A facile 1,3-dipolar cycloaddition of azomethine ylides to 2-arylidene-1,3-indanediones: synthesis of dispiro-oxindolylpyrrolothiazoles and their antimycobacterial evaluation

A facile 1,3-dipolar cycloaddition of azomethine ylide generated in situ from the reaction of 1,3-thiazolane-4-carboxylic acid and isatin to 2-arylidene-1,3-indanediones furnished novel dispiro-oxindolylpyrrolothiazoles regio- and stereo-selectively in moderate to good yields (60-92%). In vitro antitubercular screening of 27 compounds against Mycobacterium tuberculosis H37Rv (MTB) disclosed that spiro[5.3']-5'-nitrooxindolespiro-[6.3″]-1H-inden-1″,3″(2H)-dione-7-(4-bromophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole has the maximum potency with a minimum inhibitory concentration (MIC) of 1.4 μM against MTB, being 3.4 and 5.4 times more potent than ciprofloxacin and ethambutol, respectively.     

A highly atom economic,chemo-, regio- and stereoselective synthesis and evaluation of spiro-pyrrolothiazoles as antitubercular agents

The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-carboxylic acid to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones afforded novel spiro-pyrrolothiazoles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB) using agar dilution method. Among the synthesized compounds, spiro[5.3′′]-5′′-nitrooxindole-spiro-[6.3′]-1′-methyl-5′-(2,4-di-chlorophenylmethylidene)tetrahydro-4′(1H)-pyridinone-7-(2,4-dichlorophenyl)tetra-hydro-1H-pyrrolo[1,2-c][1,3]thiazole (9k) was found to be the most active with a minimum inhibitory concentration (MIC) of 0.6 μM against MTB and MDR-TB.     

Reactivity models of 1-N-vinyluracil and synthesis of a new class of potential antiviral agents by the use of 1,3-dipolar cycloaddition reactions

By the use of a convergent approach based on 1,3-dipolar cycloaddition reactions between N-protected formylnitrones generated in situ and 1-N-vinyluracil, a new class of 4'-aza-analogues of 2',3'-dideoxynucleosides is synthesized. Competitive reaction for the endocyclic bond of uracil also brings to a new isoxazolidine derivative fused with the pyrimidine nucleus.     

Solution-phase synthesis of novel delta2-isoxazoline libraries via 1,3-dipolar cycloaddition and their antifungal properties

The synthesis of novel imidazolyl substituted delta2-isoxazoline libraries are currently of high interest. We report here in the full details of a study leading to the synthesis and antifungal activities of 3-(-2-butyl-4-chloro-1H-imidazolyl)-substituted delta2-isoxazolines. The solution phase synthesis of the title compounds was accomplished via 1,3-dipolar cycloaddition of in situ generated nitryl oxides from aldoximes with mono substituted alkenes to obtain the compound libraries contain an imidazole functionality in addition to the isoxazoline rings. The newly synthesized compounds when tested in vitro in solid agar culture exerted a potent antifungal activity against Aspergillus flavus, Fusarium moniliforme and Botrydiplodia theobromae also MIC values were determined. The title 5-substituted-3-imidazolyl-delta2-isoxazoline compounds represent a novel class of potent antifungal agents.     

An intramolecular 1,3-dipolar cycloaddition reaction towards the synthesis of chiral azetidine nucleoside analogues: the D-gluco case

The diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of unsaturated nitrones, derived from methyl alpha-D-glucopyranoside with 2-furaldehyde and 2-(benzyloxy)acetaldehyde has been studied In our pevious studies with 2-furaldehyde, the cycloaddition resulted 3 diastereoisomers in a 3:1:1 ratio. In this article, how the number of the possible isomers generated by 1,3-cycloaddition could be reduced from 4 to 1 when 2-(benzyloxy)acetaldehyde was employed as an aldehyde is shown.     

Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition

Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgen's 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21-23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.     

Investigation of 1,3-dipolar cycloaddition reactions of unsaturated nitrones in ionic liquids

The effect of the media (achiral and chiral ionic liquids) on the stereochemistry of intramolecular 1,3-dipolar cycloaddition reactions of D-galactose-derived omega-unsaturated nitrones, leading to bicyclic isoxazolidines, has been investigated.     

Solid-phase synthesis of methyl carboxymycobactin T 7 and analogues as potential antimycobacterial agents

A solid-phase approach for the total synthesis of methyl carboxymycobactins 1a-d, with an on-resin cyclization leading to azopine 5 as the key step, was developed. The iron-affinity of these compounds was assessed by a competitive sulfoxine-binding assay, and antimycobacterial activity was tested against the growth of Mycobacterium avium.     

Synthesis of pyrrolizidine alkaloids via 1,3-dipolar cycloaddition involving cyclic nitrones and unsaturated lactones

The 1,3-dipolar cycloaddition of cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-furanone leads to a single adduct which was transformed into 2,6-dihydroxyhastanecine via reaction sequence involving reduction of the lactone moiety, glycolic cleavage of the terminal diol, and the N-O hydrogenolysis followed by the intramolecular alkylation of the nitrogen atom.     

Design and synthesis of some new quinoline-3-carbohydrazone derivatives as potential antimycobacterial agents

A series of 26 new quinoline derivatives carrying active pharmacophores has been synthesized and evaluated for their in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv (MTB), Mycobacterium smegmatis (MC²), and Mycobacterium fortuitum following the broth micro dilution assay method. Compounds 13e, 13i, 13k, 14a, 14c, 14i, and 14k exhibited significant minimum inhibition concentrations, when compared with first line drugs isoniazid (INH) and rifampicin (RIF) and could be ideally suited for further modifications to obtain more efficacious compounds in the fight against multi-drug resistant tuberculosis.     

Efficient synthesis of linear multifunctional poly(ethylene glycol) by copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition

Poly(ethylene glycol) (PEG) is a versatile biocompatible polymer. Improvement of its limited functionality (two chain termini) may significantly expand its current applications. In this communication, a simple and yet highly efficient strategy for the synthesis of linear multifunctional PEGs with "click" chemistry is reported. A short acetylene-terminated PEG was linked by 2,2-bis(azidomethyl)propane-1,3-diol using Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition in water at room temperature. High-molecular-weight PEGs with pendant hydroxyl groups were obtained and characterized by 1H NMR and size-exclusion chromatography. A prototype bone-targeting polymeric drug delivery system was also successfully synthesized based on this new method. It demonstrates strong biomineral-binding ability and the ease of incorporating therapeutic agents into the delivery system. This simple "click" reaction approach provides a useful tool for the development of novel functional polymers and their conjugates for biomedical applications.     

Regio- and stereo-selective synthesis of carbohydrate isoxazolidines by 1,3-dipolar cycloaddition of nitrones to 5,6-dideoxy-1,2-O-isopropylidene- alpha-D-xylo-hex-5-enofuranose.

The synthesis of 2-phenyl-3-aryl and 2-phenyl-3-aroyl derivatives 5-(1,2-O-isopropylidene-alpha-D-xylo-tetrofuranos-4-yl)isoxazolidi ne (3) from nitrones and 5,6-dideoxy-1,2-O-isopropylidene-alpha-D-xylo-hex-5- enofuranose (1) is described. The 1,3-dipolar cycloaddition reactions given mainly anti adducts 3 and 4 (greater than or equal to 95% pi-facial stereoselectivity). The cycloadducts 3 with H-3,5 cis are formed either exclusively or preponderate over the trans diastereoisomers 4.     

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents

A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4′-(4-bromophenyl)-1′-methyldispiro[acenaphthylene-1,2′-pyrrolidine-3′,2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.     

Triazole-fused sugars from nitroalkene-containing C-glycosides by a tandem 1,3-dipolar cycloaddition and intramolecular Michael addition

A synthetic method to triazole-fused sugars by treatment of nitroalkene-containing C-glycosides with sodium azide is described. Initial experiments conducted at room temperature gave only the 1,3-dipolar cycloaddition products. However, at elevated reaction temperature the tandem β-elimination/cycloaddition/Michael addition yielded 1,5-disubstituted triazole-fused sugars.     

Discovery of benzothiazole amides as potent antimycobacterial agents

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12?μg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1–2?μg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.     

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.     

Preparation of 18F-labeled peptides using the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition

An optimized procedure for preparing fluorine-18 ((18)F)-labeled peptides by the copper-catalyzed azide-alkyne 1,3-dipolar cyloaddition (CuAAC) is presented here. The two-step radiosynthesis begins with the microwave-assisted nucleophilic (18)F-fluorination of a precursor containing a terminal p-toluenesulfonyl, terminal azide and polyethylene glycol backbone. The resulting (18)F-fluorinated azide-containing building block is coupled to an alkyne-decorated peptide by the CuAAC. The reaction is accelerated by the copper(I)-stabilizing ligand bathophenanthroline disulfonate and can be performed in either reducing or nonreducing conditions (e.g., to preserve disulfide bonds). After an HPLC purification, (18)F-labeled peptide can be obtained with a 31 ± 6% radiochemical yield (n = 4, decay-corrected from (18)F-fluoride elution) and a specific activity of 39.0 ± 12.4 Ci μmol(-1) within 77 ± 4 min.     

Design and synthesis of 1,3-benzothiazinone derivatives as potential anti-inflammatory agents

A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD₅₀ value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE₂ level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.     

Chemo- and stereoselective synthesis of benzocycloheptene and 1-benzoxepin derivatives as alpha-sympathomimetic and anorexigenic agents

The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols 4a-c and 5a-c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d-f and 5d-f were carried out. Chemo- and stereoselective synthesis of 5a-f was achieved by reduction of corresponding alpha-amino ketones 3a-f with LiAl(t-BuO)3H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD50 800 and 500 mg/kg and ED50 75 and 55 mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical alpha-sympathomimetic activity.     

Discovery of novel phenoxyacetic acid derivatives as antimycobacterial agents

A series of 2-{4-[1-amino (thioxo) methyl-5-(substituted phenyl)-4,5-dihydro-1H-3-pyrazolyl]-2-methoxyphenoxy}acetic acid and 2-{4-[1-carbamoyl-5-(substituted phenyl)-4,5-dihydro-1H-3-pyrazolyl]-2-methoxyphenoxy}acetic acid were synthesized and the in vitro activity of the synthesized compounds against Mycobacterium tuberculosis H37Rv (MTB) and INH-resistant M. tuberculosis (INHR-MTB) was studied. Among the synthesized compounds, compound (3f) 2{-[4-(1-carbamoyl-5-(chlorophenyl)-4,5-dihydro-1H-3-pyrazolyl]-2-methoxyphenoxy}acetic acid was found to be the most active against M. tuberculosis H37Rv (MTB) and INH-resistant M. tuberculosis (INHR-MTB) with minimum inhibitory concentration of 0.06 microg/ml.