Chitosan-PVA-PVP/nano-clay composite: a promising tool for controlled drug delivery.

In this study, chitosan, polyvinyl alcohol (PVA), and polyvinyl pyrrolidone (PVP) were used to create ternary blends reinforced with organically modified montmorillonite nanoclay. Tramadol was used as a model drug to assess the efficacy of these ternary blends as drug delivery systems. The current work demonstrated the highly controlled release of tramadol via transdermal administration. The results of the FTIR investigation revealed the compatibility of the blending components. Among non-drug-loaded formulations, MC6 is the most stable with a 17.6% weight residue at 505 °C and MC11 is the most stable of all the drug-loaded and non-drug-loaded formulations with a weight residue of 22.0% at 505 °C. The XRD studies of the prepared formulations showed crystalline behavior. However, the SEM analysis revealed that no gaps or mixing components were uniformly dispersed in the nanocomposites. Pharmaceutical tests, such as swelling, dissolution, and permeation rates, revealed a strong influence of the PVA concentration. There was a uniform distribution of drug throughout the films with maximum encapsulation efficiency found for MC7 (96.09 ± 0.31) and minimum encapsulation efficiency for MC11 (90.56 ± 0.34)%. Compared to the sodium acetate (pH 4.5) and potassium phosphate buffers (pH 6.8) the swelling and erosion were higher in hydrochloric acid buffer (pH 1.2). An increase in PVA concentration (or decrease in PVP concentration) increases the swelling, dissolution, and permeation rates. In addition, erosion increased with increasing PVP concentration. Furthermore, the nanoclay-reinforced composite showed high permeation. Based on the obtained results, it can be concluded that the produced nanocomposite could be used as an efficient transdermal drug delivery system.

Chemical insights into the synthetic chemistry of five-membered saturated heterocycles-a transition metal-catalyzed approach.

Drug design and delivery is primarily based on the hunt for new potent drug candidates and novel synthetic techniques. Recently, saturated heterocycles have gained enormous attention in medicinal chemistry as evidenced by the medicinal drugs listed in the FDA Orange Book. Therefore, the demand for novel saturated heterocyclic syntheses has increased tremendously. Transition metal (TM)-catalyzed reactions have remained the prime priority in heterocyclic syntheses for the last three decades. Nowadays, TM catalysis is well adorned by combining it with other techniques such as bio- and/or enzyme-catalyzed reactions, organocatalysis, or using two different metals in a single catalysis. This review highlights the recent developments of the transition metal-catalyzed synthesis of five-membered saturated heterocycles.

An insight into recent developments of copper, silver and gold carbon dots: cancer diagnostics and treatment.

Cancer is one of the most fatal diseases globally, however, advancement in the field of nanoscience specifically novel nanomaterials with nano-targeting of cancer cell lines has revolutionized cancer diagnosis and therapy and has thus attracted the attention of researchers of related fields. Carbon Dots (CDs)-C-based nanomaterials-have emerged as highly favorable candidates for simultaneous bioimaging and therapy during cancer nano-theranostics due to their exclusive innate FL and theranostic characteristics exhibited in different preclinical results. Recently, different transition metal-doped CDs have enhanced the effectiveness of CDs manifold in biomedical applications with minimum toxicity. The use of group-11 (Cu, Ag and Au) with CDs in this direction have recently gained the attention of researchers because of their encouraging results. This review summarizes the current developments of group-11 (Cu, Ag and Au) CDs for early diagnosis and therapy of cancer including their nanocomposites, nanohybrids and heterostructures etc. All The manuscript highlights imaging applications (FL, photoacoustic, MRI etc.) and therapeutic applications (phototherapy, photodynamic, multimodal etc.) of Cu-, Ag- and Au-doped CDs reported as nanotheranostic agents for cancer treatment. Sources of CDs and metals alogwith applications to give a comparative analysis have been given in the tabulated form at the end of manuscript. Further, future prospects and challenges have also been discussed.

New Triazinoindole Bearing Benzimidazole/Benzoxazole Hybrids Analogs as Potent Inhibitors of Urease: Synthesis, In Vitro Analysis and Molecular Docking Studies.

Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (1-25) were synthesized. Utilizing a variety of spectroscopic methods, including 1H-, 13C-NMR, and HREI-MS, the newly afforded compounds (1-25) were analyzed. The synthesized analogs were tested against urease enzyme (in vitro) as compared to the standard thiourea drug. All triazinoindole-based benzimidazole/benzoxazole analogs (1-25) exhibited moderate to excellent inhibition profiles, having IC50 values of 0.20 ± 0.01 to 36.20 ± 0.70 µM when evaluated under the positive control of thiourea as a standard drug. To better understand the structure-activity relationship, the synthesized compounds were split into two groups, "A" and "B." Among category "A" analogs, analogs 8 (bearing tri-hydroxy substitutions at the 2,4,6-position of aryl ring C) and 5 (bearing di-hydroxy substitutions at the 3,4-position of aryl ring C) emerged as the most potent inhibitors of urease enzyme and displayed many times more potency than a standard thiourea drug. Besides that, analog 22 (which holds di-hydroxy substitutions at the 2,3-position of the aryl ring) and analog 23 (bearing ortho-fluoro substitution) showed ten-fold-enhanced inhibitory potential compared to standard thiourea among category "B" analogs. Molecular docking studies on the active analogs of each category were performed; the results obtained revealed that the presence of hydroxy and fluoro-substitutions on different positions of aryl ring C play a pivotal role in binding interactions with the active site of the targeted urease enzyme.

Nanoclay Reinforced Ternary Blends Based on Biodegradable Polymers for Drug Delivery Application.

In this study, ternary blends based on chitosan, polyvinyl alcohol, and polyethylene glycol reinforced with organically modified montmorillonite (nanoclay) clay were synthesized. These ternary blends were evaluated as transdermal drug delivery patches using tramadol as a model drug. The FTIR study showed interaction among important functional groups and compatibility among the mixing components. Among drug-loaded formulations, composite MA12 shows maximum thermal stability with 27.9% weight residue at 540°C. The prepared formulations exhibited crystalline nature as observed by XRD analysis. SEM studies revealed that there are no gaps and cracks in prepared films and nanoclay was found dispersed in the formulations. The swelling ratio was higher in pH 1.2 as compared to pH 4.5 and pH 6.8 buffers, and there was an increase in swelling with an increase in PVA concentration. Moreover, the drug release test performed in phosphate buffer pH 6.8 showed that tramadol release from nanocomposite films increases with an increase in PEG concentration. Permeation studies indicated that the rate of permeation increased with a decrease in PVA concentration. The permeation rate was found to be higher for samples without nanoclay. The overall results suggest nanocomposite films as excellent candidates for transdermal drug delivery application.

Exploring ibuprofen derivatives as α-glucosidase and lipoxygenase inhibitors: Cytotoxicity and in silico studies.

This study reports the synthesis of a series of ibuprofen derivatives, including thiosemicarbazides 4a-f, 1,3,4-oxadiazoles 5a-f, 1,3,4-thiadiazoles 6a-f, 1,2,4-triazoles 7a-f, and their S-alkylated derivatives 8a-d. All of the newly synthesized derivatives were analyzed using 1 H NMR, 13 C NMR spectroscopy, and high-resolution mass spectra (electron ionization) spectrometry. These synthetic molecules were examined for their in vitro baking yeast α-glucosidase and soybean 15-lipoxygenase (15-LOX) inhibition and cell viability studies. The results revealed that the compounds N-(3,4-dichlorophenyl)-5-[1-(4-isobutylphenyl)ethyl]-1,3,4-oxadiazol-2-amine 5f (IC50 3.05 ± 1.23 µM) and N-(3-fluorophenyl)-5-[1-(4-isobutylphenyl)ethyl]-1,3,4-oxadiazol-2-amine 5b (IC50 3.12 ± 1.21 µM) were the most potent with respect to the α-glucosidase enzyme while in case of 15-LOX, the compound 4-(2,4-dichlorophenyl)-1-[2-(4-isobutylphenyl)propanoyl]thiosemicarbazide 4e showed potent inhibition with an IC50 value of 55.41 ± 0.41 µM. All these compounds were found least toxic by displaying a blood mononuclear cell viability value of 69.2%-97.8% by the MTT assay compared to the standards when assayed at 0.25 mM concentration. Molecular docking analyses were conducted to evaluate the inhibition profiles of these derivatives against the said enzymes and the data supported the in vitro profiles.

Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents.

In recent years, drug discovery paradigm has been shifted from conventional single target inhibition toward multitarget design concept. In current research, we have reported synthesis, in-vitro, in-vivo and acute toxicity determination of N-substituted pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents. We synthesized cycloalkyl, alkyl and aryl carbonyl derivatives by the Michael addition of ketones to N-substituted maleimides using self-assembled three component system as an organocatalyst. Anti-inflammatory potential of the compounds was determined by using different in-vitro assays, like cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase, albumin denaturation and anti-protease assays. Amongst the synthesized compounds, 13a-e series of compounds showed inhibition in low micromolar to submicromolar ranges. These compounds also demonstrated COX-2 selectivity. Compound 13e with IC50 value 0.98 µM and SI of 31.5 emerged as the most potent inhibitor of COX-2. Based on in-vitro results, in-vivo anti-inflammatory investigations were performed on compounds 3b and 13evia carrageenan induced paw edema test. The possible mode of action of compounds 3b and 13e were ascertained with various mediators like histamine, bradykinin, prostaglandin and leukotriene. In-vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The selectivity of the compounds against cyclooxygenase isoforms was supported by docking simulations. Selective COX-2 inhibitors showed significant interactions with the amino acid residues present in additional secondary COX-2 enzyme pocket. Furthermore, in-silico pharmacokinetic predictions confer the drug-like characteristics.

Apoptosis of Leukemia Cells by Ocimum basilicum Fractions Following TNF alpha Induced Activation of JNK and Caspase 3.

PURPOSE: Leukemia, one of the major cancers, affects a large proportion of people around the world. Better treatment options for leukemia are required due to a large number of side effects associated with current therapeutic regimens. In the present study, we sought to determine the pathway of triggering apoptosis of leukemic cells by Ocimum basilicum (O. basilicum) plant extract. MATERIALS/METHODS: Methanolic extract of the O. basilicum plant material was prepared. The crude extract was fractionated into several fractions through column chromatography using ethyl acetate and n-hexane as eluting solvents. Cell viability of leukemic cells was assessed via Cell titer GLO assay and apoptosis was measured through Annexin V/PI staining. Two apoptotic molecules JNK and caspases were analyzed through western blotting while pro-inflammatory cytokines TNFα, CCL2 and CXCL8 using qPCR. Fractions were characterized through LC-MS. RESULTS: The most potent with lowest IC50 values among the fractions were BF2 (2:8 n-hexane:ethyl acetate) and BF3 (3:7 n-hexane:ethyl acetate). Cytotoxicity was associated with apoptosis. Apoptosis was found caspasedependent and P-JNK activation was detected sustained. A significant increase in the level of TNF α and a decrease in the level of CXCL8 were observed in BF2 and BF3 treated cells. CONCLUSION: The fractions of O. basilicum extract were found to kill cells following JNK pathway activation. Excellent results were obtained with BF2 and BF3 probably due to predominant Epicatechin and Cinnamic acid derivatives in these fractions.

Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and -pyrimidines.

Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction.

Synthesis of highly functionalized biaryls by condensation of 2-fluoro-1,3-bis(silyloxy) 1,3-dienes with 3-cyanochromones and subsequent domino "retro-Michael/aldol/fragmentation".

The Me(3)SiOTf-mediated condensation of 1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy) 1,3-dienes with 3-cyanochromones afforded 3-cyano-2-(4-ethoxy-3-fluoro-2,4-dioxobutyl)chroman-4-ones. Their reaction with triethylamine afforded fluorinated azaxanthones or biaryls. The product distribution depends on the structure of the diene. The formation of the biaryls can be explained by an unprecedented domino "retro-Michael/aldol/fragmentation" reaction.

Identification of novel urease inhibitors by high-throughput virtual and in vitro screening.

Ureases are important in both agriculture and human health. Bacterial ureases are directly involved in many farm-field problems and pathological conditions. Here, we report a structure-based virtual screening of an in-house compound bank of about 6000 molecular entities by computational docking and binding free energy calculations followed by in vitro screening. Applied protocol leads to the identification of novel urease inhibitors, which can serve as starting points for structural optimization.

2-[(4-Chloro-benz-yl)carbonyl-meth-yl]benzoic acid.

The title compound, C(16)H(13)ClO(3), is an important inter-mediate in the conversion of isocoumarin to 3,4-dihydro-isocoumarin. The two aromatic rings are oriented at a dihedral angle of 67.18 (3)°. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers. There is also a C-H⋯π contact between the benzoic acid and 4-chloro-benzyl rings.

1-(3-Chloro-benz-yl)-5-iodo-indoline-2,3-dione.

In the title compound, C(15)H(9)ClINO(2), which possesses anticonvulsant activity, the iodo-indoline ring system is essentially planar (maximum deviation 1.245 Å) and is oriented with respect to the 3-chloro-benzyl ring at a dihedral angle of 76.59 (3)°. In the crystal, there is a π-π contact between iodo-indoline ring systems [centroid-centroid distance = 3.8188 (4) Å].

3-(3-Fluoro-benz-yl)-1H-isochromen-1-one.

The asymmetric unit of the title compound, C(16)H(11)FO(2), contains two independent mol-ecules. The isochromene ring systems are planar and are oriented with respect to the fluoro-benzene rings at dihedral angles of 87.15 (3) and 87.85 (3)° in the two mol-ecules.