Synthesis of Synthetic Musks: A Theoretical Study Based on the Relationships between Structure and Properties at Molecular Scale

Synthetic musks (SMs), as an indispensable odor additive, are widely used in various personal care products. However, due to their physico-chemical properties, SMs were detected in various environmental media, even in samples from arctic regions, leading to severe threats to human health (e.g., abortion risk). Environmentally friendly and functionally improved SMs have been theoretically designed in previous studies. However, the synthesizability of these derivatives has barely been proven. Thus, this study developed a method to verify the synthesizability of previously designed SM derivatives using machine learning, 2D-QSAR, 3D-QSAR, and high-throughput density functional theory in order to screen for synthesizable, high-performance (odor sensitivity), and environmentally friendly SM derivatives. In this study, three SM derivatives (i.e., D52, D37, and D25) were screened and recommended due to their good performances (i.e., high synthesizability and odor sensitivity; low abortion risk; and bioaccumulation ability in skin keratin). In addition, the synthesizability mechanism of SM derivatives was also analyzed. Results revealed that high intramolecular hydrogen bond strength, electrostatic interaction, qH(+) value, energy gap, and low E(HOMO) would lead to a higher synthesizability of SMs and their derivatives. This study broke the synthesizability bottleneck of theoretically designed environment-friendly SM derivatives and advanced the mechanism of screening functional derivatives.