Muhammad Yar

An Annulation Reaction for the Synthesis of Morpholines, Thiomorpholines, and Piperazines from β‐Heteroatom Amino Compounds and Vinyl Sulfonium Salts

The nitrogen-containing heterocycles comprising morpholines, thiomorpholines, and piperazines are some of the most important pharmacophores in medicinal chemistry. However, the direct synthesis of such compounds by alkylation of b-amino alcohols/thiols/amines with 1,2-dihalo derivatives is often fraught with low yields and side reactions. 1,2Dihalogen derivatives are generally poor electrophiles and reactions are often accompanied by competing elimination processes. A solution to this problem is to carry out a threestep sequence employing an a-halogen acid halide as the electrophile. Following amide formation and intramolecular alkylation, reduction finally furnishes the required heterocycles. Herein, we describe the application of a novel concept to prepare these pharmacologically important heterocycles from b-amino alcohols/thiols/amines in one step and high yield. We reasoned that soft electrophiles operating under less basic conditions would minimize competing elimination pathways and therefore considered the possibility of employing Michael acceptors. This led us to vinyl onium salts (e.g., 1). We expected that, following conjugate addition of one of the heteroatoms, an ylide 4 would be generated that could undergo proton transfer with the other heteroatom (Scheme 1). The heteroatom anion generated, 5, would then attack the onium ion electrophile to effect ring-closure and produce the required heterocycle. Although vinyl onium salts have been employed in three-component coupling reactions with nucleophiles and electrophiles, their potential to react according to the pathway shown in Scheme 1 has not previously been recognized. Of the readily available vinyl onium salts, it was thought that sulfonium and phosphonium would be better at promoting the conjugate addition step than ammonium since the ylide intermediate is better stabilized. However, to promote cyclization leaving group ability of the onium is critical and this falls in the order S>N @ P. These considerations led us to examine vinyl sulfonium salts, and in particular diphenyl vinyl sulfonium salt 1. This salt was easily prepared through a modified procedure as shown in Scheme 2. In this

Bromoethylsulfonium salt--a more effective annulation agent for the synthesis of 6- and 7-membered 1,4-heterocyclic compounds.

Reaction of bromoethylsulfonium salt with 1,2-/1,3-aminoalcohols gave six- and seven-membered rings in good-to-excellent yields. The reactions proceed through generation of a vinyl sulfonium salt followed by annulation to give 1,4-heterocyclic compounds such as morpholines and benzoxazepines in a simple procedure. The method accommodates a range of nitrogen substituents and the amino alcohol can be substituted by amino thiols and diamines to give thiomorpholines, piperazines and benzodiazepines.

The Concise Synthesis of Unsymmetric Triarylacetonitriles via Pd-Catalyzed Sequential Arylation: A New Synthetic Approach to Tri- and Tetraarylmethanes

The selective synthesis of multiarylated acetonitriles via sequential palladium-catalyzed arylations of chloroacetonitrile is reported. The three aryl groups are installed via a Pd-catalyzed Suzuki-Miyaura cross coupling reaction followed by back-to-back C-H arylations to afford triarylacetonitriles in three steps with no over-arylation at any step. The triarylacetonitrile products can be converted into highly functionalized species including tetraarylmethanes. This new strategy provides rapid access to a variety of unsymmetrical tri- and tetraarylmethane derivatives from simple, readily available starting materials.

An Efficient Synthesis of Imidazolinium Salts Using Vinyl Sulfonium Salts

The synthesis of imidazolinium salts from the reaction of formamidines and (2-bromoethyl)diphenylsulfonium triflate is described. A variety of symmetrical and unsymmetrical imidazolinium triflate salts were synthesized in high yield in short reaction times under mild conditions. Aromatic and aliphatic N-substituents work well. The reaction is proposed to proceed via generation of a vinyl sulfonium salt intermediate from the bromoethylsulfonium triflate.

Synthesis and biological evaluation of novel oxadiazole derivatives: a new class of thymidine phosphorylase inhibitors as potential anti-tumor agents.

Based on the fact that the thymidine phosphorylase inhibitors are considered potential anti-tumor agents, a range of novel oxadiazole derivatives 3a-3u was designed and synthesized by a simple and facile synthetic route. The biological assay revealed that majority of compounds displayed modest inhibitory activity against thymidine phosphorylase at low micromolar concentrations (IC50 173.23±3.04 to 14.40±2.45μM). In the current study the most active compounds were 3h and 3q with IC50 values 14.40±2.45 and 17.60±1.07μM, respectively. Molecular docking studies were performed on the most active compounds (3h, 3k, 3o-3q) to show their binding mode.

pH Sensitive Hydrogels in Drug Delivery: Brief History, Properties, Swelling, and Release Mechanism, Material Selection and Applications

Improving the safety efficacy ratio of existing drugs is a current challenge to be addressed rather than the development of novel drugs which involve much expense and time. The efficacy of drugs is affected by a number of factors such as their low aqueous solubility, unequal absorption along the gastrointestinal (GI) tract, risk of degradation in the acidic milieu of the stomach, low permeation of the drugs in the upper GI tract, systematic side effects, etc. This review aims to enlighten readers on the role of pH sensitive hydrogels in drug delivery, their mechanism of action, swelling, and drug release as a function of pH change along the GI tract. The basis for the selection of materials, their structural features, physical and chemical properties, the presence of ionic pendant groups, and the influence of their pKa and pKb values on the ionization, consequent swelling, and targeted drug release are also highlighted.

Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat type 2 diabetes: in vitro biological evaluation and in silico docking.

A convenient and efficient new method has been established for the synthesis of dihydropyrimidines by inexpensive and non-toxic N-acetyl glycine (NAG) catalysed reaction of aromatic aldehydes with ethyl acetoacetate and urea/thiourea. This method is applicable for various substituted aldehydes as well as urea and thiourea. It has also been used to synthesize bicyclic oxygen-bridged pyrimidine derivatives (4d, 4j). The biological assay revealed that the majority of compounds synthesized displayed modest inhibitory activity against α-glucosidase at low micro-molar concentrations. Molecular docking studies were also performed on the most active compound, 4f (with IC50 value 112.21±0.97 μM), to show the enzyme - inhibitor interactions.

Synthesis of piroxicam loaded novel electrospun biodegradable nanocomposite scaffolds for periodontal regeneration

Development of biodegradable composites having the ability to suppress or eliminate the pathogenic micro-biota or modulate the inflammatory response has attracted great interest in order to limit/repair periodontal tissue destruction. The present report includes the development of non-steroidal anti-inflammatory drug encapsulated novel biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) electro-spun (e-spun) composite nanofibrous mats and films and study of the effect of heat treatment on fibers and films morphology. It also describes comparative in-vitro drug release profiles from heat treated and control (non-heat treated) nanofibrous mats and films containing varying concentrations of piroxicam (PX). Electrospinning was used to obtain drug loaded ultrafine fibrous mats. The physical/chemical interactions were evaluated by Fourier Transform Infrared (FT-IR) spectroscopy. The morphology, structure and pore size of the materials were investigated by scanning electron microscopy (SEM). The thermal behavior of the materials was investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Control (not heat treated) and heat treated e-spun fibers mats and films were tested for in vitro drug release studies at physiological pH7.4 and initially, as per requirement burst release patterns were observed from both fibers and films and later sustained release profiles were noted. In vitro cytocompatibility was performed using VERO cell line of epithelial cells and all the synthesized materials were found to be non-cytotoxic. The current observations suggested that these materials are potential candidates for periodontal regeneration.

Triethyl orthoformate mediated a novel crosslinking method for the preparation of hydrogels for tissue engineering applications: characterization and in vitro cytocompatibility analysis

This paper describes the development of a new crosslinking method for the synthesis of novel hydrogel films from chitosan and PVA for potential use in various biomedical applications. These hydrogel membranes were synthesized by blending different ratios of chitosan (CS) and poly(vinyl alcohol) (PVA) solutions and were crosslinked with 2.5% (w/v) triethyl orthoformate (TEOF) in the presence of 17% (w/v) sulfuric acid. The physical/chemical interactions and the presence of specific functional groups in the synthesized materials were evaluated by Fourier transform infrared (FT-IR) spectroscopy. The morphology, structure and pore size of the materials were investigated by scanning electron microscopy (SEM). Thermal gravimetric analysis (TGA) proved that these crosslinked hydrogel films have good thermal stability which was decreased as the CS ratio was increased. Differential scanning calorimetry (DSC) exhibited that CS and PVA were present in the amorphous form. The solution absorption properties were performed in phosphate buffer saline (PBS) solution of pH7.4. The 20% PVA-80% CS crosslinked hydrogel films showed a greater degree of solution absorption (183%) as compared to other compositions. The hydrogels with greater CS concentration (60% and 80%) demonstrated relatively more porous structure, better cell viability and proliferation and also revealed good blood clotting ability even after crosslinking. Based on the observed facts these hydrogels can be tailored for their potential utilization in wound healing and skin tissue engineering applications.

Organocatalyzed solvent free an efficient novel synthesis of 2,4,5-trisubstituted imidazoles for α-glucosidase inhibition to treat diabetes.

A new and efficient solvent free synthesis of 2,4,5-trisubstituted imidazoles (3a-3j) was achieved by N-acetyl glycine (NAG) catalyzed three components condensation of aldehydes, benzil and ammonium acetate. Our synthetic methodology accommodated a range of various substituted alkyl and aryl aldehydes. Evaluation of α-glucosidase inhibitory activity of these imidazole derivatives revealed that most of them presented good α-glucosidase inhibition at low micro-molar concentrations. Among the synthesized compounds, compound 3c, bearing the ortho-hydroxy phenyl substituent at position 2 displayed the highest inhibitory activity with an IC50 value 74.32±0.59 μM. In silico molecular docking for all compounds and computational studies of the most active compound 3c were also performed.