Rapid multigram scale end-to-end continuous flow synthesis of sulfonylurea anti-diabetes drugs: Gliclazide, chlorpropamide and tolbutamide

Herein we report multigram scale robust, efficient, and safe end-to-end continuous flow processes for the diabetes sulfonylurea drugs gliclazide, chlorpropamide and tolbutamide. The drugs were prepared via the treatment of an amine with a haloformate affording carbamate which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was afforded in 87 % yield within 2.5 min total residence time with 26 g/h throughput; 0.2 Kg of the drug was produced in 8 h of running the system continuously. Chlorpropamide and tolbutamide were both afforded in 94 % yield within 1 min residence time with 184-188 g/h throughput; 1.4-1.5 Kg of the drugs was produced in 8 h of running the system continuously. N-substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.

Limnocharis flava (yellow bur-head).

L. flava, commonly known as yellow bur head, is a perennial broad-leaved weed which behaves as an annual in certain habitats. It spreads throughout South-East Asia especially in rice crops, and also in South America and the USA. It prefers wet conditions such as lowland rice fields, shallow canals and ditches and reproduces both by seed and vegetatively. Heavy infestations of L. flava indicate a fertile soil. The effectiveness of drainage ditches and irrigation channels can be reduced through siltation caused by blockages of L. flava leaves and roots. Young leaves, petioles and flower stalks can be eaten as vegetables. Whole plants are used as fodder for pigs, cattle or fish and plant residues can be also be used for feed and as green manure. L. flava can be controlled by chemical such as 2,4-D herbicides and sulfonyl urea products such as bensulfuron and bensulfuron/metsulfuron. Bentazon/MCPA can be used to control multiple resistant biotype of L. flava.

Development and Evaluation of Matrix Type Transdermal Patches of Torasemide

TDDS manufacture has numerous benefits over other routes like oral delivery. It avoids limitations linked with g.i.t. absorption, enzyme effect, interaction with drug and food. This route is suitable when patient is suffering from vomiting and diarrhea. Torasemide is a loop diuretic; it comes under category of sulfonyl urea. It is prescribed in the treatment of edema, CHF, and hypertension. Whenever it is used by oral route, it is associated with many side effects like vomiting, nausea, anorexia, and increased appetite. All transdermal patches were transparent and free from any particle. Release profile of twelve batches of Torasemide was done by the means of Franz cell for 7 hrs. Maximum release was shown by MTP6 (71.28±0.19) and least in formulations of batch code MTP7(24.47±0.04). In-vitro release data were plotted in 2 different models i.e. first and Korsemeyer peppas. It was observed that release was governed by the diffusion process. On basis of different properties MTP1 batch was found to be optimum. Study concludes that by the means of patches Torasemide can be administered efficiently. Keywords: Torasemide, transdermal patches, HPMC, in-vitro release, stability studies, TDDS.

GPCRs and Insulin Receptor Signaling in Conversation: Novel Avenues for Drug Discovery

Type 2 diabetes is a major health issue worldwide with complex metabolic and endocrine abnormalities. Hyperglycemia, defects in insulin secretion and insulin resistance are classic features of type 2 diabetes. Insulin signaling regulates metabolic homeostasis by regulating glucose and lipid turnover in the liver, skeletal muscle and adipose tissue. Major treatment modalities for diabetes include the drugs from the class of sulfonyl urea, Insulin, GLP-1 agonists, SGLT2 inhibitors, DPP-IV inhibitors and Thiazolidinediones. Emerging antidiabetic therapeutics also include classes of drugs targeting GPCRs in the liver, adipose tissue and skeletal muscle. Interestingly, recent research highlights several shared intermediates between insulin and GPCR signaling cascades opening potential novel avenues for diabetic drug discovery.

In-silico Study of Sulfonylurea Family Members’ Binding Site with their Receptor Kir6.2\SUR1

Sulfonylurea family members have been used as a second preferred line in the treatment of Type II Diabetes Mellitus (TIIDM) for decades. Only one crystal structure for its receptor Kir6.2\SUR1 binding with one of sulfonylurea member; Glibenclamide (GBM), is available in Protein Data Bank (PDB) database. The aim of this manuscript is to study in-silico other sulfonylurea family members’ interactions with their receptor Kir6.2\SUR1 using a docking software in the default settings. We have checked the validity of the software for the study. Then, we have applied a rigid docking on 14 compounds of sulfonyl urea group which they have anti-hyperglycemia activity. Next, we have compared their interactions to GBM interactions with Kir6.2\SUR1.  As a result, many compounds of this family had bound to Kir6.2\SUR1 receptor in the same pocket as GBM. These results confirmed a perspective we have discussed about sulfonylurea structure activity relationship.

A second triclinic polymorph of azimsulfuron

The title compound, C13H16N10O5S (systematic name: 1-(4,6-dimethoxypyrimidin-2-yl)-3-{[1-methyl-4-(2-methyl-2H-tetrazol-5-yl)pyrazol-5-yl]sulfonyl}urea), is a second triclinic polymorph of this crystal [for the other, see: Jeonet al., (2015).Acta Cryst. E71, o470–o471]. There are two molecules,AandB, in the asymmetric unit; the dihedral angles between the pyrazole ring and the tetrazole and dimethoxypyrimidine ring planes are 72.84 (10) and 37.24 (14)°, respectively (moleculeA) and 84.38 (9) and 26.09 (15)°, respectively (moleculeB). Each molecule features an intramolecular N—H...N hydrogen bond. In the crystal, aromatic π–π stacking interactions [centroid–centroid separations = 3.9871 (16), 3.4487 (14) and 3.5455 (16) Å] link the molecules into [001] chains. In addition, N—H...N, N—H...O, C—H...O and C—H...N hydrogen bonds occur, forming a three-dimensional architecture. We propose that the dimorphism results from differences in conformations and packing owing to different intermolecular interactions, especially aromatic π–π stacking.