Synthesis and Applications of Piperazine, bis-Indole Derivatives and Gold Nanoparticles of Thiolated Ligands

Abstract

This dissertation has been divided into four chapters and each chapter has its own numbering of compounds and references. General introduction related to the importance of heterocycle based drugs, drug designing and value of lead molecules in drug designing. This research work describes synthesis and bioactivities of different class of heterocycles such as piperazine, bisindole analogs in search of important therapeutic agents and also includes functionalized gold nanoparticles for catalytic study. During this research study, a variety of piperazine, and bisindole analogs were synthesized and screened for enzyme inhibition studies (thymidine phosphorylase, urease, antioxidant, β-glucuronidase and α-glucosidase, anti-Leishmania). Functionalized gold nanoparticles were synthesized for modulating their catalytic ability. The results obtained from this study are encouraging which are discussed separately in the forthcoming chapters 1, 2, 3 and 4. In first chapter, piperazine analogues are studied. We have synthesized eighteen piperazine derivatives (1-18) and evaluated for thymidine phosphorylase, urease, antioxidant, -glucuronidase and α-glucosidase activity. All analogues showed potent thymidine phosphorylase inhibitory potential with IC50 values ranging between 0.2 ± 0.01 to 42.20 ± 0.70 μM when compared with standard 7-Deazaxanthine (IC50 value of 38.68 ± 1.12 μM). Compound 17 was found to be the most active among the series while compound 18 was found to be the least active. All these analogues showed varying degree of urease, antioxidant, -glucuronidase and α-glucosidase activity. xi In second chapter, bis-indole analogues are studied. We have synthesized twenty seven bis-indole analogues (1-27) and evaluate their anti-leishmanial, urease, antioxidant, and -glucuronidase activity. All compounds showed outstanding anti-leishmanial inhibitory potential with IC50 values ranging from 0.7 ± 0.01 to 13.30 ± 0.50 μM respectively when compared with standard pentamidine with IC50 value of 7.20 ± 0.20 μM. All analogues showed greater potential than standard except 23 when compared with standard. All these compounds showed varying degree of urease, antioxidant, -glucuronidase and α-glucosidase activity. In third chapter, functionalized gold nanoparticles are studied. We report the fabrication of a family of nanozymes comprised of bioorthogonal ruthenium catalysts inserted in the protective monolayer of gold nanoparticles. By introducing simple modifications to the functional groups at the surface of the nanozymes, we have demonstrated control over the kinetic mechanism of our system. Cationic nanozymes with hydrophobic surface functionalities tend to replicate the classical Michaelis Menten model, while those with polar groups display substrate inhibition behaviour, a key mechanism present in 20% of natural enzymes. The structural parameters described herein can be used for creating artificial nano-systems that mimic the complexity observed in cell machinery. In fourth chapter we discussed the different bioassay protocols in detail.