Identification, Optimization and Biological Evaluation of Drug Like Heterocyclic Templates for The Treatment of Type II Diabetes Mellitus

Abstract

The research work entitled “Identification, Optimization and Biological Evaluation of Drug like Heterocyclic Templates for the Treatment of Type II Diabetes Mellitus” is divided into eight chapters mentioned in brief as follows. Chapter 1 outlines historical aspects of diabetes, epidemiology, prevalence, classification and current therapies, limitations and emerging targets for management of Type 2 Diabetes Mellitus. Chapter 2 sketches about the role of G-Protein Coupled receptors as an important protein to be targeted against T2DM therapy. It also draws explains why targeting GPR40 has drawn considerable attention from both academia and industry as a novel target for the treatment of type 2 diabetes with minimal risk of hypoglycemia. Chapter 3 gives the idea about aim and objectives of the research strategy implemented, using various computational tools for the lead optimization of the drug like hetero cyclic templates. Chapter 4 describes about how 3D structures of the GPR40 receptor were constructed based on homology modeling principles. Exploring such study gives insights into the characterization of key H-bonding, hydrophobic residues, and defining the binding pocket of the receptor. Chapter 5 enlightens a common structural motif, identified in combiphore (Structure and Ligand based pharmacophore) for GPR40 modulation. Combiphore approach explores maximum structural information which can serve as a good lead to develop novel GPR40 modulators. Chapter 6 embraces 3D-QSAR techniques CoMFA, CoMSIA and HQSAR on the series 3-aryl- 3-ethoxypropanoic acids. Structural requirements for designing novel GPR40 modulators with improved activity can be achieved by designing the compounds based on their counter maps. Contour maps provides positive & negative contribution, favoured and disfavoured regions with R1 and R2 substitutions, gives hint for the modification required to design new molecules with improved biological activity. In chapter 7, synthesis of five different series namely, Pyrazole containing phenoxy acetic acid derivatives, Vanillin derivatives, pyrazol-3-yl) phenoxy) acetate derivatives, Benzoxazole and thiophene derivatives have been described in stepwise manner.Synthesis was carried out using different acetophenones and aldehydes. Apart from pyrazole, different thiophene derivatives were also synthesized as an approach towards developing green chemistry. In modern medicinal chemistry Biaryl scaffold/system have great importance as it is prime requirement of GPCR's. The easiest way to build this Biaryl system is Suzuki-Miyaura reaction which was used for the synthesis of the thiophene compound. For the synthesis of amide–bond conventional amide coupling was avoided, which involves hazardous reagents. Instead of that Schotten–Baumann reaction was carried out. These were approaches towards developing green chemistry. Structures of synthesized and purified compounds were established by IR, Mass and 1H NMR spectral data. Chapter 8 consists of toxicological and pharmacological studies of the compounds. Toxicology studies were carried out using various descriptors and properties like donar, acceptor, QPlogS, QPlogHERG, QPPCaco, QPlogBB, %Human oral absorption, using QikProp module of Schrodinger. The compounds which gave the highest molecular docking score with required amino acids were further evaluated for in-vivo activity by performing OGTT assay. Chapter 9 concludes combining rational research strategy can provides significant insights to integrate improvement in the drug design and discovery process