Scaffold hopping approaches for dual-target antitumor drug discovery: opportunities and challenges

Scaffold hopping has emerged as a practical tactic to enrich the synthetic bank of small molecule antitumor agents. Specifically, it enables the chemist to refine the lead compound's pharmacodynamic, pharmacokinetic, and physiochemical properties. Scaffold hopping opens up fresh molecular territory beyond established patented chemical domains.

The authors present the scaffold hopping-based drug design strategies for dual inhibitory antitumor structural templates in this review. Minor modifications, structure rigidification and simplification (ring-closing and opening), and complete structural overhauls were the strategies employed by the medicinal chemist to generate a library of bifunctional inhibitors. In addition, the review presents an overview of the computational methods of scaffold hopping (software and programs) and organopalladium catalysis leveraged for the synthesis of templates designed via scaffold hopping.

The medicinal chemist has demonstrated remarkable prowess in furnishing dual inhibitory antitumor chemical architectures. Scaffold hopping-based drug design strategies have yielded a plethora of pharmacodynamically superior dual modulatory antitumor agents. An integrated approach involving computational advancements, synthetic methodology advancements, and conventional drug design strategies is required to increase the number of scaffold-hopping-assisted drug discovery campaigns.