industrial applications. Cyanoacetamide derivative (2) was successfully transferred into five and six membered heterocyclic derivatives by the reaction with various chemical reagents. Addition number of moles of propylene oxide to these compounds gave nonionic surface-active agents having a good solubility, biodegradability and hence lowers the toxicity to human beings and becomes environmentally friendly. The antimicrobial and surface activities were investigated that showed the most of them have pronounced activity, which makes them suitable for diverse applications like the manufacturing of drugs, pesticides, emulsifiers, cosmetics, etc.

Synthesis and toxicity assessment of 3-oxobutanamides against human lymphocytes and isolated mitochondria.

To reduce costly late-phase compound scrubbing, there has been an increased focus on assessing compounds within in vitro assays that predict properties of human safety liabilities, before preclinical in vivo studies. The aim of our study was to answer the questions that whether the toxicity risk of a series of 3-oxobutanamide derivatives could be predicted by using of human lymphocytes and their isolated mitochondria. Using biochemical and flow cytometry assessments, we demonstrated that exposure of lymphocytes and isolated mitochondria to five 3-oxobutanamide derivatives (1-5) did not exhibit remarkable toxicity at low concentrations (50-500µM) but toxicity could be observed at high concentrations (1000 and 2000µM), particularly for N-(5-(4-bromophenyl)-3-isoxazolyl)-3-oxobutanamide (4) and N-(2-benzothiazolyl)-3-oxo butanamide (5). Compounds 4, 5 and partly N-(5-methyl-3-isoxazol yl)-3-oxo butanamide (1) also showed a marked cellular and mitochondrial toxicity while compound 5 displayed superior toxicity. Compound 5 induced cytotoxicity on human blood lymphocytes which was associated with the generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation and depletion of glutathione. Our results suggested that among assessed compounds, increased toxicity of compound 5 compared to other compounds could be likely attributed to the presence of bromine substituent in 5. Finally our findings proposed that using of antioxidants and mitochondrial/lysosomal protective agents could be beneficial in decreasing the toxicity of 5.

Use of Phthalimidoacetyl Isothiocyanate as a Scaffold in the Synthesis of Target Heterocyclic Systems, and Their Antimicrobial Assessment.

Phthalimidoacetyl isothiocyanate underwent addition-cyclization reactions with some nitrogen and carbon nucleophilic reagents. Simultaneous or subsequent cyclization of the obtained adducts gave target heterocyclic systems such as 1,2,4-triazoles, 1,3-diazines, 1,3-oxazines and thiourea attached to a phthalimido moiety. The antimicrobial activity of the synthesized compounds was tested.

Synthesis, relaxation properties and in vivo assessment of a carborane-GdDOTA-monoamide conjugate as an MRI blood pool contrast agent.

The synthesis, relaxivity measurements and in vivo assessment of a carborane-GdDOTA-monoamide (CB-GdDOTA-MA) amphiphilic conjugate as a blood pool contrast agent (BPCA) is reported. This BPCA exhibited excellent binding (87.4%) with human serum albumin (HSA) and showed a higher relaxivity value (r1 = 6.8 mM(-1) s(-1), 7 T) as compared to the clinically used BPCA, MS-325 (r1 = 5.1 mM(-1) s(-1), 9.4 T) in PBS. The blood pool contrast enhancement (CE) capability of CB-GdDOTA-MA was evaluated by performing MR angiography (MRA) in CF1 mice (n = 4) at a Gd dose of 0.1 mmol per kg body weight. The significant CE of blood vessels persisted for about 3-4 min post-injection (p.i.) and quickly diminishes over time. The significant CE of the bladder for up to 3 h p.i. indicated that the renal system is the primary clearance pathway for CB-GdDOTA-MA. However, the CE of liver tissues and intestine (up to 24 h p.i.) is suggestive of a significant hepatic uptake of the CB-GdDOTA-MA.

Gold-catalyzed 1,2-acyloxy migration/intramolecular [3+2] 1,3-dipolar cycloaddtion cascade reaction: an efficient strategy for syntheses of medium-sized-ring ethers and amines.

A highly efficient strategy for the formation of medium-sized-ring ethers and amines based on a gold-catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium-sized-ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium-sized ring synthesis.

A step-economical route to fused 1,2,3-triazoles via an intramolecular 1,3-dipolar cycloaddition between a nitrile and an in situ generated aryldiazomethane.

An intramolecular 1,3-dipolar cycloaddition strategy for rapid entry into triazole-fused heterocyclic compounds without recourse to the traditional Cu(1)-catalyzed azide-alkyne cycloadditions is described. Central to the strategy is the in situ generation of substituted diazomethanes in a two-step sequence from the corresponding aldehydes, which then undergo smooth cycloaddition with a cyano group to generate the desired fused 1,2,3-triazoles in good overall yields. The entire sequence can be carried out in a one-pot operation.

Cobalt- and iron-catalyzed redox condensation of o-substituted nitrobenzenes with alkylamines: a step- and redox-economical synthesis of diazaheterocycles.

A wide variety of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines. The cascade including benzylamine oxidation, nitro reduction, condensation, and aromatization occurs without any added reducing or oxidizing agent. The method can be extended to other alkylamines as reducing components or 2-nitrobenzamides as oxidizing components when using an iron/sulfur catalyst to afford various diazaheterocycles.

Bile acid-based 1,2,4-trioxanes: synthesis and antimalarial assessment.

A new series of bile acid-based trioxanes 23a-d, 24a-d, 25a-d, 26a, 26b, and 26d have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. The antimalarial activity of these trioxanes showed a strong dependence on the side-chain length; shortening side-chain length lead to increase in activity. The antimalarial activity also showed even stronger dependence on the stereochemistry at C3 and C6 (C21 in Figure 5) of the trioxane moiety. Of the two diastereomers isolated of each of the trioxanes, more polar one was significantly more active than the less polar one. The more polar diastereomer of the trioxanes 26a, 26b, and 26d, were the most active compounds of the series. All these three trioxanes provided 100% protection at 24 mg/kg×4 days. In this model ß-arteether provided 100% and 20% protection at 48 mg/kg×4 days and 24 mg/kg×4 days, respectively.

Atom-economical synthesis of N-heterocycles via cascade inter-/intramolecular C-N bond-forming reactions catalyzed by Ti amides.

Direct and efficient catalytic reactions with excellent regioselectivity for the preparation of a series of substituted isoindoles, isoquinolines, and imidazoles are reported. Reaction of C(6)H(4)(2-CN)C[triple bond]C-R with an array of amines, catalyzed by 10 mol % of [sigma:eta(1):eta(5)-(OCH(2))(Me(2)NCH(2))C(2)B(9)H(9)]Ti(NMe(2)) (1), gives a series of substituted isoindoles in very high yields. In a similar manner, interaction of C(6)H(4)(2-CH(2)CN)C[triple bond]C-Ph with various kinds of amines affords a wide range of substituted isoquinolines. On the other hand, treatment of propargylamines (R'C[triple bond]CCH(2)NHR'') with nitriles in the presence of 10 mol % of 1 produces a class of substituted imidazoles in high yields. A possible reaction mechanism is proposed, involving sequential inter- and intramolecular C-N bond formation via hydroamination/cyclization reaction of cyanoalkynes with amines or nitriles with propargylamines catalyzed by titanium amides.

Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols.

Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.

Greener and sustainable approaches to the synthesis of pharmaceutically active heterocycles.

Green chemistry is a rapidly developing field providing a proactive avenue for the sustainable development of future science and technology. Green chemistry can be applied to the design of highly efficient, environmentally benign synthetic protocols to deliver life-saving medicines, and to accelerate lead optimization processes in drug discovery, while minimizing environmental impact. It also offers enhanced chemical process economics, concomitant with a reduced environmental burden. This review summarizes relatively environmentally benign protocols for the synthesis of pharmaceutically active heterocycles that highlight the advantages of using green chemistry, for example, by proceeding under microwave irradiation or in aqueous reaction media.

Orally active 1,2,4-trioxanes: synthesis and antimalarial assessment of a new series of 9-functionalized 3-(1-arylvinyl)-1,2,5-trioxaspiro[5.5]undecanes against multi-drug-resistant plasmodium yoelii nigeriensis in mice.

Using easily accessible keto-trioxanes 7a-g as the starting materials, a series of new variously functionalized 1,2,4-trioxanes 10-36 have been prepared and evaluated for antimalarial activity against multi-drug-resistant Plasmodium yoelii nigeriensis in mice in the dose range of 24 mg/kg x 4 days to 96 mg/kg x 4 days by oral route. Trioxanes 10, 12, 14, 16, 18, 20, and 22 have shown promising antimalarial activity. Trioxanes 14 and 18, the two most active compounds of the series, provide 100% and 60% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively. In this model beta-arteether provides 100% and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively.

Solid-supported copper catalysts for atom-transfer radical cyclizations: assessment of support type and ligand structure on catalyst performance in the synthesis of nitrogen heterocycles.

A range of solid supported pyridinemethanimine 9-11 and polyamine 12-15 ligands have been prepared on silica, polystyrene, and JandaJel supports. The CuCl and CuBr complexes of these supported ligands have been used to assess both the effect of the ligand type and the nature of the support upon a representative range of copper-mediated atom transfer 5-exo-trig 6, 24-25, 5-exo-dig 26, 4-exo-trig 28, and 5-endo-trig 27, 38 radical cyclizations to give nitrogen heterocycles. In addition, the effect of the nature of the support on the stereochemical outcome of the 5-exo cyclization of 25 has been probed. Generally, it was found that the type of support (e.g., polystyrene, silica, or JandaJel) had very little effect upon the efficiency and selectivity of the processes but that the nature of the ligand type immobilized was the important factor. Thus, the 5-exo cyclization of 6 and 24-26 proceeded more rapidly with the PMI ligands 9-11, whereas 4-exo cyclizations 28 and 5-endo radical polar crossover reactions 27 and 38 proceeded more efficiently with the JJ-TEDETA ligand 15. The efficiency of the supported ligands was also compared to their solution counterparts 4 and 5. The reusability of P-PMDETA ligand system 13 was assessed in the cyclization of 6.