**2. Development of Delpazolid (LCB01-0371)**

LegoChem Biosciences (Daejeon, Korea) is a company that develops effective and safe drugs using legochemistry technology, which enables the manipulation of substances by attaching and detaching compounds around scaffold-like Lego blocks. LegoChem Biosciences searches for novel candidate substances based on the concept that a good scaffold with novel blocks, based on medicinal chemistry, can accelerate the process of improving previous scaffolds with weak activity or have side effects. Delpazolid (code No: LCB01-0371), a derivative of oxazolidinone, is the first candidate antibiotic substance identified by LegoChem Biosciences.

Delpazolid is an antibiotic that targets Gram-positive bacteria (MRSA, VRE) including *M. tuberculosis*. It is currently undergoing a phase 2 clinical trial for oral (PO) administration and a phase 1 trial for intravenous (IV) administration to treat Gram-positive (MRSA, VRE) bacteraemia. Cyclic amidrazone blocks were applied to the key scaffold of delpazolid (Figure 1). In general, after a drug is absorbed, it must be dissolved well to ensure proper secretion. Most small molecules with suboptimal pharmacokinetic (PK) profiles tend to have low solubility. In general, small-molecule ligands that bind their targets with high efficiency are more hydrophobic, and hydrophobic interactions are essential for increased ligand efficiency [7]. Hydrophobicity not only increases target binding efficacy, but also decreases the solubility of a small molecule. The cyclic amidrazone (Figure 1) on the side chain of delpazolid maintains its hydrophobicity to some extent and has a slightly basic pH similar to that of carboxylate. Therefore, it can be charged by obtaining a proton from carboxylic acid under human physiological conditions, which enhances the solubility and PK profile. Therefore, the drug is accumulated slowly and excreted well, and can be administered over the long-term with minimal side effects.

**Figure 1.** (**A**). Synthetic scheme showing that delpazolid can be synthesised in only seven steps with difluoro-nitrobenzene as the starting material. Each step shows a high yield and the products are easily purified without chromatography. The red color indicates cyclic amidrazone. (**B**). Chemical structure of linezolid.
