Investigation of various ligand design approaches and synthesis of diverse heterocyclic bioactive compounds

Structure-based design and ligand-based design are one of the most common approaches used to develop new inhibitors against druggable protein targets in various human disorders. Mcl-1 is a protein belongs to Bcl-2 family which has a prime role in apoptosis and therefore its targeting improvises its mitogenic effect in a number of serious complications such as neurodegenerative disorders and cancers. However, various heterocyclic cores were used to developed Mcl-1 inhibitors in last few decades (mainly, polyphenols, thiazoles, thiazolo[3,2-a]pyrimidinone, indoles, acenaphthylene-phenalenes, pyrroles, isoquinoline-quinolines, anthraquinone-quinazolines, naphthols, salicylic-anthranilic acids, benzylpiperazines, pyrazolo[1,5-a]pyridines, isoindolines, imidazolidine-2,4-dione, non-peptidomimetic macrocycles), and is compiled in objective 2.1 of chapter 2 of this thesis. Also, various naturally-derived compounds (such as gymnochrome-F, oxy-polyhalogenated diphenyl ethers, anacardic acids, endiandric acids, marinopyrroles cryptosphaerolide, meiogynins) were also discovered in the past and had shown low micromolar activity against Mcl-1. However, lack of their biophysical studies leads to objective 2.2 of chapter 2 where the concept of multiple-receptor conformation and multiple-ligand conformation was used initially to evaluate the employed methodology, used for finding the precise and accurate docking structures of these naturally derived Mcl-1 inhibitors. Finally, the resulted dock scores of respective naturally derived Mcl-1 inhibitors were compared with their Mcl-1 binding affinities. The previous ligand design information clearly indicates simple structures such as diphenyl propenone structures could be beneficial in tight binding to P2-P3 or P3-P4 pocket of Mcl-1 protein. Based on parent structure binding, further exploration of these structures were performed to enhance the scope of the structure-activity relationship (such as synthesis of pyrazolines, pyrazoles, O-phenyl alkyl bromides, N-substituted pyrazoles, 5-amino-4-cyano-diphenyl pyridines, symmetrical and asymmetrical triphenyl pyridines, imidazoles and indoles). However, a novel synthetic method was also developed to improve the yield and scope of triphenyl pyridines. Chapter 3 involves the designing and synthesis of non-peptidomimetic secondary protein structures as alpha-helix or as beta-sheets where Objective 3.1 contains synthesis of Bis-triphenyl pyridine core and Triphenyl pyridine-pyrazole core as BH3 alpha helix. This is the first time that a Bis-triphenyl core and triphenyl pyridine pyrazole core is reported. However, the second objective (objective 3.2) provides a computational study of macrocycle-embedded carbohydrates for serotonin isoforms and ions channels (Negi et al., Eur J Med Chem, 2019, 176, 292-309). The highlights of this study were the construction of the homology models of NK2, 5HT1A, 5HT2A Site-2 of the sodium channel and retro screening of in-house compounds. In chapter 4, special focus was given on the biophysical studies of somatostatin isoforms and fucosidase enzyme (Zhou et al., 2019, Biorg Chem, 2019, 84, 418-433). Initially, homology models of somatostatin isoforms (Negi et al., Eur J Med Chem, 2019, 163, 148-159) and fucosidase enzymes were constructed and later, successfully found in agreement with Ramachandran plot, Errat plot and ProSA. Also, various ligand metrics based on lipophilicity were also used. Also, the computational studies were correlated with the IC50/Ki data.2023-09-2