Synthesis and characterization of a pH/temperature-dual responsive hydrogel with promising biocompatibility features for stimuli-responsive 5-FU delivery.

The tunable properties of stimuli-responsive copolymers or hydrogels enable their application in different fields such as biomedical engineering, tissue engineering, or even drug release. Here we introduce a new PNIPAM-based triblock copolymer material comprising a controlled amount of a novel hydrophobic crosslinker 2,4'-diacryloyloxy benzophenone (DABP) and acrylic acid (AAc) to achieve lower critical solution temperature (LCST) between ambient and body temperatures. The dual stimuli-responsive p(NIPAM-co-DABP-co-AAc) triblock copolymer material and hydrogel were synthesized, and their temperature and pH-responsive behaviors were systematically investigated. The hydrogel exhibited excellent temperature and pH-responsive properties with an LCST of around 30 °C. Moreover, the synthesized copolymer has been demonstrated to be nontoxic both in vitro and in vivo. When the hydrogel was preloaded with the model drug 5-fluorouracil (5-FU), the designed hydrogel released the drug in a temperature and pH-controlled fashion. It was observed that the prepared hydrogel has the ability to entrap 5-FU, and the loading is more than 85%. In the case of temperature-controlled release, we observed almost complete release of 5-FU at lower temperatures and sustained release behavior at higher temperatures. In addition, the hydrogel matrix was able to retard the release of 5-FU in an acidic environment and selectively release 5-FU in a basic environment. By realizing how the hydrogel properties influence the release of drugs from preloaded hydrogels, it is possible to design new materials with myriad applications in the drug delivery field.

Ruthenium (II) Catalyzed C(sp2 )-H Bond Alkenylation of 2-Arylbenzo[d]oxazole and 2-Arylbenzo[d]thiazole with Unactivated Olefins.

Functionalization of the bio-relevant heterocycles 2-arylbenzo[d]oxazole and 2-arylbenzo[d]thiazole has been achieved through Ru(II)-catalyzed alkenylation with unactivated olefins leading to selective formation of the mono-alkenylated products. This approach has a broad substrate scope with respect to the coupling partners, affords high yields, and works for gram scale synthesis using a readily available Ru-based catalyst. Mechanistic studies reveal a C-H activation pathway for the dehydrogenative coupling leading to the alkenylation. However, the results of the ESI-MS-guided deuterium kinetic isotope effect studies indicate that the C-H activation stage may not be the rate-determining step of the reaction. The use of a radical scavenging agent such as TEMPO did not show any detrimental effect on the reaction outcome, eliminating the possibility of the involvement of a free-radical pathway.

Cyclic enaminone as new chemotype for selective cyclooxygenase-2 inhibitory, anti-inflammatory, and analgesic activities.

The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.

Transient-Ligand-Enabled ortho-Arylation of Five-Membered Heterocycles: Facile Access to Mechanochromic Materials.

Reported herein is the first example of a direct arylation of heteroarenes by a transient-ligand-directed strategy without the need to construct and deconstruct the directing group. A wide range of heteroarenes undergoes the coupling with diverse aryl iodides to assemble a large library of highly selective and functionalized 3-arylthiophene-2-carbaldehydes. This route provides an opportunity to rapidly access new mechanofluorochromic materials. Moreover, a novel strategy for mechanochromic luminogens with chromism trends of red- and blue-shifts has been disclosed for the first time by facile functional-group modifications to a common structural core.

Microwave Assisted Synthesis of Biorelevant Benzazoles.

The benzazole scaffolds are present in various therapeutic agents and have been recognized as the essential pharmacophore for diverse biological activities. These have generated interest and necessity to develop efficient synthetic methods of these privileged classes of compounds to generate new therapeutic leads for various diseases. The biological activities of the benzazoles and efforts towards their synthesis have been summarized in a few review articles. In view of these, the aim of this review is to provide an account of the developments that have taken place in the synthesis of biorelevant benzazoles under microwave irradiation as the application of microwave heating has long been recognized as a green chemistry tool for speedy generation of synthetic targets. Attention has been focused to those literature reports wherein the use of microwave irradiation is the key step in the formation of the heterocyclic ring system or in functionalization of the benzazole ring system to generate the essential pharmacophoric feature. The convenient and economic way to synthesize these privileged class of heterocycles through the use of microwave irradiation that would be beneficial for the drug discovery scientist to synthesize biologically active benzazoles and provide access to wide range of reactions for the synthesis of benzazoles constitute the theme of this review. Examples have been drawn wherein the use of microwave heating offers distinct advantage in terms of improved product yields and reduction of reaction time as compared to those observed for the synthesis under conventional heating.

Synchronous double C-N bond formation via C-H activation for a novel synthetic route to phenazine.

A novel synthetic strategy for phenazine formation is reported following self-coupling of anilines by Pd-Ag binary nanocluster-catalysed synchronous double C-N bond formation via non-radical mode of ortho-aryl C-H activation.

Palladium catalyzed Csp2-H activation for direct aryl hydroxylation: the unprecedented role of 1,4-dioxane as a source of hydroxyl radicals.

A novel strategy for direct aryl hydroxylation via Pd-catalysed Csp(2)-H activation through an unprecedented hydroxyl radical transfer from 1,4-dioxane, used as a solvent, is reported with bio relevant and sterically hindered heterocycles and various acyclic functionalities as versatile directing groups.

2-(2-Arylphenyl)benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation.

The 2-(2-arylphenyl)benzoxazole moiety has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The 2-(2-arylphenyl)benzoxazoles 3a-m have been synthesized by Suzuki reaction of 2-(2-bromophenyl)benzoxazole. Further synthetic manipulation of 3f and 3i led to 3o and 3n, respectively. The compounds 3g, 3n, and 3o selectively inhibited COX-2 with selectivity index of 3n much better than that of the COX-2 selective NSAID celecoxib. The in vivo anti-inflammatory potency of 3g and 3n is comparable to that of celecoxib and the nonselective NSAID diclofenac at two different doses, and 3o showed better potency compared to these clinically used NSAIDs.

Cooperative catalysis by palladium-nickel binary nanocluster for Suzuki-Miyaura reaction of ortho-heterocycle-tethered sterically hindered aryl bromides.

The palladium-nickel binary nanocluster is reported as a new catalyst system for Suzuki-Miyaura cross-coupling of ortho-heterocycle-tethered sterically hindered aryl bromides. The inferior results obtained with the reported Pd/Ni salts/complexes or individual Pd/Ni nanoparticles as catalyst reveal the cooperative catalytic effect of the Pd and Ni nanoparticles in the Pd-Ni nanocluster. The broad substrate scope with respect to variation of the 2-arylbenzoxazole moiety and boronic acids, which offers a means for diversity generation and catalyst recyclability, marks a distinct advantage.

Synergistic dual activation catalysis by palladium nanoparticles for epoxide ring opening with phenols.

Synergistic dual activation catalysis has been devised for epoxide phenolysis wherein palladium nanoparticles induce electrophilic activation via coordination with the epoxide oxygen followed by nucleophilic activation through anion-π interaction with the aromatic ring of the phenol, and water (reaction medium) also renders assistance through 'epoxide-phenol' dual activation.

Protecting group-free concise synthesis of (RS)/(S)-lubeluzole.

Three new, concise, and protecting group-free synthetic routes for (RS)- and (S)-lubeluzole are reported in higher (46-62%) overall yields compared to the reported procedures (6-35%). The key steps involve C-N bond formation via epoxide aminolysis and nucleophilic substitution of 2-chlorobenzothiazole with suitably designed precursor amines and are performed in aqueous medium. Water offers an advantage in promoting the reactions compared to organic solvents and its role is envisaged as hydrogen-bond mediated electrophile-nucleophile dual activation.