DESIGN, SYNTHESIS, AND APPLICATIONS OF INDOLE AND ISOINDOLE DERIVATIVES

Abstract

The present work entitled “Design, Synthesis, and Applications of Indole and Isoindole Derivatives” has been divided into six chapters. Chapter 1 covers the general description of various synthetic methodologies of indole and isoindolin-1-one heterocyclic compounds and their biological applications. Chapter 2 covers the in-silico studies of 3-acyl-3-hydroxyisoindolin-1-one derivatives as potential MAO-B inhibitors for neurodegenerative diseases focusing on PD. A large library of 279 derivatives was created and molecular docking of the complete library was performed. Then, the top two docked scored compounds were further investigated using other parameters such as MDS, MM-GBSA binding free energy, ADME, and DFT studies. Two ligands, 3 hydroxy-2-(4-isopropylphenyl)-3-(4-(trifluoromethyl)benzoyl)isoindolin-1-one (90) and 2 (3,4-dichlorophenyl)-3-hydroxy-3-(4-(trifluoromethyl)benzoyl)isoindolin-1-one (173) displayed superior docking score values of -12.088 kcal/mol and -12.085 kcal/mol, respectively. MDS over 500 ns demonstrated the stability of both the ligands 90 and 173 with RMSD and RMSF values below 2 Å. ADME profiling of both ligands indicated favourable pharmacokinetic parameters, while DFT analysis showed high chemical reactivity and low kinetic stability. This suggested that ligands 90 and 173 exhibit strong potential as promising lead candidates for MAO-B inhibition. Chapter 3 discusses a new Selectfluor-mediated synthetic route for the regioselective synthesis of 3-acyl-3-hydroxyisoindolin-1-ones from N-substituted-2‑(1-alkynyl)benzamides with sodium bicarbonate as mild base in acetonitrile solvent. Water was used as the source for oxidation and hydroxylation. All the derivatives of 3-acyl-3-hydroxyisoindolin-1-ones were synthesized and characterized with 73-85% isolated yield. Control experiments revealed that this new synthetic method followed free radical pathway. Anti-oxidant activities of synthesized compounds are also discussed in this chapter. Chapter 4 covers the in-silico studies of N-alkenylindole derivatives to evaluate their inhibitory activity against MAO-B. A library of 147 N-alkenylindole ligands was made and molecular docking of the complete library with the MAO-B protein target was performed. Further, the top two docked scored ligands were investigated using other in-silico tools which were MDS, MM-GBSA binding free energy, ADME, and DFT studies. Two ligands, 3-(1 (1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1H-indol-2-yl)phenol (66) and 2-(4-fluorophenyl)-1 (1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)-1H-indole (63) showed superior docking scores of 11.8 kcal/mol and -11.4 kcal/mol, respectively in their library. MDS performed over 500 ns 9 demonstrated lower RMSD and RMSF values for ligand 66 compared to ligand 63, indicating greater ligand 66-protein docked complex stability. Post-MDS MM-GBSA calculations depicting energetically favourable interactions. ADME profiling of both ligands indicated favourable drug-likeness and physicochemical properties. Whereas DFT analysis showed higher chemical reactivity and low kinetic stability of ligand 66 compared to ligand 63. Chapter 5 covers a new metal-free synthetic method for the regioselective synthesis of N alkenylindoles from 2-(1-alkynyl)anilines and cyclic ketones catalyzed by molecular iodine in toluene:DMF (20:1, v/v) solvent ratio. This developed method facilitated the synthesis of 19 derivatives with yields ranging from 56 to 73 % yield, of which 18 are new derivatives. This developed method was well tolerated the presence of both electron-donating and electron-withdrawing groups including hetero-aromatic rings. According to control experiment, this new synthetic route follows an ionic pathway. Moreover, the antioxidant activities of the synthesized N-alkenylindole compounds were evaluated and discussion in this chapter. Chapter 6 is the conclusion chapter where all the work carried out has been summarized, followed by future prospects and social impact.