In recent years, the flourishing of synthetic methodology studies has provided concise access to numerous molecules with new chemical space. These compounds form a large library with unique scaffolds, but their application in hit discovery is not systematically evaluated. In this work, we establish a synthetic methodology-based compound library (SMBL), integrated with compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We screen the library and identify small-molecule inhibitors to interrupt the protein–protein interaction (PPI) of GIT1/β-Pix complex, an unrevealed target involved in gastric cancer metastasis. The inhibitor 14-5-18 with a spiro[bicyclo[2.2.1]heptane-2,3’-indolin]−2’-one scaffold, considerably retards gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered undruggable as they are hard to target, the successful application illustrates the structural specificity of SMBL, demonstrating its potential to be utilized as compound source for more challenging targets.

A cascade Michael addition/alkylation reaction between 3-chlorooxindoles and α-cyano chalcones catalyzed using a multifunctional quinine-derived aminoindanol-thiourea substance was investigated. A series of spirooxindoles incorporating a densely substituted cyclopropane motif were efficiently obtained with moderate to excellent diastereo- and enantioselectivity and further transformed to products with versatile structural diversity. Density functional theory (DFT) calculations indicated that the tentative intramolecular hydrogen bonds in the chiral catalyst were crucial for the stereocontrol.

A two-year long-term workshop centered around a phenotypic whole-cell screening strategy for integrating cutting-edge knowledge and discoverybased laboratory experiences was developed to serve as a preparatory course for enhancing the teaching quality of the upper-level discovery-based research internship curriculum for pharmacy major undergraduates. The workshop comprises four modules that integrate lessons and experiments into a genuine research project, which initiates with a medicinal-chemistry course, run concurrently in the second year and culminates with the discovery-based research internship curriculum for pharmacy major students as a corequisite in the last year. The effective implementation of the featured pedagogical approaches in the modules is detailed as described. A group of students (N = 4) passed the instructor−student two-way choice and were enrolled in the senior-level phenotypic hit discovery laboratory project. The students synthesized a small library of molecules, tested them in an antibacterial assay, and further designed new compounds to analyze structure−activity relationships. Furthermore, positive feedback from students revealed that the phenotypic hit discovery oriented workshop enabled them to gain in-depth cutting-edge knowledge and provided an understanding of how medicinal chemists engage in new drug discovery research. The student's early exposure to troubleshooting or exploring unexpected results in an authentic scientific environment inspired them with ambition and confidence to engage with new drug discovery. We hope that this workshop will serve as a springboard for those wishing to educate medicinal chemists at an undergraduate level with modern strategies that are relevant to the current and future drug discovery landscape.