Bioactive compounds and sustainable approaches in drug discovery and development

This thesis investigates sustainable synthetic strategies for three major drug modalities, peptides, peptidomimetics, and small molecules within the broader context of green chemistry. As biologically active compounds range from small molecules to complex peptides, modern drug discovery increasingly requires methods that balance efficiency, selectivity, and environmental responsibility. While small molecules have historically dominated pharmaceuticals, peptides offer access to broader biological targets, and peptidomimetics address their inherent metabolic instability. The growing emphasis on sustainability, reinforced by initiatives such as the ACS GCIPR and the Twelve Principles of Green Chemistry, motivates the development of greener synthetic routes. Chapter 2 presents a sustainable chemo enzymatic synthesis of liraglutide, a 31 mer peptide drug. By replacing DMF in solid phase peptide synthesis with greener NBP/DMC mixtures and employing enzymatic ligation in aqueous media, this approach improves solvent greenness, yield, and process mass intensity while simplifying purification. Chapter 3 describes the design and synthesis of short antimicrobial peptidomimetics inspired by LTX 109. Structural modifications, including alternative cationic residues, aromatic substitutions, and nonproteinogenic amino acids, were introduced using green methods. The resulting library shows broad antimicrobial activity, low cytotoxicity, and strong biofilm inhibition, with molecular dynamics highlighting the importance of hydrophobic tuning and amphiphilic balance. Chapter 4 develops a late stage diversification strategy for generating constitutional isomers and des methyl analogues of the natural product delavatine A. Site selective C–H functionalization enables efficient access to analogues for SAR studies aimed at understanding the role of methylation and scaffolds relevant to the biological activity. Chapter 5 explores sustainable Suzuki–Miyaura cross couplings combining robust N,N-based PYA ligands, benign solvents (HEP, water), and low palladium loadings. In situ catalyst generation and controlled Pd recovery align catalytic efficiency with green chemistry principles.